1 Departments of Hematology and Medical Oncology, Princess Margaret Hospital/University Health Network, Toronto, Canada and Department of Medicine, University of Toronto, Toronto; 2 Department of Biostatistics, Princess Margaret Hospital/University Health Network, Toronto, Canada
Received 9 October 2003; revised 12 January 2004; accepted 14 January 2004
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ABSTRACT |
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Unresectable biliary tract cancer has a very poor prognosis. A combination of weekly gemcitabine plus continuous infusional 5-fluorouracil (5-FU) (GEM/CVI 5-FU) was evaluated as therapy for this cancer.
Patients and methods:
The charts of 27 patients with advanced biliary tract adenocarcinoma treated with GEM/CVI 5-FU at the Princess Margaret Hospital were evaluated for response, survival and toxicity. The treatment consisted of a 30-min infusion of gemcitabine at 900 mg/m2 on days 1, 8 and 15 of a 28-day cycle plus 5-FU given via a peripherally inserted central line at 200 mg/m2/day continuously for 21 days, every 28 days.
Results:
Objective responses were observed in nine patients (33%; 95% confidence interval 17% to 54%). An additional eight patients (30%) achieved stable disease for a median of 4 months (range 2.311). Median time to progression and overall survival were 3.7 and 5.3 months, respectively. Direct chemotherapy-related toxicity was mild, with only 11% grade 3 myelosuppression. Central venous catheter complications were common (26%). There were no treatment-related deaths.
Conclusions:
This study shows that GEM/CVI 5-FU is active and well tolerated in advanced and metastatic biliary tract cancers.
Key words: biliary tract cancer, chemotherapy, 5-fluorouracil, gemcitabine
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Introduction |
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To date, chemotherapy has had limited impact on this disease, due to the absence of agents with substantial activity in these tumors and the overall morbidity of this patient population. Published chemotherapy studies in general have been limited by the small numbers of patients with biliary cancer, and by the inclusion of tumors from other, more common, primary sites such as hepatocellular and pancreatic cancers. Fluoropyrimidines were considered to be the mainstay of palliative chemotherapy; however, response rates from phase III trials are in the range of 010% [5, 6]. Combinations including 5-fluorouracil (5-FU) have not demonstrated a clear superiority over single-agent 5-FU, but result in added toxicity [57]. A study by Glimelius et al. [8] suggested there was a benefit to chemotherapy in biliary tract cancer. They compared 5-FU or 5-FU/etoposide with best supportive care in pancreatic and biliary cancers. The median survival time in the subset of 37 biliary patients was 6.5 months for the chemotherapy group (either regimen) and 2.5 months for the best supportive care group, but did not reach statistical significance in this subgroup analysis. The quality of life analysis showed a statistical difference favoring the use of chemotherapy.
Clearly, improving outcomes for patients with this aggressive cancer in advanced stages will necessitate the use of more active and well-tolerated therapies. Regimens containing platinum analogs evaluated in phase II studies have reported higher response rates than seen previously (2045%) [915], but also significant toxicity (2050% grade 3 hematological toxicity), which would limit their use in most patients with biliary cancer. The novel nucleoside analog, gemcitabine, is a chemotherapeutic agent with a favorable therapeutic profile. It has shown single-agent activity in phase II trials in this cancer ranging from 8% to 36% [1519]. Gemcitabine and 5-FU in combination appear to have synergy in preclinical studies [20], while clinically their toxicity profiles are non-overlapping. A phase III trial by Hidalgo et al. [21], evaluating 5-FU administered in a protracted intravenous infusion plus weekly gemcitabine in patients with pancreatic cancer, showed promising activity. The dose-limiting toxicity consisted of neutropenia or thrombocytopenia, but the regimen was otherwise well tolerated. During 19972001 a similar combination regimen of weekly gemcitabine and protracted continuous venous infusion of 5-FU by ambulatory pump (GEM/CVI 5-FU) was piloted at the Princess Margaret Hospital, in patients with advanced biliary cancer who were suitable for systemic therapy. This case series has been reviewed for response, survival and toxicity.
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Patients and methods |
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Treatment and dose modifications
GEM/CVI 5-FU treatment consisted of a 30-min infusion of gemcitabine at 900 mg/m2 on days 1, 8 and 15 of a 28-day cycle, plus 5-FU given via a peripherally inserted central line at 200 mg/m2/day continuously for 21 days, every 28 days. The dose and schedule were derived from the recommended dose of the phase III pancreatic trial by Hidalgo et al. [21]. Dose reductions for gemcitabine-related myelosuppression were as per the institutions standard, as follows: day 8 and 15 dose reductions based on blood count parameters: if absolute neutrophil count (ANC) was 0.51 x 109/l and/or platelet count 50100 x 109/l, 75% of full dose was given. If ANC was <0.5 x 109/l and/or platelet count <50 x 109/l, gemcitabine was held for 1 week, or omitted if day 15. Otherwise, full dose was given for ANC >1 x 109/l and platelet count >100 x 109/l. 5-FU dose reductions were at the discretion of the treating oncologist, but on average were 25%.
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Results |
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The median number of cycles administered for this chemotherapy combination was four (range one to 15). The final reason for withdrawing the therapy was disease progression in 63%, treatment break in 30% and treatment-related toxicity in 7%. It is also of note that five patients in this series took a treatment break from chemotherapy while responding and were re-challenged with GEM/CVI 5-FU after clear progression off treatment. Out of the five, two had repeat responses and three achieved durable stable disease when exposed the second time.
Survival and time to progression analysis
The median overall survival was 5.3 months (95% CI 3.310.6). One- and 2-year survival rates are estimated to be 26% and 15%, respectively (Figure 1). Of the seven patients alive at 1 year, six had achieved a partial response and one stable disease on treatment. Similarly, of the four patients surviving at least 2 years, three had achieved a partial response and one stable disease on treatment. The median time to progression or death for all patients in this series was 3.7 months (95% CI 2.36.2) (Figure 2). Those obtaining an objective response took a median of 9 months (range 423) to progress. Combining the patients with stable disease and those with objective responses, the median time to progression was 6.2 months (range 2.323).
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Discussion |
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Almost half the treatment-related serious adverse events were due to the presence of the central venous catheter required for the protracted infusion of 5-FU. The rates of venous thrombosis and line infection we observed (7% and 19%, respectively) are comparable to other reported series of cancer patients receiving chemotherapy via a central line [23]. However, reduced toxicity, leading to improved patient benefit plus convenience, would likely be achieved if the CVI 5-FU was substituted with an oral fluoropyrimidine such as capecitabine. Capecitabinegemcitabine combinations are presently under investigation in biliary tract cancers in our center.
The prognosis of patients with advanced or metastatic biliary cancer remains extremely poor, with median survivals rarely exceeding 6 months. A number of recent phase II trials using newer chemotherapeutic agents suggest a level of chemosensitivity not previously seen. Gemcitabine [12, 1519], 5-FU [7, 9, 10, 14, 15], capecitabine [13, 24] and cisplatin [9, 11, 12, 14] all appear to be active, and perhaps more so in combination. One of the better-tolerated 5-FUcisplatin regimens was reported by Taïeb et al. [9], who incorporated the de Gramont 5-FU regimen with modest doses of cisplatin. Response rates of 34% are quite comparable to our results, but more grade 3/4 hematological toxicity (41% versus 11%) was seen. The median overall survival of 9.5 months is superior to our series, although it is difficult to compare survival between single-arm studies. The difference seen could be due to the better baseline PS of the patients treated in the Taïeb et al. study (ECOG PS 0/1, 86% versus 44%). Rao et al. [25] recently reported a randomized study involving 47 patients with advanced biliary cancer treated with epirubicincisplatin5-FU (ECF) versus 5-FUetoposideleucovorin (FELV). The response rates were 19% and 16%, respectively, with no survival advantage demonstrated for either treatment arm. The toxicity appeared significant (grade 3/4 toxicity >36% and 76%, respectively). Adding cisplatin to gemcitabine in gallbladder cancer appeared to be active (response rates of 47%), but at the cost of added toxicity [12].
Combination chemotherapy is active in advanced biliary cancer and may translate into improved quality and quantity of life for patients if toxicity can be minimized. Cisplatin-containing regimens produce higher rates of myelosuppression and gastrointestinal upset than we have observed with the GEM/CVI 5-FU regimen, and are therefore likely to be poorly tolerated in this morbid patient population. We conclude that further evaluation of gemcitabine-based combinations in advanced biliary cancer is warranted.
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FOOTNOTES |
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