Japanese Journal of Clinical Oncology 33:353-356 (2003)
© 2003 Foundation for Promotion of Cancer Research
A Phase II Trial of Tegafur-Uracil Plus Leucovorin (LV) in the Treatment of Advanced Biliary Tract Carcinomas
1 Division of Hematology-Oncology, Department of Internal Medicine and 2 Department of Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: To evaluate the efficacy and safety profile of oral tegafur-uracil (tegafur combined with uracil in a molar of 1:4 ratio) plus leucovorin (LV) in patients with advanced biliary tract carcinoma (BTC).
Methods: Sixteen chemotherapy-naïve patients (nine males and seven females with a median age of 58.0 years) with BTC were prospectively enrolled in this study. The dose of tegafur-uracil (UFUR; TTY Biopharm Co. Ltd, Taipei, Taiwan) was 300 mg/m2/d (according to the dose of tegafur) and LV was 60 mg/day on day 1–28, followed by a 1-week break. The site of primary tumor included 10 intrahepatic cholangiocarcinomas (CC), one perihilar CC, four gallbladder cancers and one periampullar cancer. Fourteen patients were evaluated for tumor response.
Results: No objective complete or partial responses were observed. Two patients had stable disease and 12 patients had disease progression. The median time to progression was 68 days (8–159 days) and the median survival time was 155 days (69–570 days). Sixteen patients were evaluable for toxicity. Grade III/IV toxicities were found in two patients only; one patient had grade III thrombocytopenia and one patient stopped therapy early due to grade IV diarrhea.
Conclusions: Oral tegafur-uracil plus LV is well tolerated but ineffective in patients with advanced BTC.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Advanced, surgically unresectable biliary tract carcinoma (BTC) is incurable. The results of treatment of advanced BTC to date have been discouraging, possibly due to its rarity. 5-fluorouracil (5-FU) is the most common and extensively studied single agent used for systemic application in BTC (1,2). At present, there have been only few reports on chemotherapy for advanced BTC. Most of the single-agent data have been obtained with bolus or infusion of 5-FU, while other single-agent data are primarily anecdotal. Treatment trials using 5-FU either as a single agent or in combination chemotherapy for BTC have shown limited impact on survival and response (3–6). The 5-FU-based regimen is still the mainstay for patients with advanced BTC in present clinical practice.
Tegafur-uracil (tegafur combined with uracil in a molar of 1:4 ratio) represents a second-generation oral 5-FU prodrug that is converted to 5-FU in tissue. It has been reported to be less toxic and have a higher therapeutic index (7). Uracil prevents degradation of 5-FU by inhibiting dipyrimidine dehydrogenase (DPD) that leads to an increased level of 5-FU in the plasma and tumor tissues (8). It appears that prolonged tegafur-uracil administration results in a similar or higher Cmax (maximum concentration achieved) as well as AUC (area under the curve) compared with that achieved with continuous infusion of 5-FU, although their pharmacokinetic patterns are different (9). Tegafur-uracil has been widely studied in Japan and its anti-tumor activity has been demonstrated in a variety of gastrointestinal cancers including colorectal cancer (10) and gastric cancer (11). This drug has been approved in Taiwan for use in metastatic colorectal, gastric and breast cancer since 2000. Previous studies have demonstrated that the effect of 5-FU can be modulated by leucovorin (LV), resulting in a higher response rate in colorectal cancer (12). Oral tegafur-uracil plus LV also showed increased efficacy and an acceptable toxic profile (13). Mani et al. (14) reported in 1999 that tegafur-uracil (UFT; Bristol-Myers Squibb, Wallingford, CT) and LV had no activity for 13 Western patients with BTC but with no obvious toxicity. However, the additional advantage of tegafur-uracil is its oral administration, an important consideration in improving the quality of life in patients with cancer. Tegafur-uracil and LV are common, conventional regimens in general practice in Taiwan and Far Eastern countries, but there have been no well-designed phase II studies for Oriental patients with BTC to date. Therefore, we conducted this study to examine whether oral tegafur-uracil and LV is effective and tolerable in Chinese patients with advanced BTC.
The purpose of this phase II study was to evaluate response rate, time to progression, overall survival, and toxicity of oral tegafur-uracil plus LV as the first-line treatment in patients with advanced BTC.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility Criteria
Eligibility criteria included histologically confirmed unresectable or metastatic carcinoma of biliary tract or periampular Vater area; at least 18 years old; ECOG performance status score of 0–2; and having at least one measurable site of disease. Patients could not have received prior chemotherapy, but prior local radiotherapy to non-target lesions was allowed (at least 4 weeks later after radiotherapy). Patients must have white blood count
4000 cells/µl, platelet count 100 000/µl, serum bilirubin level <3.0 mg/dl (bil. 
5 if patient has a good biliary drainage), serum creatinine level <1.5mg/dl. This protocol was reviewed and approved by the internal review board at our institution. Written informed consent was obtained from all patients prior to study entry.
Treatment Schedule
The dose of tegafur-uracil (UFUR; TTY Biopharm Co. Ltd, Taipei, Taiwan) was 300 mg/m2/d (according to the dose of tegafur) on day 1–28, followed by a 1-week break. The calculated tegafur-uracil dose was rounded to the nearest 100 mg. The total daily dose was divided into three doses administered orally or by feeding tube every 8 hours (at approximately 7 am, 3 pm and 11 pm). If the capsule dose could not be divided equally, the highest dose was administered in the morning and the lower dose in the evening. LV was supplied as 15 mg tablets and was administered orally at a dose of 60 mg/d. LV was administered concurrently with tegafur-uracil: the first LV dose (at 7 am) was 30 mg, and the 3 pm and 11 pm doses were 15 mg each. Patients were asked to take the medication with 120 cc to 240 cc of water and to consume no food 1 hour before and after ingestion of the medication. The course of therapy was defined as 28 consecutive days of treatment. The patients were scheduled to undergo follow up examinations at the clinic on day 1 and day 15 of the four-week treatment course.
Response Evaluation
Response was evaluated based on the World Health Organization (WHO) criteria: a complete response (CR) was defined as complete disappearance of all assessable disease; a partial response (PR) was defined as a decrease of at least 50% in the sum of the products of the longest tumor dimension and its greatest perpendicular diameter and no increase in the size of any other known disease; stable disease (SD) was defined as decrease of <50% or an increase of <25% in tumor size; progressive disease (PD) was defined as a >25% increase in the sum of the products of the two diameters of at least one tumor, or as the presence of a newly developed lesion. All objective responses had to be confirmed by a second evaluation 4 weeks later. Response indicators were measured after every two courses of treatment, or earlier in the case of clinical suspicion of progression. Pre-therapeutic contrast computed tomography (CT scan) to document measurable disease should be obtained within 4 weeks before the treatment initiation. Complete blood count, differential count and chemistries should be done within 2 weeks before treatment. Complete blood count and differential count were checked before each course and on day 15 during the course. Blood biochemistry was checked before the beginning of each course. Treatment was discontinued in cases of disease progression, patient refusal or unacceptable toxicity.
Toxicity Evaluation
Toxicity was assessed and reported following the WHO toxicity grade. Duration, maximum intensity, seriousness and relationship of toxicity to medication was judged by the investigator, and considered along with all interventions when each adverse event was recorded.
Statistical Analysis
A standard Gehan two-stage design was employed in this protocol (15). If no CR or PR was noted in the first cohort of 14 patients, a response rate of > 20% could be excluded with 95% confidence and accrual would stop. If at least one CR or PR was observed, 30 or more patients were to be entered in the study to determine the response rate more accurately. The time to disease progression was calculated from the day of the first time of chemotherapy to the day of first documented evidence suggestive of disease progression or start of additional anticancer therapy. Survival time was calculated from the start of the therapy to death and was established by the Kaplan–Meier method.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Sixteen patients were enrolled in this study between October 2000 and April 2002. There were nine males and seven females with a median age of 58.0 years (range: 26–77). Their clinical data are summarized in Table 1. A total of 27.65 courses of treatment were administered with a median of 2 (range 0.29 to 4) to 16 patients. Three patients did not finish the first course of treatment: two patients had rapid disease progression, and one patient therapy was stopped due to grade IV diarrhea.
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Two patients were not evaluated for response. One patient received laparotomy for acute appendicitis after completion of first course of treatment. No signs of disease progression or side effects of chemotherapy were noted during the operation and post-operative course. One patient was withdrawn from the study due to grade IV diarrhea in the first course of treatment. Fourteen patients were evaluated for tumor response. No objective complete or partial responses were observed. Two patients had stable disease and 12 patients had disease progression. Therefore, this study was terminated early according to our protocol design that specified termination in the absence of any responders in the first cohort of 14 patients. At of the end of February 2003, 14 of the study patients had died and two were still alive. The median time to progression and median survival were 68 days (8–159 days) and 155 days (69–570 days), respectively. The Kaplan–Meier survival curve is provided in Fig. 1.
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Sixteen patients were evaluable for toxicity and their toxicity grades are listed in Table 2. Only one patient stopped therapy early in the first course of therapy because of severe diarrhea. Hematologic toxicity was uncommon: no infection episodes were found during the therapy, no patients with neutropenia, three patients with mild hemoglobulin change during the therapy, and development of grade III thrombocytopenia in one patient. No grade III/IV toxicity as indicated by anorexia, nausea, vomiting, and fatigue was noted. No renal or liver function impairment was noted in the 16 patients. There was no treatment-related death.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Oral tegafur-uracil plus LV demonstrated no effects against BTC. In this study, several patients even had a rapidly progressive disease course and died within 2 months, although they had quite good performance status at the beginning of the treatment. This finding reflects the ineffectiveness of oral tegafur-uracil plus LV as well as the aggressive behavior of the disease itself. The side effects of tegafur-uracil plus LV for BTC were minimal except for two patients with severe adverse events. Our results are thus very similar to those of Mani et al. (14), who found that tegafur-uracil and LV had no beneficial effect for 13 patients with BTC. They found no hematological toxicity and neither did we in this study. The major grade III/IV toxicities of diarrhea, nausea, and vomiting in their study were less than 15%. They also reported that nine patients had experienced rapid disease progression. The median time to progression and median survival time were only 9 and 28 weeks, respectively.
It was reported that tegafur-uracil plus LV can provide a safer and more convenient oral alternative to a standard bolus 5-FU/LV in patents with metastatic colorectal cancer (16). However, the oral tegafur-uracil plus LV seem to have no efficacy equivalent to 5-FU/LV in patients with BTC. In contrast to oral tegafur-uracil plus LV, various parenteral schedules of 5-FU/LV or combination with other agents have proven to be effective in BTC. In our previous two studies using 24-hour infusion of high-dose 5-FU/LV alone (6) and with mitomycin (17), response rates were shown to be 33% and 26%, respectively. The time to progression and median survival time in the both studies were better than in the present series. A recent study by Taieb et al. (18) using biweekly 48-hour infusion of high dose 5-FU and LV (LV5-FU2-P regimen) showed a 34% response rate among 29 patients. Their median survival time was 9.5 months, nearly twice those in this study and Mani’s series. In our previous two studies and Taieb’s LV5-FU2-P regimen, fewer than 10% of the patients experienced grade III/IV toxicity after receiving 24-hour or 48-hour infusion of high-dose 5-FU/LV. Ellis et al. (19) reported that 40% of their patients responded to 5-FU 200 mg/m2/d given as a protracted infusion of low dose 5-FU with bolus cisplatin (CDDP) and epirubicin, with only minimal hematological and non-hematological toxicities. The conventional 5-day infusion of 5-FU 1.0 gm/m2 with cisplatin for BTC had a 24% response rate, but severe grade III/IV myelotoxicity was noted (4). The 4-day bolus of 5-FU/LV and carboplatin also showed a 21.4% response rate and moderate myelosuppression. The conventional infusion or bolus 5-FU/LV still has at least 20% activities for BTC with a higher percentage of myelotoxicity as compared with 24-h or 48-h infusion of high-dose 5-FU/LV and protracted infusion of low dose 5-FU. Nevertheless, infusion of 5-FU with variable schedules or combinations is still the mainstay of chemotherapy for patients with BTC despite different side effects (2,3).
In conclusion, oral tegafur-uracil plus LV for BTC is not effective, and no further investigation is warranted. Improvements in chemotherapy for BTC are needed which should include new cytotoxic agents and infusion of 5-FU-based regimens.
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FOOTNOTES |
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+ For reprints and all correspondence: Jen-Shi Chen, Division of Hematology-Oncology, Departments of Internal Medicine, Chang Gung Memorial Hospital, 199 Tung Hwa North Road, Taipei 105, Taiwan. E-mail: fong0301{at}ms18.hinet.net
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Received June 27, 2003; accepted July 1, 2003
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