Japanese Journal of Clinical Oncology Advance Access originally published online on August 3, 2006
Japanese Journal of Clinical Oncology 2006 36(9):552-556; doi:10.1093/jjco/hyl075
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© 2006 Foundation for Promotion of Cancer Research
Early Phase II Study of Uracil–Tegafur Plus Doxorubicin in Patients with Unresectable Advanced Biliary Tract Cancer
1 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, 2 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, 3 Department of Gastroenterology, National Kyushu Cancer Center, Fukuoka, 4 Department of Gastroenterology, Aichi Cancer Center, Nagoya and 5 Department of Imaging Diagnosis, Tochigi Cancer Center, Utsunomiya, Japan
For reprints and all correspondence: Junji Furuse, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. E-mail address: jfuruse{at}east.ncc.go.jp
Received May 19, 2006; accepted June 19, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Standard chemotherapy for advanced biliary tract cancer has not been established. The purpose of this study was to evaluate the efficacy and toxicity of a combination chemotherapy of uracil–tegafur (UFT) and doxorubicin in patients with unresectable advanced biliary tract cancer.
Methods: Patients with histologically or cytologically confirmed, measurable biliary tract cancer, including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer and ampulla of Vater cancer, which was not amenable to surgery, were eligible for the study. Patients received oral UFT 300 mg/m2 per day divided into two doses on Days 1–14 and intravenous doxorubicin 30 mg/m2 on Day 1. This cycle was repeated every 21 days. Additional courses of this regimen were given until a maximum of 15 courses, disease progression or the appearance of unacceptable toxicity.
Results: Twenty-four patients from five institutions were enrolled between March 2004 and November 2004. Of the 24 patients, three had partial responses for an objective response rate of 12.5% (95% confidence interval, 2.7–32.4%), 13 patients had stable disease, 7 had progressive disease and the final patient was not evaluated. Grade 3 toxicity was observed in 5 of the 24 patients (20.8%), and these toxicities included anorexia, fatigue, anemia and neutropenia. None had grade 4 toxicity. The median progression-free and overall survival time was 2.5 and 7.6 months, respectively.
Conclusions: Combination chemotherapy of UFT and doxorubicin was well tolerated and showed preliminary moderate activity against advanced biliary tract cancer. Further investigation in a late phase II study involving a large number of patients is recommended.
Key Words: advanced biliary tract cancer • systemic chemotherapy • uracil–tegafur • doxorubicin
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Biliary tract cancer is one of the common causes of cancer death in Japan, with an estimated 16 000 deaths annually (1). Although surgery currently remains the only potentially curative treatment, most patients are found to have an unresectable advanced stage of disease. The curative resection rates for gallbladder cancer range from 10 to 30% (2,3). Although patients with unresectable disease receive various palliative treatments, including systemic chemotherapy, the prognosis remains extremely poor.
A previous report showed improved survival in patients with biliary tract cancer with 5-fluorouracil (5-FU)-based chemotherapy compared with the best supportive care (4). Efforts have been made to develop promising regimens for biliary tract cancer using clinical trials of systemic chemotherapy (5). In various reports on chemotherapy for biliary tract cancer, fluoropyrimidines have been considered as the basis of chemotherapy (5–8). Furthermore, cisplatin or anthracycline antitumor antibiotic agents such as doxorubicin and epirubicin have been used as combination chemotherapy with 5-FU (9–12). However, no standard chemotherapy has currently been identified that can clearly prolong survival.
In Japan, only three anticancer agents—uracil–tegafur (UFT), doxorubicin, and cytarabine—are strictly approved by the Ministry of Health, Labor, and Welfare for biliary tract cancer. UFT is an orally administered drug that is a combination of uracil and tegafur in a 4:1 molar concentration ratio. Tegafur is a 5-FU prodrug that is hydroxylated and converted to 5-FU by hepatic microsomal enzymes. Uracil prevents degradation of 5-FU by inhibiting dihydropyrimidine dehydrogenase, which leads to an increased level of 5-FU in plasma and tumor tissues (13,14). Doxorubicin is an anthracycline antibiotic that induces various biological effects and has one of the widest spectra of antitumor activity against lymphomas, leukemias, soft tissue sarcomas and a variety of carcinomas. However, in previous reports (15–17), UFT had little activity or doxorubicin was not examined enough as a single agent in treating patients with advanced biliary tract cancer. Cytarabine has not been applied for biliary tract cancer.
Some regimens that include a combination of a fluoropyrimidine and an anthracycline antibiotic, such as the FAM regimen (5-FU, doxorubicin, and mitomycin) and the CEF regimen (cisplatin, epirubicin, and 5-FU), showed moderate activity (9–12). A combination of a fluoropyrimidine and an anthracycline antibiotic should have some efficacy against biliary tract cancer, but no such regimen has ever been assessed. Since UFT+doxorubicin is the only doublet regimen currently covered by health insurance in Japan, we conducted an early phase II study to evaluate the antitumor activity and toxicity of this combination (the UFD regimen) in patients with unresectable advanced biliary tract cancer. The objectives of this study were to evaluate response rate, toxicity, progression-free survival and overall survival.
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PATIENTS AND METHODS |
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PATIENTS ELIGIBILITY
Eligibility criteria for enrollment in the study were: (i) histologically or cytologically confirmed biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder or ampulla of Vater cancer); (ii) measurable disease on computed tomography (CT) or magnetic resonance imaging (MRI); (iii) unresectable disease; (iv) no prior chemotherapy; (v) age
20 years old; (vi) Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; (vii) adequate bone marrow function (leukocyte count 4000 cells/mm3, platelet count 100 000 cells/mm3 and hemoglobin 9.0 g/dl), renal function (serum creatinine concentration 
upper limit of normal) and hepatic function (serum bilirubin level 2.0 mg/dl, serum albumin level 3.0 g/dl, serum aspartate transaminase (AST) and alanine transaminase (ALT) levels 2.5 times upper limit of normal); (viii) life expectancy 8 weeks; and (ix) written informed consent from the patient. Percutaneous biliary drainage was performed in patients with obstructive jaundice and these patients were required to have serum bilirubin levels of 3.0 mg/dl and serum AST and ALT levels 5 times the upper limit of normal before enrollment. Exclusion criteria were: serious complications such as active infection, active gastrointestinal ulcer, cardiac disease, or renal disease; central nervous system metastasis; marked pleural effusion or ascites; symptomatic interstitial pneumonitis; and pregnancy or lactation for women. The study was approved by the local institutional review boards at all participating centers.
TREATMENT METHODS
UFT was administered orally at a dose of 300 mg/m2 per day (400 mg/body per day in patients with body surface <1.50 m2 and 500 mg/body/day in patients with body surface 1.50 m2) divided into two doses, for 14 consecutive days followed by 1 week of rest. Doxorubicin was given as a 10 min intravenous infusion on Day 1 of each cycle at a dose of 30 mg/m2. This cycle was repeated every 21 days provided that patients had recovered sufficiently from the drug-related side effects. Patients continued to receive additional courses of this regimen until a maximum of 15 courses, evidence of disease progression or the appearance of unacceptable toxicity. When hematological toxicity greater than grade 3 or non-hematological toxicity greater than grade 2 was observed, treatment was delayed until the toxicity subsided to grade 1 or less. If the daily dose of UFT was considered to be intolerable, the dose was reduced by 100 mg/day (one capsule/day). In general, patients were treated as outpatients and admitted to the hospital only for management of toxicities and treatment-related complications.
ASSESSMENT OF RESPONSE AND TOXICITY
Physical examination, complete blood cell counts, serum chemistries and urinalysis were performed at baseline and at least twice in 3 weeks after initiating treatment. Patients underwent dynamic CT or MRI to evaluate response at 4- to 6-week intervals after the start of treatment. Computed tomography or MRI was performed by obtaining contiguous transverse sections using the helical scanning method at a section thickness of 5 mm. Tumor response was assessed using the Response Evaluation Criteria in Solid Tumors (18). Objective responses were confirmed by a second evaluation at least 4 weeks later. Toxicity was graded according to the National Cancer Institute common toxicity criteria, version 2.0. Progression-free survival was calculated from the first day of treatment until evidence of tumor progression, clinical progression or death due to any cause. Overall survival was calculated from the first day of treatment until death due to any cause. Survival data were analyzed using the Kaplan–Meier method. The statistical significance of differences between the survival curves was determined using the log-rank test. Differences with P-values <0.05 were considered significant.
STUDY DESIGNS
The primary end point of this study was the overall response rate, and data from at least 19 patients were accrued. In this study, the threshold response rate was defined as 5% and the expected response rate was set as 15%. If no responses were observed in the 19 patients and the upper limit of the 95% confidence interval (95% CI) did not exceed the expected rate of 15%, the UFD regimen was judged to have no activity against biliary tract cancer. If response was confirmed in one or more of the 19 patients, the decision of whether or not to proceed to a further study using the UFD regimen was taken on the basis of other factors, such as the safety and rate of response or stable disease in this study.
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RESULTS |
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PATIENT CHARACTERISTICS
A total of 24 patients were enrolled in this study between March 2004 and November 2004. Patient characteristics are shown in Table 1. The 24 patients received 96 cycles of the UFD regimen. The median number of cycles administered per patient was 4 (range, 1–10 cycles). All patients discontinued this treatment: 21 experienced disease progression, two patients refused further treatment because of nausea, vomiting, and/or anorexia and one patient experienced cholangitis. After abandoning the UFD treatment, seven patients received second-line treatment: four patients had systemic chemotherapy with gemcitabine, S-1, UFT or doxorubicin; two patients had radiotherapy; and one patient moved to another hospital to receive immunotherapy. The remaining 16 patients received only the best supportive care after the UFD treatment. The tumor response, toxicity and survival were evaluated on an intention-to-treat basis.
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TUMOR RESPONSE
Partial response was achieved in 3 of the 24 patients (2 with intrahepatic cholangiocarcinoma and 1 with gallbladder cancer), but no complete response was observed. Overall response rate was, thus, 12.5% (95% CI 2.7–32.4%). Stable disease was noted in 13 patients (54.2%) and progressive disease (PD) was noted in 7 patients (29.2%). The remaining patient who refused the treatment was not evaluated.
TOXICITY
Toxicities of all 24 patients are shown in Table 2. During treatment, the most common toxicities were nausea and leukopenia, observed in 15 of the 24 patients (62.5%). Other major symptoms were neutropenia, fatigue and anorexia. Grade 3 toxicity was observed in 5 of the 24 patients (20.8%), with anorexia, fatigue, neutropenia and/or anemia. No grade 4 toxicity was observed in any of the 24 patients. There were no treatment-related deaths during the study.
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SURVIVAL
Disease progression was finally observed in 23 of the 24 patients, and 18 of the 24 patients died of disease progression. The median progression-free survival was 2.5 months (Fig. 1). The median overall survival time was 7.6 months and the 1-year survival rate was 19.7% (Fig. 2). Figure 3 shows survival curves for patients with intrahepatic or extrahepatic cholangiocarcinoma and for patients with gallbladder carcinoma. The median survival time of the gallbladder carcinoma group was 5.0 months, and that of the intrahepatic and extrahepatic cholangiocarcinoma group was 11.0 months. There was a statistically significant difference in the survival curves between the two groups (P = 0.0034).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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No standard chemotherapy for unresectable advanced biliary tract cancer has been established yet. In Japan, only three anticancer agents—UFT, doxorubicin and cytarabine—have been approved for biliary tract cancer by the Ministry of Health, Labor, and Welfare of Japan. Cytarabine is not actually being applied in patients with biliary tract cancer now. Therefore, the practice of systemic chemotherapy in Japan is limited to regimens using UFT and/or doxorubicin. This study was conducted to confirm the efficacy and safety of the combination chemotherapy of UFT and doxorubicin, and the expected response rate was set as 15%. In this study, we achieved a 12.5% response rate, with an additional 54.2% of patients achieving stable disease. The UFD regimen could stabilize biliary tract cancer in 66.7% of the patients treated. Regimens of UFT alone or UFT plus leucovorin were reported to have objective responses of 5 and 0%, respectively, and more than 60% patients were evaluated as having progressive disease in these regimen (15–17). The UFD regimen is considered to have more activity for biliary tract cancer compared with regimens with UFT alone.
With regard to toxicity, the UFD regimen was generally well tolerated. Nausea, fatigue, leukopenia, neutropenia and anorexia were commonly observed but were managed without discontinuing the protocol in most patients. Grade 3 toxicity was observed in 20.8% of patients with anorexia, fatigue, neutropenia, and/or anemia, and no grade 4 toxicity was observed. Considering its safety and convenience, we can use this regimen in outpatient care with only minor toxicity.
In this study, the median overall survival of the UFD regimen was 7.6 months, which was better than 5.2 or 6.5 months of UFT plus leucovorin (15,16). However, the median survival in a study of UFT alone was 8.8 months (17). Recently, gemcitabine has shown promise as a new agent in the treatment of biliary tract cancers. In recent phase II trials, the single agent gemcitabine had an objective response of over 20% (19,20). Moreover, gemcitabine-based combination regimens are reported to have generally higher response rates (21–25). On the other hand, median survivals were also varied in those regimens, from 7.5 to 15.4 months.
Some possible reasons may explain the discrepancy between the response rate and survival in various chemotherapy regimens. Every trial, including the current study, has consisted of a small number of patients, which may be the major cause of the discrepancy. Another reason may be the heterogenicity of biliary tract cancer. The survival can be affected by various factors such as performance status and site of the disease. Chemotherapy favored longer survival in patients with a performance status of 0 or 1, but not in patients with a performance status of 2 (12). Regarding the site of the disease, the median survival in patients with gallbladder cancer was statistically significantly shorter than that in patients with intrahepatic or extrahepatic cholangiocarcinoma in this study. This tendency was seen in another trial of gemcitabine and capecitabine, and it probably reflects the more aggressive biology of gallbladder cancer (24). However, it is not practical to conduct clinical trials separately for gallbladder cancer and cholangiocarcinoma, because each site of these biliary tract cancers is relative rare. In patients with biliary tract cancer, the survival benefit of chemotherapy should be evaluated in randomized studies, including biliary tumor type and performance status in the stratification strategy.
Clinical trials of combination regimen using new anticancer agents, such as gemcitabine, capecitabine and oxaliplatin, have recently been conducted in Western countries (19–24). Whereas clinical trials of a single agent, gemcitabine or S-1, organized by pharmaceutical companies have been conducted in Japan (25,26). This difference between Japan and Western countries is attributable to the system of organizing clinical trials, and in Japan it is almost impossible to conduct clinical trials of new agents not approved by the Ministry of Health, Labor, and Welfare. Biliary tract cancer is rare in Western countries, and large global studies that include Japan should be conducted to establish a standard chemotherapy for biliary tract cancer. A system to conduct or join global clinical trials needs to be established in Japan.
In conclusion, combination chemotherapy with UFT and doxorubicin (the UFD regimen) was well tolerated and showed preliminary moderate activity against advanced biliary tract cancer. Further investigation in late phase II studies in a larger number of patients is recommended, and a multicenter late phase II study is currently ongoing in a Japanese chemotherapy study group for biliary tract and pancreatic cancers.
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Acknowledgments |
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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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