INTRODUCTION

Adenocarcinomas of the gallbladder and bile ducts (cholangiocarcinoma) have a poor prognosis. Although surgical resection of the primary tumor is potentially curative therapy, less than 25% of patients will be resectable at presentation, and among those patients, relapse rates are high.^1-4 Patients with unresectable disease will receive variable palliative therapy, with a median survival of less than 1 year. Biliary bypass or stenting is often required if chemotherapy is contemplated.

To date, chemotherapy has had limited impact on the natural history of this disease because of both the absence of agents with substantial activity and the overall morbidity of treatment in this patient population. No standard chemotherapy has been identified that can clearly prolong survival. Fluoropyrimidines have been considered the basis of palliative chemotherapy despite response rates (seen in small phase III trials) in the range of 0% to 10%.^5-7 Older combination chemotherapy, including fluorouracil (FU), has not demonstrated a clear superiority over single-agent FU but has resulted in added toxicity. However, Glimelius et al⁸ showed there was improved quality of life for biliary cancer patients treated with FU-based chemotherapy versus best supportive care.

Clearly, improving outcomes for patients with this aggressive cancer will necessitate the use of more active and well-tolerated therapies. A number of recent phase II trials using newer chemotherapeutic agents suggest a level of chemosensitivity not previously seen. Gemcitabine,^9-18 newer FU regimens,^15-17 capecitabine,^18-20 and platinum analogs^20-25,13,14 all seem to be active and, perhaps, are more active in combinations. The larger phase II trials report objective response rates (ORRs) ranging from 15% to 45%. Differences in response rates between gallbladder and cholangiocarcinoma have not been seen; however, some series report poorer overall survival for patients with gallbladder cancer compared with cholangiocarcinoma.^13,14 Regimens containing cisplatin or its analogs evaluated in phase II studies of biliary cancer have, in general, reported slightly higher response rates (20% to 45%) than those seen previously but also have significant toxicity (20% to 50% ≥ grade 3 toxicity), which may limit their applicability. The nucleoside analog gemcitabine is a chemotherapeutic agent with a favorable therapeutic profile. It has shown ORRs ranging from 15% to 35% in a number of phase II trials in biliary cancers and seems consistently active and well tolerated as a single agent.

The combination of gemcitabine and a fluoropyrimidine in biliary cancers is worthy of further evaluation. The toxicity profile of these agents are known to be nonoverlapping, and combinations have been well tolerated.^26,27 Besides their known activity in a number of tumor types, both drugs interfere with the pyrimidine biosynthesis pathways and may act synergistically. Indeed, preclinical studies including xenograft models support this hypothesis.^28,29 Clinically, Gebbia et al¹⁶ suggested improvement in response rates and median survival in biliary cancer with an infusional FU-gemcitabine combination over gemcitabine alone. We had also explored concurrent gemcitabine with continuous venous infusional (CVI) FU in biliary cancer with encouraging disease control rates (response rate, > 30%).³⁰ Unfortunately, the treatment was associated with considerable central venous catheter–related adverse events. A strategy to reduce toxicity and, thereby, improve patient benefit was proposed with the substitution of capecitabine for the FU, thus eliminating the need for the central venous catheter. Capecitabine also seems to be active and well tolerated as a single agent in this disease (response rate, 19%)¹⁸ and has the advantage of easy oral administration. A gemcitabine-capecitabine (GemCap) regimen has been developed in a phase I trial for pancreas cancer patients,²⁷ and thus, extrapolation to biliary cancer patients is reasonable.

We report the results of a single-institution phase II trial of GemCap combination for patients with advanced biliary cancer. The objectives of the trial were to determine the response rate, time to disease progression, survival, and safety profile.

PATIENTS AND METHODS

Patients were eligible if they had pathologically proven, measurable, unresectable, locally advanced or metastatic adenocarcinoma arising from the intra- and extrahepatic biliary ducts or gallbladder. No prior chemotherapy for advanced disease was allowed. Additional inclusion criteria included age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and adequate organ functions (neutrophils ≥ 1.5 × 10/L, platelets ≥ 100 × 10/L, serum creatinine ≤ 160 μmol/L or actual or calculated creatinine clearance ≥ 60 mL/min, ALT ≤ 5 × upper limit of normal [ULN], and total bilirubin ≤ 3 × ULN and stable for 2 weeks). Written informed consent was obtained from each patient. The protocol and the informed consent form were approved by the Research Ethics Review Board of the Princess Margaret Hospital, Toronto, Canada.

RESULTS

Forty-five patients with advanced biliary cancer were enrolled between July 2001 and January 2004. Demographics and other baseline characteristics are listed in Table 1. Fifty-one percent of patients had cholangiocarcinoma, and 49% had gallbladder cancer. Forty patients (89%) had metastatic disease, 10 of which experienced disease recurrence after a prior resection with curative intent. Eleven patients had undergone exploratory laparotomy to determine unresectability, whereas the remaining 24 were clearly unresectable based on radiologic evidence of distant metastatic disease. The five patients with locally advanced disease at baseline had cholangiocarcinomas. Most patients had good performance status at start of therapy (ECOG performance status of 0 to 1 in 82%), and the median age was 62 years (range, 38 to 84 years). Baseline median total bilirubin was 12 μmol/L (range, 5 to 62 μmol/L). All patients were assessable for efficacy and toxicity analysis. Nine patients received second-line treatments after progressive disease on GemCap (three patients received cisplatin-based chemotherapy, three received irinotecan-based chemotherapy, two received conformal radiotherapy to the primary tumor, and one received radiofrequency ablation to a residual liver metastasis).

Over 350 cycles of GemCap chemotherapy were delivered, with a median of seven cycles per patient (range, one to 24 cycles). Across all cycles, patients received more than 90% of initial prescribed chemotherapy. The primary reason for discontinuing treatment was progressive disease (86%, or 32 of the 37 patients who completed treatment). Three patients requested a break, and two discontinuations were at the physician's discretion because of other comorbidities. Eight patients remain on study treatment. Twenty-eight patients (62%) have died. Median follow-up time per patient is 11 months (range, 1.1 to 34 months.) Of the 17 patients who are still alive, the median duration of follow-up is 14 months (range, 9.6 to 34 months.)

Two patients achieved a complete response, and 12 patients achieved partial responses, for an overall ORR of 31% (Table 2). Four patients who met the criteria for response only did so after 6 months of treatment. The median time to progression for the responders was 13.8 months (range, 6.7 to 28.7 months.)

An additional 19 patients (42%) experienced SD for a median duration of 7 months (95% CI, 5.8 months to not available). Nine of the 19 patients with SD had minor responses where tumor shrinkage was less than 30% (range, 8% to 28%). Fifteen patients with SD have progressed (median, 6.1 months; range, 3.3 to 22 months), and four patients are progression free at 9.6, 11.3, 13, and 16 months.

The median overall survival time was 14 months (95% CI, 7.3 to not available), and the median progression-free survival time was 7 months (95% CI, 4.6 to 11.8 months; Figs 1 and 2). One-year progression-free survival and overall survival rates were 30% and 49%, respectively. Tumor type (cholangiocarcinoma v gallbladder cancer) was the only statistically significant predictor of overall survival in this series (hazard ratio = 3.61; 95% CI, 1.35 to 9.67; P = .011) or progression-free survival (hazard ratio = 2.37; 95% CI, 1.11 to 5.06; P = .026). As of this analysis, the median survival time for cholangiocarcinoma patients was 19 months v 6.6 months for gallbladder cancer patients. Progression-free survival time was 9.0 months for cholangiocarcinoma patients and 4.4 months for gallbladder cancer patients.

This combination of GemCap was generally well tolerated (Table 3). There were no treatment-related deaths. No patients discontinued treatment because of toxicity. Gemcitabine- or capecitabine-related specific toxicity resulted in at least one cycle delay or dose reduction in 53% and 29% of patients, respectively. Grade 3 and 4 toxicity was infrequent other than neutropenia, which was seen in 12% of all cycles delivered but resulted in only one brief episode of febrile neutropenia. Infectious complications (11% of patients) were not common or problematic despite the prevalence of biliary stents. Grade 2 and 3 hand-foot syndrome was observed in 29% of patients. Mild fatigue during treatment (grade 2) was reported in 42% of patients. There was no grade 3 or 4 gastrointestinal toxicity seen. The subset of patients whose baseline bilirubin was 1.5 to 3 × ULN (n = 8) did not have a toxicity profile different from the rest of the patients on study, including an absence of grade 4 toxicity. No treatment-related liver toxicity was observed in any of the patients on this study.

DISCUSSION

There is no current standard chemotherapy in advanced biliary cancer. Oncology practices vary considerably, and range from not offering patients chemotherapy because of concern over lack of efficacy and detrimental toxicity to offering patients multiple-drug regimens. Clinical trials in cholangiocarcinomas and gallbladder cancer have suffered from the relative rarity of these tumors and the generally morbid patient population. The recent surge of new phase II trials in biliary cancer reflects not only the lack of consensus on the best treatment but also an increase in research interest on how to manage this challenging disease. Table 4 lists the larger, more recent trials.

We report here one of the largest series in biliary cancer. This combination of GemCap is a conveniently administered, well-tolerated regimen. A response rate of 31% plus an additional disease stabilization rate of 42% gives an overall disease control rate of 73%. The group experiencing either ORRs or SD on GemCap had a median progression-free survival time of 10 months (range, 8.6 to 19 months), suggesting durable activity. The median overall survival time on study of 14 months is encouraging. These efficacy data compare favorably with other trials, including those with more toxic regimens (Table 4). The patients enrolled onto this trial reflect a fairly typical biliary cancer population considered for chemotherapy. Most patients had metastatic disease and presented with liver function abnormalities, which were stabilized with stenting before the start of chemotherapy.

It is also encouraging that the GemCap regimen was well tolerated in these patients with liver dysfunction and/or biliary stents. Transient neutropenia, thrombocytopenia, fatigue, and hand-foot syndrome were commonly observed but were easily managed without discontinuing the protocol. The high rate of venous thrombosis and line infections seen in our previous study of biliary cancer (26% total from CVI FU plus gemcitabine) was absent in this series, which substituted capecitabine for the CVI FU. An argument could be made that a more dose-intense regimen might be feasible and may produce slightly higher response rates, but almost certainly, this would come at the cost of more toxicity and perhaps fewer cycles of chemotherapy delivered on average. Indeed, other regimens, including those with platinum analogs, do not actually seem to provide significant improvements in response rates or prolonged median survivals when compared with older series or with this study (Table 4). In keeping with the preclinical data supporting synergy, lower than single-agent doses of both gemcitabine and capecitabine in this trial achieved a promising antitumor effect. The durable SD on this regimen may be impacting the encouraging observed median survival.

Carcinomas of the biliary tract and gallbladder may be biologically sufficiently different as to lead to different sensitivities to chemotherapy; however, this study shows responses to be similar (ORR, 34% v 27%, respectively), as do other trials. The shorter median survival for gallbladder cancer seen in this study compared with cholangiocarcinomas probably reflects a more aggressive biology of gallbladder cancer. Because of their relative rarity (4% of cancers of the gastrointestinal tract³⁴), it may not be practical to separate the biliary cancers in clinical trials, but planned randomized studies should include biliary tumor type in the stratification strategy.

The amount of antitumor activity seen here combined with a tolerable toxicity profile argues that GemCap may yield benefit in this patient population. This regimen warrants further evaluation in a randomized study with survival end points to determine whether this combination is superior to a single agent. Given that gemcitabine is one of the better studied agents, with data supporting efficacy and tolerability in biliary cancer, it would make a reasonable comparative arm. The success of such a large trial would necessitate the participation of multiple centers or cooperative groups, yet it has the potential to change practice globally. Given its therapeutic profile, GemCap should also be evaluated in the adjuvant setting to attempt reduction of incurable recurrences. Preliminary data suggest targeted agents, such as epidermal growth factor receptor inhibitors, also have activity in advanced biliary cancer³⁵ and should be explored in combination with GemCap.

Authors' Disclosures of Potential Conflicts of Interest

The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Ron Feld, Amgen Canada, AstraZeneca Canada, Merck Frosst Canada. Honoraria: Ron Feld, EXIMIAS, Merck Frosst Canada. Research Funding: Ron Feld, AstraZeneca, EXIMIAS, GlaxoSmithKline; Eric Chen, Hoffman-La Roche. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.