Gemcitabine concurrent with continuous infusional 5-fluorouracil in advanced biliary cancers: a review of the Princess Margaret Hospital experience

J. J. Knox1,*, D. Hedley1, A. Oza1, L. L. Siu1, G. R. Pond2 and M. J. Moore1

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


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

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 2.3–11). 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


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Biliary tract cancers, consisting of carcinomas of the gallbladder or biliary tree (cholangiocarcinoma), are aggressive tumors with a poor prognosis. While surgical resection of the primary tumor and the areas of local extension remain the most effective therapy, <25% of patients will be resectable at presentation [14]. The remaining 75% will receive palliative therapy, with a median survival of ~6 months. In addition, those undergoing potentially curative resections experience high rates of relapse and are generally incurable at recurrence. Most patients die of progressive cachexia, gastrointestinal bleed, sepsis or hepatic failure.

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 0–10% [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 (20–45%) [915], but also significant toxicity (20–50% 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 I–II 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 1997–2001 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.


    Patients and methods
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
After approval by the local institutional ethics review board, the charts of all patients with biliary cancers initiated on GEM/CVI 5-FU from November 1997 to July 2001 were reviewed for patient characteristics, tumor response, time to disease progression, survival and toxicity to treatment. No patients were excluded from this analysis as long as they received the first dose of cycle 1 therapy. Time to disease progression was estimated from the date of first treatment to the first date of recorded disease progression. The Kaplan–Meier method was used to estimate overall and progression-free survival. RECIST criteria were applied retrospectively to define radiological response to therapy. An attempt at estimating patient benefit was obtained from clinic notes based on a clear statement of improved pain symptoms or performance status, or decreased analgesic use on treatment. Otherwise, a patient benefit was assumed to be absent. Patients were evaluated at baseline with physical exam, hematology, complete chemistry including liver functions, and computed tomography imaging. A complete blood count was obtained weekly, and chemistry prior to each treatment cycle. Patients were evaluated for response with clinical assessment at least monthly, and radiologically every two to three cycles. Patients were withdrawn from treatment for clinical and radiological progression, toxicity or at patient request. Patient follow-up continued to death. Some patients, without progression, were permitted treatment breaks and re-initiated on the same regimen at progression.

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 I–II pancreatic trial by Hidalgo et al. [21]. Dose reductions for gemcitabine-related myelosuppression were as per the institution’s standard, as follows: day 8 and 15 dose reductions based on blood count parameters: if absolute neutrophil count (ANC) was 0.5–1 x 109/l and/or platelet count 50–100 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%.


    Results
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patients’ characteristics
Twenty-seven patients initiated GEM/CVI 5-FU for treatment of advanced adenocarcinoma of the biliary tract between November 1997 and July 2001 at the Princess Margaret Hospital. Baseline patient characteristics are listed in Table 1. The mean age was 55 years (range 27–69), and patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) ranging from 0 to 3. Most (85%) were receiving GEM/CVI 5-FU as their first-line chemotherapy. Forty-one per cent had prior resection of their primary tumor with curative intent, and were offered this chemotherapy after documentation of unresectable progression or metastatic disease. Median time to progression from primary surgery was 11.3 months (range 1.4 months to 5.1 years). The remaining 59% were unresectable at diagnosis. Almost all patients in this series had metastatic disease (93%) at the time of GEM/CVI 5-FU initiation, with liver and lymph nodes being the predominant sites. At last follow-up, 26 of 27 patients had died and median overall survival was estimated to be 5.3 months (range 0.2–35.2).


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Table 1. Patient characteristics
 
Response to treatment
The overall objective response to treatment was 33% [95% confidence interval (CI) 17–54%] with nine partial responses. An additional eight patients (30%; 95% CI 14% to 50%) achieved stable disease for a median of 4 months (range 2.3–11). The remaining 10 patients (37%) came off treatment for disease progression. More responses were seen in patients with gallbladder cancer (five of seven; 71%) than for patients with cholangiocarcinoma (four of 20; 20%). However, durable stable disease (actually minor responses with a median duration of 4 months) was seen in eight of 20 cholangiocarcinoma patients treated (40%). Some degree of clinical or patient improvement was estimated in all nine patients with objective responses, seven of eight patients with stable disease and two of 10 patients whose disease progressed within the first two cycles of therapy. One of the four patients with a baseline ECOG PS of 3 was amongst the responders, with improvement of her PS to 1.

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 3.3–10.6). 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 2.3–6.2) (Figure 2). Those obtaining an objective response took a median of 9 months (range 4–23) to progress. Combining the patients with stable disease and those with objective responses, the median time to progression was 6.2 months (range 2.3–23).



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Figure 1. Overall survival with 95% confidence intervals.

 


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Figure 2. Progression-free survival with 95% confidence intervals.

 
Toxicities
There were no treatment-related deaths. Hematological toxicity was manageable, with 11% grade 3 and no grade 4 toxicity (Table 2). Only one patient developed febrile neutropenia, and there were no bleeding events related to treatment. Central catheter infections were common, and resulted in treatment delays and/or discontinuation of therapy in 18% of patients. Two patients developed upper extremity deep venous thrombosis associated with the central catheter. Severe mucositis requiring delays and dose reductions occurred in three patients (11%). Severe hand–foot syndrome was not seen, but grade 1 or 2 toxicity was observed in six patients (22%). Five patients (19%) developed elevated liver enzymes and bilirubin on treatment, which corrected with replacement of their biliary stents. All five continued on treatment. One patient, a 67-year-old man with ischemic heart disease, experienced a non-fatal myocardial infarction during his first cycle of chemotherapy.


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Table 2. Toxicity (National Cancer Institute Common Toxicity Criteria) (n = 27)
 

    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
To date there is no agreement on the best palliative chemotherapy for advanced biliary tract cancer. With an overall response rate of 33%, an additional 30% with durable stable disease and modest hematological and non-hematological toxicity, our results compare very favorably with other regimens evaluated in this tumor site. The inconvenience and complications of the central venous catheter are a significant drawback of this regimen, as discussed below. Gebbia et al. [22] have also reported on 22 biliary cancer patients receiving a combination gemcitabine–5-FU regimen, with response rates of 36% and mild toxicity similar to our results. A starting performance status of ECOG 2 or 3 in over 50% of the patients in our series reflects the usual patient population with this disease, some of whom are not typically included in phase II trials. This may explain why the overall survival seen remains poor (median 5.3 months; 1-year overall survival 26%). The observation of repeat durable responses or stabilization with re-challenges of the same regimen suggests that quality of life can be optimized for some patients with intermittent chemotherapy once a tumor response is established.

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. Capecitabine–gemcitabine 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-FU–cisplatin 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 epirubicin–cisplatin–5-FU (ECF) versus 5-FU–etoposide–leucovorin (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.


    FOOTNOTES
 
* Correspondence to: Dr J. J. Knox, Princess Margaret Hospital, 5-218, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. Tel: +1-416-946-2399; Fax: +1-416-946-6546; E-mail: jennifer.knox{at}uhn.on.ca Back


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 Results
 Discussion
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