© 2005 European Society for Medical Oncology
Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma
Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
* Correspondence to: Dr S. Thongprasert, Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chiang Mai University, 110 Intawaroros Road, Chiang Mai 50200, Thailand. Tel: +66-53-945477; Fax: +66-53-215600; Email: sthongpr{at}mail.med.cmu.ac.th
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Abstract |
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Objectives: The prognosis for patients with unresectable biliary tract cancer is poor and existing chemotherapy is relatively ineffective. Therefore, a need exists for new, effective chemotherapeutic regimens. The aim of this study was to determine the efficacy and safety profile of gemcitabine plus cisplatin in patients with unresectable biliary tract cancer (cholangiocarcinoma) and gall bladder cancer.
Methods: From December 2000 to July 2002, 43 patients received gemcitabine 1250 mg/m2 in a 30-min i.v. infusion on d1, 8 and cisplatin 75 mg/m2 in a 2-h i.v. infusion on d1 (with appropriate hydration), every 3 weeks.
Eligibility: Normal hematologic parameters and creatinine levels; serum bilirubin <5 mg/dl.
Results: Forty-three patients enrolled; 40 were assessable (three patients were not assessable due to incomplete treatment; they chose to discontinue chemotherapy after the first cycle). There were 23 males and 17 females, median age 50 years (range 31–69), median Karnofsky PS 80%. Tumor types: cholangiocarcinoma (39), gall bladder cancer (1). Median number of chemotherapy courses was four (range 1–8). Overall response rate was 27.5% (PR in 11 pts), with 32.5% SD and/or minor response. Median survival time was 36 weeks. Grade 3 hematologic toxicity: anemia (4.33%), leukopenia (1.73%). Non-hematologic toxicity (i.e. rash, nausea, vomiting, neuropathy and myalgia) ranged from mild to moderate.
Conclusions: Gemcitabine plus cisplatin is active in biliary tract carcinoma. These data warrant further investigation of single-agent gemcitabine versus gemcitabine plus cisplatin or its derivative, i.e. oxaliplatin.
Key words: biliary tract carcinoma, cisplatin, gemcitabine
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Advanced cholangiocarcinomas and gall bladder cancers are incurable, and both types of cancer share a common pathology and behavior. There is no standard chemotherapy or chemotherapeutic regimen for these diseases. In most studies, fluorouracil (5-FU) alone or 5-FU-based regimens have consistently yielded response rates of less than 10–30% [1
–5]. Recently, new drugs, i.e. gemcitabine, have shown promise as a new agent in the treatment of biliary tract cancer. In a phase II trial, 18 patients treated with single-agent gemcitabine had 22% objective response [6]. Studies incorporating gemcitabine plus cisplatin were recently reported in the treatment of biliary tract tumors and gall balder cancer. A study conducted in India enrolled 30 patients with gall bladder carcinoma [7]. Among 17 assessable patients, one complete response and eight partial responses were seen. The second trial, from Argentina [8], reported three complete responses (CRs) and two partial responses (PRs) in 11 patients with either gall bladder or cholangiocarcinoma. In Thailand, we have a high incidence of cholangiocarcinoma and we primarily explored the response to gemcitabine plus cisplatin in cholangiocarcinoma/bile duct tumors, and gall bladder adenocarcinomas. Our secondary objective was to determine the time to disease progression, overall survival and toxicity.
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Patients and methods |
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Study inclusion criteria
Patients were required to have histologic or cytologic proof of locally advanced or metastatic cholangiocarcinoma or gall bladder carcinoma. Eligibility also called for bidimensionally measurable disease by computed tomography or ultrasound; at least 18 years of age; and a Karnofsky performance status of 60% or higher. Patients had to have adequate organ function with an absolute neutrophil count (ANC) of at least 1500/µl, and platelet count of at least 100 000/µl. For those with a cholangiocarcinoma primary tumor, total bilirubin of 5.0 mg/dl or less, alanine aminotransferase and/or aspartate aminotransferase of no more than 2.5 above normal, albumin levels of at least 2.5 mg/dl, and creatinine levels of 1.5 mg/dl or less were necessary. Patients with prior chemotherapy for metastatic disease were ineligible for enrollment in this study.
Schema of study
Patients who met the eligibility criteria were given gemcitabine at 1250 mg/m2/day by 30-min intravenous infusion on days 1 and 8, and cisplatin at 75 mg/m2/day by 2-h intravenous infusion on day 1, repeated every 21 days. Physical examination and symptom assessment were made every 3 weeks and computed tomography scans were carried out at 12 weeks. The patients were treated until the appearance of disease progression or unacceptable toxicity. If the disease responded, treatment might continue for two more cycles. If the disease was stable or progressed at 12 weeks, treatment was discontinued and the patients were kept on follow up.
Dose modification for gemcitabine
The dose of gemcitabine was reduced to 1000 mg/m2 in subsequent cycles in the case of an ANC nadir of <500/mm3 for >7 days, a platelet nadir of <50 000/mm3 for >7 days, any grade of thrombocytopenia associated with bleeding, or febrile neutropenia. Once a dose reduction for subsequent cycles was required, re-escalation of dose was not allowed. Also no second dose reduction was allowed. If the above toxic effects recurred at a reduced dose level, study treatment had to be discontinued and the patient was taken off the study.
The day 8 dose of gemcitabine was reduced to 1000 mg/m2 in the case of an ANC of 
1000–1500/mm3, and platelets of 50 000–100 000/mm3. In the case of ANC or platelet counts lower than the above, the day 8 dose of gemcitabine was omitted. Day 8 dose reductions or omissions of gemcitabine did not affect dosing in the subsequent cycles and could be carried out in as many treatment cycles as required. The subsequent chemotherapy cycle was given on time if the ANC was >1500/mm3 and platelets >100 000/mm3. If lower, chemotherapy was postponed for a minimum of 1 week. If counts did not reach the above values after 2 weeks, chemotherapy was discontinued.
Evaluation criteria
All patients were assessable for toxicity from the time of the first chemotherapy dose. All patients who underwent two or more treatment cycles were assessable for a response. Standard tumor measurements were used, in keeping with the following definitions: CR was defined as a complete disappearance of the tumor for at least 4 weeks after time documentation; PR was defined as more than a 50% decrease in the sum of the products of the two largest perpendicular diameters of all measurable lesions, as determined 4 weeks apart, consecutively; stable disease (SD) was defined as not only no CR or PR, but also no objective progression; progressive disease (PD) was defined as a 25% or greater increase in the size of any measurable lesion or the appearance of new lesions or ascites.
Time to progression was calculated from the first treatment day to the identification date of progressive disease or death. Duration of response was measured from the date of response notation to the first record of disease progression or death, and survival was measured from the first day of treatment to death.
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Results |
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After the protocol was reviewed and approved by the institutional ethical committees, the study started to accrue patients (Table 1). All patients were informed about the nature of the study and gave consent. Of 43 patients who entered the study, three were non-assessable, these three refused chemotherapy after receiving the first dose, they did not come back for follow-up. Of 40 assessable cases, there were 23 males and 17 females. Their median age was 50 years (range 31–69 years), and median Karnofsky performance status 80% (range 60–90%). Thirty-nine cases were of cholangiocarcinoma and one case was of gall bladder carcinoma. Eleven cases (27.5%) achieved PR, 13 stable disease (32.5%), and 16 cases did not respond to chemotherapy (progression of disease 40%). Time to progression was 20.6 weeks (range 1–82 weeks), median survival time was 36.0 weeks (range 3.44–95.0 weeks). Toxicity was mild to moderate (Table 2), ototoxicity was observed in three cases, mild to moderate nausea and vomiting were seen in all cases despite prophylactic antiemetics. Anemia grade 3 was seen in 4.33%, neutropenia grade 3 in 1.73% and thrombocytopenia grade 3 in 2.38% of cases.
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Cancer of the biliary tree occurs frequently in the northeastern part of Thailand and has been increasing in the north with a poor overall prognosis. As a result of the relative infrequency of biliary tract malignancies worldwide, only a limited number of clinical trials have been published that describe chemotherapy regimens for advanced disease. However, drug activity in these cancers appears to be similar to that in adenocarcinoma of the pancreas and gall bladder cancer. Historically, 5-FU has been the most active single agent, although response rates are only in the order of 10–15% [1
]. Other agents that have been reported as active in biliary tract cancer are mitomycin, doxorubicin and nitrosoureas, although the numbers of patients are too small to reliably assess the rate of response. Reports of combination chemotherapy regimens are likewise hampered by small numbers. The FAM (5-FU, adriamycin and mitomycin) regimen [2], as designed for gastric cancer, produced responses in four of 13 patients, whereas the combination of the 5-FU prodrug tegafur (Ftorafur), doxorubicin and carmustine (BCNU) produced responses in three of seven patients. The combination of 5-FU and leucovorin resulted in objective responses in nine of 28 patients (32%) [3]. The regimen was generally well tolerated, but it needs further study. Another study combining a continuous infusion of 5-FU with cisplatin produced six partial remissions out of 24 patients, one of whom was still alive 6 years after the initiation of therapy [4]. Glimelius et al. reported the improvement in survival and quality of life in advanced pancreatic and biliary cancer treated with 5-fluorouracil/leucovorin and etoposide [5]. Recently, gemcitabine has shown promise as a new agent in the treatment of biliary tract cancers [6–11]. In a recent phase II trial, 18 patients treated with gemcitabine had an objective response of 22% [6]. A study of gemcitabine plus cisplatin in unresectable gall bladder cancer was reported at the ASCO meeting 2001 with a response rate of 53% [7]. Gemcitabine plus oxaliplatin [12, 13] in advanced pancreatic and/or biliary adenocarcinoma was recently reported. Of note, single-agent gemcitabine versus gemcitabine plus cisplatin in pancreatic cancer resulted in increased response rate and prolongation of survivals; however, there was no significant different in survival [14]. The role of gemcitabine plus cisplatin as demonstrated in this study and in other phase II studies needs to be clarified. We plan to conduct a phase II/III randomized study of gemcitabine plus cisplatin versus single-agent gemcitabine or versus gemcitabine plus oxaliplatin in order to find the best regimen for biliary tract cancer.
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Acknowledgements |
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This study was supported in part by Eli Lilly Co., Thailand.
Received for publication March 15, 2004. Revision received August 4, 2004. Accepted for publication September 15, 2004.
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References |
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