© 2005 Foundation for Promotion of Cancer Research
Single-agent Gemcitabine in the Treatment of Advanced Biliary Tract Cancers: a Phase II Study
1 Department of Internal Medicine and 2 Department of Surgery, Dong-A University Hospital, Busan, Korea
For reprints and all correspondence: Hyo-Jin Kim, Department of Internal Medicine, Dong-A University Hospital, 3-1 Dongdaeshin dong, Seo-gu, Busan, 602-715, Republic of Korea. E-mail: kimhj{at}mail.donga.ac.kr
Received September 2, 2004; accepted December 4, 2004
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Abstract |
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Objective: Patients with advanced biliary tract cancers have a dismal prognosis. The aim of this study was to evaluate the efficacy and safety of gemcitabine as a single agent in the treatment of patients with unresectable biliary tract cancers.
Methods: From May 2002 to April 2004, 23 chemotherapy-naïve patients with locally advanced or metastatic biliary tract adenocarcinomas were enrolled. The median age was 59 years (range 37–76). Fifteen patients (65.2%) had cholangiocarcinomas and eight (34.8%) had gallbladder adenocarcinomas. Patients received gemcitabine 1000 mg/m2 over 60 min once a week for 2 weeks followed by a week off therapy. Treatment was discontinued when unacceptable toxicities occurred or there was evidence of disease progression.
Results: A total of 110 cycles of chemotherapy were performed with a median of four cycles (range 1–10). The median follow-up was 13.4 months. Among the 23 patients, six (26.1%) had a partial response, eight (34.8%) had stable disease and nine (39.1%) had disease progression despite treatment. The overall response rate was 26.1% [95% confidence interval (CI) 22.08–30.12]. The median time to disease progression was 8.1 months (95% CI 3.33–12.87) and the median overall survival was 13.1 months (95% CI 1.64–24.56). Toxicities were generally mild and treatment was well tolerated. Of the 23 patients, one patient experienced a grade 3–4 neutropenia and one a grade 3–4 thrombocytopenia; however, no cases of febrile neutropenia or treatment-related deaths were noted.
Conclusion: In this phase II trial, therapy with gemcitabine was well tolerated and clinically active in patients with locally advanced or metastatic biliary tract cancers.
Key Words: gemcitabine • biliary tract cancer • cholangiocarcinoma
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The percentage of cases of biliary tract cancers, adenocarcinomas of the gallbladder and bile ducts is much lower in the Western nations [
4% of all gastrointestinal malignant neoplasms in the USA (1)] compared with some Asian countries such as Korea. In Korea, the high incidence and mortality rate of primary liver cancers constitute a serious medical and socio-economic problem. This is especially true of cholangiocarcinomas, which account for >20% of all primary liver cancers (2,3). Therefore, the development of an effective treatment strategy for cholangiocarcinomas is an important medical issue in Korea. Complete surgical excision of biliary tract cancers is the only therapy to have shown a survival benefit. For those with unresectable biliary tract tumor, the median survival is only a few months and the 5-year survival for all stages of gallbladder adenocarcinomas and cholangiocarcinomas is 5–10% (3).
5-Fluorouracil, mitomycin C, methotrexate, etoposide, doxorubicin and cisplatin have been used with poor results against biliary tract cancers. In previous studies that used the above chemotherapy agents against biliary tract tumors, only 10–20% revealed a partial response (4–7). However, gemcitabine has shown remarkable biological activity against biliary tract cancers in some clinical studies. Gemcitabine is a novel nucleoside analog demonstrating biological activities in a broad spectrum of solid tumors including pancreatic cancers (8). Because the biliary apparatus (gallbladder and bile ducts) shares a common embryological origin with the exocrine pancreas, gemcitabine was considered as a reasonable choice to be tried against biliary tract cancers. Although the numbers of patients in past studies have been small, recent phase II studies with gemcitabine showed an encouraging clinical response and survival benefit with acceptable toxicities for biliary tract cancers (9–14). Therefore, we conducted a phase II study to evaluate the efficacy and safety of gemcitabine as a single agent in the treatment of patients with locally advanced or metastatic biliary tract cancers.
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PATIENTS AND METHODS |
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PATIENT SELECTION
Patients with pathologically confirmed, surgically unresectable (locally advanced or metastatic) adenocarcinoma of the gallbladder or biliary tract were enrolled. Patients with recurrent cancer after previous surgery or radiation therapy were also enrolled. However, patients who had received prior chemotherapy were excluded. All patients had two-dimensional measurable lesions on computed tomography (CT) scan or magnetic resonance imaging (MRI). Patients with central nervous system metastasis were excluded. All patients had to have life expectancy >2 months. The treatment protocol was reviewed and approved by the institutional review board. Written informed consent was obtained from all patients.
Other inclusion criteria were ages 18–75 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, adequate bone marrow reservoir [white blood cell count 
4000/mm3, absolute neutrophil count (ANC) 2000/mm3, hemoglobin 9.0 g/dl, platelet count 100 000/mm3], adequate hepatic and renal function (serum total bilirubin level <3.0 mg/dl, hepatic transaminase level less than three times the upper limit of normal, serum creatinine level <1.5 mg/dl). Exclusion criteria included pre-existing undesirable medical or surgical conditions such as severe infections, uncompensated cardiac or pulmonary disease, recent major operations unrelated to the biliary tract cancer, pregnancy and/or lactation.
PRE-TREATMENT AND FOLLOW-UP EVALUATION
Initial evaluation included a complete history and physical examination, complete blood cell count (CBC), chemistry and electrolyte, urine analysis, stool examination, electrocardiogram, chest X-ray, abdominal CT scan and whole body radioisotope bone scan. Chest X-ray and tumor marker (CA19-9) measurement were repeated before starting each cycle of chemotherapy. CBC with differential count, hepatic and renal function tests was repeated weekly. Abdominal CT scan or MRI was performed after every three cycles of chemotherapy for regular evaluation. Additional imaging studies were performed when disease progression was suspected.
RESPONSE, SURVIVAL AND TOXICITY EVALUATION
Intention-to-treat analysis was applied to the efficacy and survival rates when analyzed. Responses to chemotherapy were assessed according to the World Health Organization (WHO) criteria. Two-dimensional measurable lesions of the tumor were re-evaluated by abdominal CT scan or MRI after every three cycles of chemotherapy, regularly. A physician and a radiologist reviewed the CT films independently and assessed the response. A complete response (CR) was defined as the complete disappearance of all evidence of the tumor. A partial response (PR) was defined as a decrease of tumor size of 50% in all indicator lesions. Stable disease (SD) was defined as a decrease of tumor size <50% or an increase <25% in all indicator lesions. Progression of disease (PD) was defined as an increase of tumor size 25% in any measurable lesions or the development of any new lesion. CR, PR or SD should have lasted for at least four consecutive weeks without evidence of disease progression. Therefore, in cases of CR, PR or SD, secondary assessment by imaging study was required.
Time to disease progression (TTP) was calculated from the date of patient enrollment to the date of the following events of disease progression: first documented evidence of advanced local invasion or metastasis, or death from any cause without prior evidence of advanced local invasion or metastasis. Overall survival (OS) was calculated from the date of patient enrollment to the date of death (15).
Chemotherapy-related toxicities were graded according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTC).
TREATMENT PROTOCOL AND DOSE MODIFICATION GUIDELINE
Gemcitabine was administered on days 1 and 8 for 2 weeks followed by 1 week of rest in each cycle. Gemcitabine 1000 mg/m2 in normal saline 500 ml was infused intravenously over 60 min.
In cases of grade 3–4 neutropenia or thrombocytopenia, the next chemotherapy schedule would be delayed until there was sufficient recovery of ANC or platelet count (ANC 1500/mm3, platelet count 75 000/mm3). The dose of gemcitabine would also be reduced by 25% in the next cycles.
Patients with PD were withdrawn from the study. If the patients' medical conditions could tolerate more chemotherapy, they could receive second-line chemotherapy with a continuous FAM regimen (5-fluorouracil, doxorubicin and mitomycin-C) or capecitabine at the physician's discretion. If CR was achieved, an additional three cycles of chemotherapy were performed and then stopped. In patients with PR or SD, treatment was continued until unacceptable toxicities occurred or there was evidence of disease progression. All measurable lesions would be re-evaluated by imaging studies after every three cycles of chemotherapy to re-assess the response.
STASTISTICAL ANALYSIS
The analyses were performed using SPSS version 10.0 (SPSS Inc, Chicago, IL). P < 0.05 was considered statistically significant. Survival data were analyzed statistically by the Kaplan–Meier survival method to obtain TTP and OS curves. The log-rank test was used to compare the distributions. A 95% confidence interval (CI) was calculated for the median event time of the distributions.
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RESULTS |
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PATIENT CHARACTERISTICS
From May 2002 to April 2004, 23 chemotherapy-naïve patients with locally advanced or metastatic biliary tract adenocarcinomas who met the inclusion criteria were enrolled. There was no one who had percutaneous transhepatic bile drainage or endoscopic retrograde bile drainage before chemotherapy. The characteristics of the 23 patient are summarized in Table 1. The median age was 59 years (range 37–76). There were 14 men (60.9%) and nine women (39.1%). Twenty patients (87.0%) had a performance status of 0 or 1, and three patients (13%) had a performance status of 2. Nine patients (39.1%) had intrahepatic cholangiocarcinomas, six (26.1%) had extrahepatic cholangiocarcinomas and eight (34.8%) had gallbladder adenocarcinomas. Thirteen patients (56.5%) had one metastatic site and 10 (43.5%) had multiple metastatic sites. The most common metastatic sites were lymph nodes, whereas the most common advanced local invasion site was the liver. Fourteen patients (60.9%) had prior surgery and five (21.7%) had received prior radiation therapy. Thirteen patients (56.5%) had a CA19-9 level <40 U/ml and 10 patients (43.5%) had a level >40 U/ml.
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EFFICACY
All 23 patients were available for evaluation. At the time of this analysis, 13 patients had died but none were treatment-related deaths. The median follow-up was 13.4 months. A total of 110 cycles of chemotherapy were performed with a median of four cycles (range 1–10). Of the 23 patients, six (26.1%) achieved PR, eight had SD (34.8%) and nine had PD (39.1%) despite treatment. Overall response rate was 26.1% (95% CI 22.08–30.12). The response results are summarized in Table 2. In patients with PD, six received second-line chemotherapy: three with a continuous FAM regimen and the other three with capecitabine. However, there was no response to the second-line chemotherapy. When response rates were adjusted for variables such as age, sex, performance status, primary site of origin (gallbladder versus bile ducts), number of metastases, site of metastasis, prior surgery or radiation, level of CA19-9 and second-line chemotherapy, there was no statistically significant correlation between response rates and these variables.
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The median TTP of all patients was 8.1 months (95% CI 3.33–12.87) and the median OS was 13.1 months (95% CI 1.64–24.56). The Kaplan–Meier survival curves are shown in Figures 1 and 2. Survival analysis was adjusted for the variables such as age, sex, primary site of origin, sites of metastases, prior surgery or radiation, level of CA19-9 and second line chemotherapy; however, this did not show any statistically significant correlation between survival and these variables. There was no survival differences between each group of patients with gallbladder adenocarcinoma, intrahepatic and extrahepatic cholangiocarcinomas. Although the median TTP of gallbladder adenocarcinomas was slightly longer than those of intrahepatic and extrahepatic cholangiocarcinomas (5.5 versus 4.5 months, 5.5 versus 4.0 months, respectively), there was no statistical importance (P = 0.7825, P = 0.7021, respectively). However, when survival analysis was adjusted for ECOG performance status and number of metastases, these variables did show statistically significant differences in TTP and OS. In patients with performance status 0–1 versus performance status 2, TTP was 8.4 versus 2.2 months (P = 0.0038) and OS was 17.3 versus 5.2 months (P = 0.0288), respectively. In patients with only one metastasis versus multiple metastases, TTP was 12.4 versus 4.7 months (P = 0.0175). However, there was no statistically significant difference of OS between only one metastasis and multiple metastases (P = 0.4158). Survival results are summarized in Table 3.
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SAFETY
All patients were assessed for toxicity by NCI-CTC. Hematological adverse reactions to gemcitabine were mild and the patients tolerated the therapy well. Among the 23 patients, only one patient experienced grade 3–4 neutropenia and another experienced grade 3–4 thrombocytopenia. Of the total 110 cycles, only three cycles (2.7%) were reported to have developed grade 3–4 neutropenia and four cycles (3.6%) grade 3–4 thrombocytopenia. No hepatotoxicity, nephrotoxicity, case of a febrile neutropenia or treatment-related deaths were noted. Nausea, vomiting, diarrhea, alopecia and skin rash were rarely observed (grade 1 or 2). Hematological and non-hematological toxicities are summarized in Table 4. Because the toxicities were mild, gemcitabine dose omission or reduction was rare. The relative dose intensity of gemcitiabne was 95%.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Because of the high incidence of biliary tract cancer and its poor prognosis in Korea, detection at an early stage is important. However, because symptoms from the cancer manifest themselves late in the disease course, most patients are already in the advanced stages of the disease at the time of detection and do not qualify for surgical treatment. Therefore, the role of chemotherapy is important.
Recent phase II studies with gemcitabine have shown encouraging efficacy and survival rates compared with conventional chemotherapies such as 5-fluorouracil, mitomycin C, methotrexate, etoposide and doxorubicin (4–7). Gemcitabine (2'-2' difluorodeoxycytidine) is a novel nucleoside analog that functions as a pyrimidine antimetabolite by mimicking the structure of the natural nucleoside deoxycytidine. It is incorporated into the end of the elongating DNA strand and works as a masked chain terminator in DNA synthesis (16–19). In recent studies with gemcitabine for unresectable pancreatic adenocarcinomas, gemcitabine revealed remarkable clinical benefits and potential for survival improvement (8,20,21). Because the biliary apparatus (gallbladder and bile ducts) shares a common embryological origin with the exocrine pancreas, gemcitabine was considered as a reasonable agent for the treatment of biliary tract adenocarcinomas. From the late 1990 s until recently, several phase II studies with gemcitabine as a single-agent treatment of biliary tract cancers have been performed (9–14). In these studies, the response rates ranged from 20 to 40% and the median overall survival ranged from 6 to 12 months (22,23). Recently, combination treatments with gemcitabine and other chemotherapy agents such as 5-fluorouracil in biliary tract cancers have shown a response rate of 30–55% with a median survival of 8–11 months (13,14,24–26). Based on these encouraging results, it is expected that gemcitabine may improve response and survival rates for the treatment of unresectable biliary tract adenocarcinomas. However, large randomized phase III studies are needed to confirm the efficacy of gemcitabine in these patients.
Several schedules with various dose intensities have been tried in the previous phase II gemcitabine studies against biliary tract cancers. However, there were no response and survival rate differences among the various gemcitabine administration schedules from previous studies (9–14). In our study, we adopted a 3-week gemcitabine administration schedule (gemcitabine 1000 mg/m2 was infused on days 1 and 8) and a slow gemcitabine infusion protocol (infused for 60 min, not for 30 min).
We previously have reported a similar 3-week gemcitabine and cisplatin administration schedule (gemcitabine 1000 mg/m2 was given on days 1 and 8, cisplatin 60 mg/m2 was given on day 1) for the treatment of advanced non-small cell lung carcinomas (NSCLCs). The 3-week schedule showed efficacy and survival rates comparable with the conventional 4-week schedules that were widely used for NSCLCs (27). Therefore, we adopted a 3-week gemcitabine administration schedule for the biliary tract cancers.
In a recent study with gemcitabine for unresectable pancreatic adenocarcinoma, Tempero et al. reported that a fixed dose rate (FDR) infusion of gemcitabine may improve the survival rate (28). The authors prospectively compared two groups of patients (n = 92 patients) with different gemcitabine infusion protocols. In the standard arm (n = 49 patients), patients received gemcitabine 2200 mg/m2 over 30 min on days 1, 8 and 15. In the FDR arm (n = 43 patients), patients received gemcitabine 1500 mg/m2 over 150 min (10 mg/m2/min) on days 1, 8 and 15. The median survival for all patients was 5.0 months in the standard arm and 8.0 months in the FDR arm (P = 0.013). For patients with metastases, the median survival was 4.9 months in the standard arm and 7.3 months in the FDR arm (P = 0.094). The 1-year survival rates for all patients were 9% in the standard arm and 28.8% in the FDR arm (P = 0.014). However, more hematological toxicities were reported in the FDR arm than in the standard arm. The authors report that the survival benefit from the FDR protocol may be due to the higher intracellular concentrations of gemcitabine triphosphate, which may also be the cause of the higher hematological toxicities. Although more studies need to be performed to confirm the survival benefit of the FDR gemcitabine infusion protocol, the implications of this study are very encouraging. In our study, we planned a similar slow gemcitabine infusion protocol expecting survival benefits. However, we had to adjust the infusion rate to reduce the hematological toxicities seen in the study by Tempero et al. Therefore, a motified gemcitabine infusion protocol was adopted (gemcitabine 1000 mg/m2 was infused for 60 min; 16.7 mg/m2/min). Consequently, we could obtain acceptable response and survival rates compared with other gemcitabine administration protocols without the potential for increased hematological toxicities. We expect that there will be more studies to evaluate the efficacy and toxicities of FDR infusion of gemcitabine in biliary tract cancers.
Bone marrow suppression is a well known complication of gemcitabine therapy. In previous studies with gemcitabine and cisplatin for NSCLCs, neutropenia and thrombocytopenia have been reported as the major dose-limiting toxicities (29,30). However, in several phase II studies with single-agent gemcitabine for biliary tract cancers, grade 3–4 neutropenia or thrombocytopenia were rarely observed. In our study, among the total 110 cycles given, grade 3–4 neutropenia occurred in only three cycles (2.7%) and grade 3–4 thrombocytopenia occurred in four cycles (3.6%). Other toxicities were mild and well tolerated by most patients.
CONCLUSION
Recent clinical studies demonstrate that gemcitabine has good biological activities against biliary tract cancers as a single agent or in combination with other medications. To clarify the survival advantage conferred by gemcitabine, a large randomized phase III study needs to be performed. This phase II study suggests that gemcitabine as a single agent is biologically active and well tolerated in the treatment of unresectable biliary tract cancers.
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