Japanese Journal of Clinical Oncology Advance Access published online on October 17, 2007
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hym116
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© 2007 Foundation for Promotion of Cancer Research
A Multi-center Retrospective Analysis of Survival Benefits of Chemotherapy for Unresectable Biliary Tract Cancer
1 Department of Biostatistics, Kyoto University School of Public Health, Kyoto
2 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba
3 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo
4 Department of Gastroenterology, Aichi Cancer Center, Nagoya
5 Department of Gastroenterology, National Kyushu Cancer Center, Fukuoka
6 Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama
7 Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka
8 Gastroenterological Center, Yokohama City University, Yokohama
9 Department of Imaging Diagnosis, Tochigi Cancer Center, Utsunomiya
10 Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
* For reprints and all correspondence: Naohiro Yonemoto, Department of Biostatistics, Kyoto University School of Public Health, Yoshida-konoe, Sakyou, Kyoto, Japan. E-mail: nyonemoto{at}pbh.med.kyoto-u.ac.jp
Received April 27, 2007; accepted July 28, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODRESULTSDISCUSSIONConflict of interestReferences |
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Background: This study examined the effect of five systemic chemotherapy regimens on survival in patients with unresectable biliary tract cancer (BTC) as compared with the best supportive care (BSC).
Methods: This study retrospectively reviewed data from 413 consecutive patients with BTC who were seen at any of nine central hospitals in Japan between April 2000 and March 2003. Patients were eligible if they had intra- or extrahepatic cholangiocarcinoma or gallbladder cancer with no prior chemotherapy. Hazard ratios of treatment regimens were estimated using the Cox proportional hazard model and the propensity score method.
Results: Three-hundred and four patients were enrolled: 125 (41.1%) received BSC and 179 (58.9%) took chemotherapy. Of those who received chemotherapy, 58 (19.1%) took gemcitabine (GEM), 45 (14.5%) took a cisplatin (CDDP)-based regimen, 30 (9.9%) took a 5-fluorouracil (5-FU)-based regimen, 27 (8.9%) took 5-FU + doxorubicin + mitomycin (FAM) and 20 (6.6%) took S-1. The response rate was 8.4% (n = 15). The CDDP-based regimen was associated with a high frequency of toxicity symptoms. The adjusted hazard ratio for GEM in the Cox regression was 0.53 (95% CI 0.34–0.82) and the hazard ratio for the CDDP-based regimen was 0.49 (95% CI 0.36–0.99).
Conclusion: Chemotherapy with GEM may benefit patients with BTC.
Key Words: biliary tract cancer • chemotherapy • survival • retrospective study • clinical trial
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODRESULTSDISCUSSIONConflict of interestReferences |
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Biliary tract cancer (BTC) is a relatively rare disease in the United States and Western Europe (1), but a frequent and serious cancer in Japan. It is the sixth leading cause of cancer death in Japan, killing approximately 15 000 people every year (2), and the incidence is increasing. BTC have traditionally been divided into cancers of the gallbladder, the extrahepatic bile ducts and the ampulla of Vater, whereas intrahepatic bile-duct cancers have been classified as liver cancer (1). Lately, however, the term BTC has been used to include the gallbladder, the intrahepatic cholangiocarcinoma, the extrahepatic cholangiocarcinoma and the ampulla of Vater (1). Worldwide, incidence and mortality rates of intrahepatic cholangiocarcinoma are increasing, while incidence rates of extrahepatic cholangiocarcinoma and gallbladder cancer are slightly decreasing (3).
Surgical resection is the only curative treatment for BTC, but it is only feasible if the cancer is detected early. The 5-year survival rate for resectable patients is around 40% (1). Because of the lack of early symptoms, most patients are diagnosed at an advanced stage, by which time the cancer has often metastasized or invaded the adjacent liver or hepatic artery. Such patients are not candidates for surgical resection and their prognosis is extremely poor (1). It remains unclear if chemotherapy could benefit patients with unresectable BTC(1–2). No chemotherapy or radiotherapy has yet been proven to substantially improve outcomes (1).
Many clinical trials of single- and multi-drug regimens have been conducted for BTC, but the reported response rates, toxicity and survival times have been variable. Most of the clinical trials conducted to date have been phase II trials. Only three phase III trials (4–6) and two observational studies (7,8) have been published, and limited information from real-world clinical practice is available. In the phase III study by Glimelius et al. (5), although overall survival was superior in the treated group, 6 m vs 2.5 months in the best supportive care (BSC) group, the difference did not remain significant. This result was from subgroup analysis in the study and might be below the statistical power.
Although the efficacy of conventional systemic chemotherapy seems negligible, there is no agreement on the standard chemotherapeutic regimen to replace it. A large number of multi-drug regimens have been tested in phase II trials and the results suggest that patients with advanced BTC might benefit from (1) 5-fluorouracil (5-FU) and cisplatin (9,10); (2) epirubicin (11); (3) S-1 (12); (4) 5-FU, leucovorin, and mitomycin C (13); (5) uracil-tegafur (14); (6) uracil-tegafur and doxorubicin (15); (7) gemcitabine (GEM) (16–21); (8) GEM and 5-FU (22,23); (9) GEM, 5-FU, and leucovorin (24,25); (10) GEM and cisplatin (26–30); (11) GEM and capecitabine (31–33); (12) GEM and oxaliplatin (34–36); and (13) oxaliplatin (37).
These data require further investigation. Many of the chemotherapeutic regimens listed above have been investigated in small, uncontrolled studies, with generally disappointing results. The major weaknesses of these studies in establishing a standard therapy are the rarity and heterogeneity of BTC, small sample sizes and the lack of a control group to provide data on survival times. Which regimen is appropriate as a reference arm in a large phase III trial remains unknown.
The objective of this study was to clarify the impact of systemic chemotherapy on BTC, particularly unresectable biliary and gallbladder cancer, using a multicenter observational study in Japan. We analyzed survival time in a group of patients who were treated with systemic chemotherapy or BSC.
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PATIENTS AND METHOD |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODRESULTSDISCUSSIONConflict of interestReferences |
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Study Design
We retrospectively reviewed 413 unresectable BTC patients seen between April 2000 and March 2003 at nine central hospitals in Japan. Patients were eligible if they had unresectable, locally advanced or metastatic adenocarcinoma arising from intrahepatic cholangiocarcinoma (n = 126), extrahepatic cholangiocarcinoma (n = 97), gallbladder cancer (n = 169) or papilla of Vater cancer (n = 21). Two-hundred and seven patients were treated with systemic chemotherapy, seven with arterial injection chemotherapy, 45 with radiotherapy, 15 with chemoradiotherapy and 137 received BSC.
We excluded patients with cancer of the papilla (because the number of patients was very small), arterial-injection chemotherapy, unclassified chemotherapy, radiotherapy, prior chemotherapy and missing clinical variables (serum carbohydrate antigen 19-9 (CA19-9) or carcinoembryonic antigen (CEA)) from the analysis (Fig. 1).
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Classification Of Chemotherapy Regimens
Chemotherapy regimens were classified into five types: 5 FU-based; S-1 alone; gemcitabine (GEM) alone; 5-FU, doxorubicin and mitomycin C (FAM); and cisplatin (CDDP)-based regimens. The 5 FU-based regimens comprised uracil-tegafur alone, 5-FU alone and 5-FU plus leucovorin. The CDDP-based regimen was of four types: a combination of CDDP, epirubicin and 5-FU; 5-FU plus CDDP; CDDP plus etoposide; or CDDP alone. Patients treated with irinotecan alone, low-dose 5-FU plus CDDP, carboplatin alone or doxorubicin plus vincristine were unclassified and excluded from the analysis.
The pathology report used cytological examination for the possible cases or clinical diagnosis for impossible other cases. Toxicity was scored weekly according to WHO criteria (38). Follow-up computed tomography was performed after every course of chemotherapy to objectively assess tumor response according to the Response Evaluation Criteria in Solid Tumors (39) at each hospital.
Definition of Clinical Variables
Clinical variables used in this study were treatment, tumor type, age, gender, performance status (PS), status of surgery, evidence for unresectability, biopsy, hepatic metastasis, pleural metastasis, distant lymph node metastasis, lung metastasis, bone metastasis, ascites, biliary drainage, total bilirubin, CEA level and CA19-9 level.
These variables were measured immediately before chemotherapy (for the treated group) or at the time of diagnosis (for the BSC group). Continuous variables were dichotomized using the following cutoffs: age, 60 years; CEA, 10 ng/ml; CA19-9, 1000 U/ml; and total bilirubin, 3 mg/dl. Categorical variables such as pre-surgery, biopsy and ascites were dichotomized to presence or absence of the characteristic. PS categories were collapsed into 3 levels: 0, 1 and 2–4.
Statistical Methods
Overall survival was measured from the first day of treatment (chemotherapy group) or from the day of diagnosis (BSC group) to the date of death or last visit. The study enrolled period ended on March 31, 2003, and observations on those patients remaining at the end of the study were censored. Survival curves were calculated by the Kaplan–Meier method (40). Differences in survival among subgroups according to each factor were evaluated by logrank tests. Hazard ratios and 95% confidence intervals (CI) were estimated by the Cox regression (41). Multivariate Cox regression (41) and the Cox regression by modeling the propensity score were performed for adjustment of confounders (42,43). We used 16 covariates (tumor type, age, gender, PS, status of surgery, evidence for unresectability, biopsy, hepatic metastasis, peritoneal metastasis, distant lymph node metastasis, lung metastasis, ascites, biliary drainage, total bilirubin, CEA level and CA19-9 level) for adjustment. Statistical significance was defined as a two-sided P-value of 0.05 or less. The analyses were performed using the statistical software JMP 5.01.J and SAS version 8.01 (SAS Institute Inc., Cary, NC, USA).
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RESULTS |
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Patient Characteristics
The final analysis population comprised 304 patients (Table 1). Duration of follow-up time on the patients was median 4.57 months (range 0.10–52.57 months). Ninety-three patients (30.6%) had intrahepatic cholangiocarcinoma, 64 patients (21.1%) had extrahepatic cholangiocarcinoma and 147 patients (48.4%) had gallbladder cancer. Pathologic confirmation in cytological examination was 202 patients. Somewhat less than half (125 (41.1%)) of the patients received BSC and 179 (58.9%) took chemotherapy. Of the chemotherapy group, 30 patients (9.9%) were on 5-FU-based regimens, 20 patients (6.6%) took S-1, 58 patients (19.1%) took GEM, 27 patients (8.9%) took FAM and 44 patients (14.5%) were on CDDP-based regimens.
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Response and Toxicity
Partial response was achieved in 15 of 179 chemotherapy patients (three with intrahepatic cholangiocarcinoma, two with extrahepatic cholangiocarcinoma and 10 with gallbladder cancer), but complete response was observed in no patients. Overall response rate was thus 8.4%. Stable disease was observed in 85 patients (47.5%) and progressive disease in 67 patients (37.4%). None (0%) of those on a 5 FU-based regimen showed a partial response, 11 (36.7%) remained stable and 11 (36.7%) showed progressive disease. Three (15.0%) patients treated with S-1 showed a partial response, 10 (50.0%) remained stable and six (30.0%) showed progressive disease. Of those given GEM, four (6.9%) showed a partial response, 29 (50.0%) remained stable and 23 (39.7%) showed progressive disease. Three (11.1%) of the patients taking FAM showed a partial response, 11 (40.7%) remained stable and 13 (48.2%) showed progressive disease. Of those on a CDDP-based regimen, five (11.4%) showed a partial response, 24 (54.6%) remained stable and 11 (31.8%) showed progressive disease.
The data were also analyzed by tumor type. Three (6.0%) of the patients with intrahepatic cholangiocarcinoma showed a partial response, 24 (48.0%) remained stable, and 20 (40.0%) showed progressive disease. Two (5.7%) of the patients with extrahepatic cholangiocarcinoma showed a partial response, 17 (48.5%) remained stable and 12 (34.2%) showed progressive disease. Ten (10.6%) of the gallbladder cancer patients showed a partial response, 44 (46.8%) remained stable and 35 (37.2%) showed progressive disease.
As for toxicity, 40 (22.4%) had grade 3 nonhematological toxicities and 28 (15.6%) had grade 4 hematological toxicities. Among the patients taking 5-FU, five (16.7%) had grade 3 nonhematological toxicities. Of those taking S-1, 5 (25.0%) had grade 3 nonhematological toxicities. Of those taking GEM, 10 (17.2%) showed grade 3 nonhematological toxicities and two (3.5%) had grade 4 hematological toxicities. Two (7.4%) patients on the FAM regimen had grade 3 and six (22.2%) had grade 4 hematological toxicities. Among patients on a CDDP-based regimen, 18 (40.9%) had Grade 3 nonhematological toxicities and 20 (45.5%) had grade 4 hematological toxicities.
Survival
The number of deaths was 87 (69.6%) of the 125 BSC patients and 150 (83.8%) of the 179 chemotherapy patients. The median overall survival time was 3.12 months (95% CI 2.50–4.11) for BSC patients and 7.38 months (95% CI 6.25–8.77) for chemotherapy patients. Figure 2 shows the survival curves for the chemotherapy and the BSC groups. The difference in survival times was significant (logrank test P-value < 0.0001).
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When the data for the chemotherapy group was analyzed by tumor type, the median overall survival time was 8.44 months (95% CI 5.15–11.2) for intrahepatic cholangiocarcinoma, 10.15 months (95% CI 5.38–13.7) for extrahepatic cholangiocarcinoma, and 6.50 months (95% CI 5.25–8.04) for gallbladder cancer. There was a statistically significant difference between extrahepatic cholangiocarcinoma and gallbladder cancer (logrank test P-value 0.029), but no difference between intrahepatic cholangiocarcinoma and gallbladder cancer (logrank test P-value 0.072). Gallbladder cancer patients died sooner than cholangiocarcinoma patients despite their better response to treatment.
Applying the Cox model yielded a hazard ratio for GEM of 0.50 (95% CI 0.35–0.72) and for CDDP-based regimens of 0.51 (95% CI 0.34–0.76; Table 2). Figure 3 shows the survival curves for patients on each regimen and receiving BSC. The median time to treatment failure was 2.76 months (95% CI 1.74–4.40) for GEM patients and 5.52 months (95% CI 2.07–6.77) for CDDP-based regimens.
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The adjusted hazard ratio in the Cox regression model for GEM was 0.53 (95% CI 0.34–0.82) and for CDDP-based regimens was 0.49 (95% CI 0.36–0.99). The adjusted hazard ratio in the Cox regression by modeling the propensity scores for GEM was 0.54 (95% CI 0.36–0.80) and for CDDP-based regimens 0.60 (95% CI 0.36–0.99; Table 3). Hazard ratio estimates obtained using the Cox regression and the propensity score were similar.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODRESULTSDISCUSSIONConflict of interestReferences |
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There is no standard chemotherapy for advanced biliary tract cancer. This study reports the impact of five types of chemotherapy on BTC compared with BSC. GEM was the most effective treatment, with a reduction in mortality of about 50%. GEM has already been shown to be an effective therapy for BTC in phase II trials (16–21). Response rates in GEM ranged from 8 to 36% and overall survival times from 6.3 to 16 months (44). The treatment is remarkably well tolerated, with very few patients (<5%) experiencing grade 4 hematologic toxicities. Hematologic adverse effects were infrequent and almost exclusively mild to moderate (44). A systematic review of the evidence on GEM from 13 single-arm phase II trials showed that GEM may be a reasonable option for treating BTC (45). Although GEM had been previously approved for solid tumors other than BTC (2), it was only approved for BTC in Japan in June of 2006.
CDDP-based regimens reduced mortality by 40%. However, we found a high frequency of grade 3 and 4 toxicities, making it unlikely that CDDP-based regimens can be used as standard therapy for BTC. Adverse events such as inflammation of the biliary duct and hematological toxicity have been reported in other trials (25,46).
The combination of GEM with CDDP or other new platinum products such as oxaliplatin or with other anticancer drugs (47) might be an attractive option. A pooled analysis of the evidence from 112 single-arm phase II trials showed that GEM combined with platinum may be promising drugs for treating BTC (48). Results of the pooled analysis in phase II trials and our study are similar. In the UK, ABC trial-01 evaluates the role of CDDP in combination with GEM compared with GEM alone (49). A similar trial is ongoing in Japan. In future randomized trials, we recommend comparing GEM with a combination regimen of GEM and new platinum products such as oxaliplatin(34–36).
Although the result of S-1 in this study was not good, S-1 trials for regulatory approved had finished yet in Japan. The result of the trial was good. The response rate was 35% and median survival time was 9.4 months (50). The GEM + S-1 trial has not been done yet. In future, S-1 or GEM + S-1 combined chemotherapy will be tested.
The limitations of this study are its retrospective nature and its nonrandomized design. There were some unbalances of baseline information in patient characteristics between the chemotherapy group and the BSC group. The proportion of patients with PS 2–3 or older age (over 60 years) in the BSC group was higher than in the chemotherapy group. We adjusted for known, measurable confounders through multivariate analysis and propensity score methods, but the study may still by limited by unmeasured confounders or information biases such as misclassification. We have no information for second- or third-line regimen each arm in this study. The second- or third-line treatment may affect the outcome of overall survival times. Our results should be supplemented by prospective trials using survival as the endpoint. The sample size was not large, and when the data was broken down by both disease and treatment regimen, some categories had few observations. For example, the S-1 treatment group included no patients with intrahepatic cholangiocarcinoma, and a much higher percentage of gallbladder cancer (90%) than the study group as a whole. This limits the interpretation of the results of the S-1 regimen. In the study, the low-dose CDDP regimen used a low dose under 10 mg. We thought that it should not classify within the class both this and another regimen with 80 mg/m2 such as the CEA regimen. In addition, we consulted chemotherapy experts in a nonresearch group. Through this process, we decided that the classification of chemotherapies in the study and these regimens were separate. We did not classify low dose 5-FU plus CDDP regimen within the CDDP regimen and excluded the patients from the study. This classification may be subject to other opinions. We reviewed all patients for 3 years from September to December 2004 more than a year and a half from starting the treatment. Most lost cases were patients who moved to other hospitals on their own decision. We could not follow them in the study. This is a limitation in the study.
Survival times for patients with BTC can be affected by factors such as PS and tumor type. Gallbladder cancer patients had shorter survival times than patients with intrahepatic or extrahepatic cholangiocarcinoma (15,21,23), possibly reflecting the more aggressive biology of gallbladder cancer (25). Alternatively, the pattern could result from differing sensitivities to chemotherapy due to biological differences between biliary tract and gallbladder cancers. Such differences in sensitivity could not clearly explain the difference in survival between patients with biliary tract and gallbladder cancer in this study. Future randomized trials should employ stratified randomization by strong prognostic factors such as type of cancer, PS and presence of metastases.
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Conflict of interest |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODRESULTSDISCUSSIONConflict of interestReferences |
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None declared.
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Acknowledgment |
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This study was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODRESULTSDISCUSSIONConflict of interestReferences |
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1 De Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. New Engl J Med (1999) 341:1368–78.
2 Okusaka T. Chemotherapy for biliary tract cancer in Japan. Semin Oncol (2002) 6(Suppl 20):51–3.
3 Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer (2002) 2:10.[CrossRef][Medline]
4 Falkson G, MacIntyre JM, Moertel CG. Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer (1984) 54:965–9.[CrossRef][Web of Science][Medline]
5 Glimelius B, Hoffman K, Sjoden PO, Jacobsson G, Sellstrom H, Enander LK, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol (1996) 7:593–600.
6 Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, et al. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer (2005) 92:1650–54.[CrossRef][Web of Science][Medline]
7 Ishii H, Furuse J, Yonemoto N, Nagase M, Yoshino M, Sato T. Chemotherapy in the treatment of advanced gallbladder cancer. Oncology (2004) 66:138–42.[CrossRef][Web of Science][Medline]
8 Kiba T, Nishimura T, Matsumoto S, Hatano E, Mori A, Yasumi S, et al. Single-agent gemcitabine for biliary tract cancers. Study outcomes and systematic review of the literature. Oncology (2006) 70:358–65.[CrossRef][Web of Science][Medline]
9 Ducreux M, Rougier P, Fandi A, Clavero-Fabri MC, Villing AL, Fassone F, et al. Effective treatment of advanced biliary tract carcinoma using 5-fluorouracil continuous infusion with cisplatin. Ann Oncol (1998) 9:653–6.
10 Ducreux M, Van Cutsem E, Van Laethem JL, Gress TM, Jeziorski K, Rougier P, et al. EORTC Gastro Intestinal Tract Cancer Group: a randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma: results of the 40955 EORTC trial. Eur J Cancer (2005) 41:398–403.[CrossRef][Web of Science][Medline]
11 Cantore M, Mambrini A, Fiorentini G, Rabbi C, Zamagni D, Caudana R, et al. Phase II study of hepatic intraarterial epirubicin and cisplatin, with systemic 5-fluorouracil in patients with unresectable biliary tract tumors. Cancer (2005) 103:1402–7.[CrossRef][Web of Science][Medline]
12 Ueno H, Okusaka T, Ikeda M, Takezako Y, Morizane C. Phase II study of S-1 in patients with advanced biliary tract cancer. Br J Cancer (2004) 91:1769–74.[CrossRef][Web of Science][Medline]
13 Raderer M, Hejna MH, Valencak JB, Kornek GV, Weinlander GS, Bareck E, et al. Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer. Oncology (1999) 56:177–80.[CrossRef][Web of Science][Medline]
14 Ikeda M, Okusaka T, Ueno H, Morizane C, Furuse J, Ishii H. A phase II trial of Uracil-tegafur (UFT) in patients with advanced biliary tract carcinoma. Jpn J Clin Oncol (2005) 35:439–43.
15 Furuse J, Okusaka T, Funakoshi A, Yamao K, Nagase M, Ishii H, et al. Early Phase II study of uracil-tegafur plus doxorubicin in patients with unresectable advanced biliary tract cancer. Jpn J Clin Oncol (2006) 36:552–6.
16 Penz M, Kornek GV, Raderer M, Ulrich-Pur H, Fiebiger W, Lenauer A, et al. Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol (2001) 12:183–6.
17 Tsavaris N, Kosmas C, Gouveris P, Gennatas K, Polyzos A, Mouratidou D, et al. Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer. Invest New Drugs (2004) 22:193–8.[CrossRef][Web of Science][Medline]
18 Eng C, Ramanathan RK, Wong MK, Remick SC, Dai L, Wade-Oliver KT, et al. A Phase II trial of fixed dose rate gemcitabine in patients with advanced biliary tree carcinoma. Am J Clin Oncol (2004) 27:565–9.[CrossRef][Web of Science][Medline]
19 Park JS, Oh SY, Kim SH, Kwon HC, Kim JS, Jin-Kim H, et al. Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study. Jpn J Clin Oncol (2005) 35:68–73.
20 von Delius S, Lersch C, Schulte-Frohlinde E, Mayr M, Schmid RM, Eckel F. Phase II trial of weekly 24-hour infusion of gemcitabine in patients with advanced gallbladder and biliary tract carcinoma. BMC Cancer (2005) 5:61.[CrossRef][Medline]
21 Okusaka T, Ishii H, Funakoshi A, Yamao K, Ohkawa S, Saito S, et al. Phase II study of single-agent gemcitabine in patients with advanced biliary tract cancer. Cancer Chemother Pharmac (2006) 57:647–53.[CrossRef]
22 Murad AM, Guimaraes RC, Aragao BC, Rodrigues VH, Scalabrini-Neto AO, Padua CA, et al. Phase II trial of the use of gemcitabine and 5-fluorouracil in the treatment of advanced pancreatic and biliary tract cancer. Am J Clin Oncol (2003) 26:151–4.[CrossRef][Web of Science][Medline]
23 Knox JJ, Hedley D, Oza A, Siu LL, Pond GR, Moore MJ. Gemcitabine concurrent with continuous infusional 5-fluorouracil in advanced biliary cancers: a review of the Princess Margaret Hospital experience. Ann Oncol (2004) 15:770–4.
24 Hsu C, Shen YC, Yang CH, Yeh KH, Lu YS, Hsu CH, et al. Weekly gemcitabine plus 24-h infusion of high-dose 5-fluorouracil/leucovorin for locally advanced or metastatic carcinoma of the biliary tract. Br J Cancer (2004) 90:1715–19.[Web of Science][Medline]
25 Alberts SR, Al-Khatib H, Mahoney MR, Burgart L, Cera PJ, Flynn PJ, et al. Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial. Cancer (2005) 103:111–8.[CrossRef][Web of Science][Medline]
26 Malik IA, Aziz Z, Zaidi SH, Sethuraman G. Gemcitabine and Cisplatin is a highly effective combination chemotherapy in patients with advanced cancer of the gallbladder. Am J Clin Oncol (2003) 26:174–7.[CrossRef][Web of Science][Medline]
27 Doval DC, Sekhon JS, Gupta SK, Fuloria J, Shukla VK, Gupta S, et al. A phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer. Br J Cancer (2004) 90:1516–20.[CrossRef][Web of Science][Medline]
28 Thongprasert S, Napapan S, Charoentum C, Moonprakan S. Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Ann Oncol (2005) 16:279–81.
29 Lee GW, Kang JH, Kim HG, Lee JS, Lee JS, Jang JS. Combination chemotherapy with gemcitabine and cisplatin as first-line treatment for immunohistochemically proven cholangiocarcinoma. Am J Clin Oncol (2006) 29:127–31.[CrossRef][Web of Science][Medline]
30 Kim ST, Park JO, Lee J, Lee KT, Lee JK, Choi SH, et al. A Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer. Cancer (2006) 106:1339–46.[CrossRef][Web of Science][Medline]
31 Kornek GV, Schuell B, Laengle F, Gruenberger T, Penz M, Karall K, et al. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol (2004) 15:478–83.
32 Knox JJ, Hedley D, Oza A, Feld R, Siu LL, Chen E, et al. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol (2005) 23:2332–8.
33 Cho JY, Paik YH, Chang YS, Lee SJ, Lee DK, Song SY, et al. Capecitabine combined with gemcitabine (CapGem) as first-line treatment in patients with advanced/metastatic biliary tract carcinoma. Cancer (2005) 104:2753–8.[CrossRef][Web of Science][Medline]
34 Andre T, Tournigand C, Rosmorduc O, Provent S, Maindrault-Goebel F, Avenin D, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol (2004) 15:1339–43.
35 Verderame F, Russo A, Di Leo R, Badalamenti G, Santangelo D, Cicero G, et al. Gemcitabine and oxaliplatin combination chemotherapy in advanced biliary tract cancers. Ann Oncol (2006) 17(Suppl 7):vii68–vii72.
36 Harder J, Riecken B, Kummer O, Lohrmann C, Otto F, Usadel H, et al. Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer. Br J Cancer (2006) 95:848–52.[CrossRef][Web of Science][Medline]
37 Androulakis N, Aravantinos G, Syrigos K, Polyzos A, Ziras N, Tselepatiotis E, et al. Oxaliplatin as first-line treatment in inoperable biliary tract carcinoma: a multicenter phase II study. Oncology (2006) 70:280–4.[CrossRef][Web of Science][Medline]
38 World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. (1979) Offset publication Geneva: World Health Organization.
39 Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst (2000) 92:205–16.
40 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc (1958) 63:457–81.[CrossRef]
41 Cox DR. Regression models and life-tables (with discussion). J R Stat Soc (Ser B) (1972) 34:187–220.
42 Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika (1983) 70:41–55.
43 Robins JM, Mark SD, Newey WK. Estimating exposure effects by modelling the expectation of exposure conditional on confounders. Biometrics (1992) 48:479–95.[CrossRef][Web of Science][Medline]
44 Scheithauer W. Review of gemcitabine in biliary tract carcinoma. Semin Oncol (2002) 29(Suppl 20):40–45.[Web of Science][Medline]
45 Dingle BH, Rumble RB, Brouwers MC. Cancer Care Ontario's Program in Evidence-Based Care's Gastrointestinal Cancer Disease Site Group: the role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer: a systematic review. Can J Gastroenterol (2005) 19:711–6.[Web of Science][Medline]
46 Okada S, Ishii H, Nose H, Yoshimori M, Okusaka T, Aoki K, et al. A phase II study of cisplatin in patients with biliary tract carcinoma. Oncology (1994) 51:515–17.[Web of Science][Medline]
47 Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol (2006) 24:3069–74.
48 Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer (2007) 96:896–902.[CrossRef][Web of Science][Medline]
49 Valle JW, Wasan H, Johnson P, Bridgewater J, Maraveyas A E., Jones, et al. Gemcitabine, alone or in combination with cisplatin, in patients with advanced or metastatic cholangiocarcinoma (CC) and other biliary tract tumors: a multicenter, randomized, phase II (the UK ABC-01) study. (2006) ASCO 2006 Gastrointestinal Cancers Symposium abstract 98. Atlanta, GA.
50 Boku N, Okusaka T, Furuse J, Ohkawa S, Yamao K, Masumoto T, et al. Phase II study of S-1 in patients with unresectable or recurrent biliary tract cancer (BTC). Ann Oncol (2006) 17(Suppl):ix318.
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