© 2004 Foundation for Promotion of Cancer Research
Gemcitabine and Cisplatin Combination Chemotherapy in Intrahepatic Cholangiocarcinoma as Second-line Treatment: Report of Four Cases
Division of Oncology, Department of Internal Medicine, Catholic University of Medical College, Seoul, Korea
For reprints and all correspondence: Kyung Shik Lee, Department of Internal Medicine, St Kangnam Mary's Hospital, Banpo-dong 505, Seocho-gu, 137-040, Seoul, Korea. E-mail: angelamd{at}catholic.ac.kr
Received April 1, 2004; accepted June 1, 2004
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Abstract |
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Background: Intrahepatic cholangiocarcinoma is a chemoresistant cancer for which effective chemotherapy is not yet available. We investigated the efficacy and toxicity of the combination of gemcitabine and cisplatin as second-line chemotherapy in four patients with advanced, progressive intrahepatic cholangiocarcinoma.
Methods: Four patients were enrolled who had previous chemotherapy with epirubicin, cisplatin and protracted infusion of 5-FU. All these patients treated with gemcitabine 1000 mg/m2 intravenously (i.v.) on days 1 and 8 for 30 min, cisplatin 75 mg/m2 i.v. on day 1 for 90 min, given every 21 days.
Results: Two patients had partial response (PR), and two had stable disease (SD), with one of the latter showing a decrease in tumor size of 35%. Median time to progression was 5 months (range, 3–9 months) and median survival was 9 months (range, 8–16 months). Toxicity was mild and tolerable.
Conclusions: Gemcitabine and cisplatin combination chemotherapy may be an effective regimen for advanced intrahepatic cholangiocarcinoma. Further study is warranted to determine the efficacy of this combination regimen.
Key Words: refractory cholangiocarcinoma • gemcitabine • cisplatin
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INTRODUCTION |
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Intrahepatic cholangiocarcinoma is a primary adenocarcinoma of the liver that arises from the intrahepatic duct. These tumors constitute about 5–20% of primary liver cancers and are thus the second most common cancer (1,2) The prognosis is generally poor because most patients present with advanced disease. Conventional surgery including hepatic resection is considered the most effective treatment, but many cases are inoperable at the time of diagnosis.
There is no effective chemotherapy for the majority of patients with advanced stage intrahepatic cholangiocarcinoma. The most commonly used chemotherapeutic agent is 5-fluorouracil (5-FU). There have been several small trials of combination regimens, including 5-FU, cisplatin, mitomycin and/or leucovorin, which have been reported to have response rates varying from 20 to 30% (3–5).
Gemcitabine is an active drug for lung, breast and pancreatic cancers and several recent reports have suggested that this drug also has efficacy in the treatment of biliary cancer (6–8). Cisplatin may also have some efficacy in biliary cancer and it may act synergistically with gemcitabine, as described previously (9). The combination of gemcitabine and cisplatin has been used in the treatment of lung and bladder cancer (10,11).
In this retrospective case report, we describe the use of gemcitabine and cisplatin in the treatment of four patients with advanced intrahepatic cholangiocarcinoma, who had progressive disease after epirubicin, cisplatin and protracted infusion of 5-FU (ECF) combination chemotherapy.
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PATIENTS AND METHODS |
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PATIENTS
Four patients with advanced or metastatic intrahepatic cholangiocarcinoma were treated with gemcitabine and cisplatin combination chemotherapy between May 2002 and February 2003. All patients had adenocarcinoma of the intrahepatic bile duct confirmed by histology or cytology for primary hepatic mass, without elevating
-fetoprotein (AFP). All four patients had documented progressive disease after previous chemotherapy at the time of accrual. Prior to treatment, all four patients had adequate organ function as follows: (1) adequate bone marrow reserve (WBC count >4000/µl, platelet count >100 000/µl); (2) normal cardiac function; (3) normal renal function (serum creatinine <1.5 times the upper normal limit); (4) adequate hepatic function [aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 times the upper normal limit and total bilirubin <1.5 times the upper normal limit]. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status of 
3 and an estimated life expectancy of at least 12 weeks. Patients with extrahepatic cholangiocarcinoma, gall bladder cancer and ampulla of Vater caner were not included. All patients and/or their legal representatives signed informed consent forms.
TREATMENT SCHEDULE
All patients received chemotherapy as the following schedule: gemcitabine 1000 mg/m2 intravenous (i.v.) on day 1 and day 8 for 30 min, cisplatin 75 mg/m2 i.v. on day 1 for 90 min, given every 21 days. Patients received gemcitabine on day 8 at an outpatient unit. Appropriate i.v. hydration was given along with the cisplatin.
The dose of gemcitabine was adjusted on day 8 based on WBC, platelet count and liver function test. If the absolute neutrophil count (ANC) was <1000/µl or the platelet count was <75 000/µl on day 8, the dose of gemcitabine was reduced by 20%. If ANC was <500/µl or the platelet count was <50 000/µl, gemcitabine was omitted. If the serum bilirubin level was 2.0–3.0 mg/dl and AST/ALT was <5 times the upper normal limit, the dose of gemcitabine was reduced by 20%. If the serum bilirubin level was >3.0 mg/dl or AST/ALT was >5 times the upper normal limit, gemcitabine was also omitted. If ANC was <1500/µl or the platelet count was <75 000/µl at the start of a new cycle, treatment was delayed for recovery without dose reduction. The cisplatin dose was modified based on the serum creatinine level. If serum creatinine was 1.5–2.0 mg/dl, the cisplatin dose was reduced by 50% and if serum creatinine was >2.0 mg/dl, cisplatin was omitted. If grade 3/4 hematological toxicity developed following dose reduction, treatment was stopped.
ASSESSMENT OF RESPONSE AND TOXICITY
In addition to physical examination, peripheral blood count and blood chemistry, we assessed performance status and performed a chest X-ray at each patient visit. Baseline computed tomography (CT) scans were performed and repeated after two treatment cycles. Response to treatment was assessed according to World Health Organization (WHO) criteria. Before each cycle, patients were assessed for toxicity according to National Cancer Institute Common Toxicity Criteria (NCI-CTC).
STATISTICS
Time to progression (TTP) was defined from the first day of chemotherapy to the day of confirmed progression. Overall survival (OS) was calculated from the first day of chemotherapy with gemcitabine and cisplatin to death or last follow-up.
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RESULTS |
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CLINICAL CHARACTERISTICS
Demographic features and clinical characteristics of the patients are summarized in Table 1. Two patients were stage IIIC and other two patients were stage IV according to the AJCC cancer staging system (5th edn, 2002). Case 1 patient had recurrent cancer since undergoing surgery, followed by adjuvant 5-FU chemoradiation 3 years previously. All patients had received systemic chemotherapy with epirubicin, cisplatin and protracted infusion of 5-FU.
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TREATMENT RESPONSE AND TOXICITY PROFILE
All patients were evaluable for response. The total number of cycles was 19. Of the four patients, two had partial response (PR) and the other two had stable disease (SD). In one of the two patients with SD, tumor size decreased 35%, not reaching the criteria for PR. Time to progression and survival data are shown in Table 2. Median TTP and survival were 5 and 9 months, respectively. Clinical improvement was observed, such as appetite, pain and performance status (from ECOG 3 to ECOG 2), even in case 2 patient who had SD.
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Toxicity was mild and easily manageable. Grade 3 neutropenia was observed for two episodes in one patient, who recovered without support of growth factor. Grade 3 thrombocytopenia was more common than neutropenia, but there was no bleeding event during the treatment cycle. There was no grade 4 hematological toxicity. Non-hematological toxicity was mild and well tolerable. Only one episode of grade 3 vomiting was noticed. There was no treatment delay or hospitalization due to toxicity of chemotherapy (Table 3).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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No effective standard therapy is yet available for advanced biliary tract cancer. Recently, several phase II clinical trials with gemcitabine as a single therapy have been conducted in advanced biliary cancer. In a trial in 24 patients with advanced biliary tract cancer, gemcitabine showed a 16% response rate with a median survival of 6.5 months (3). In another trial, a 22% response rate was observed in 32 patients with biliary tract cancer treated with gemcitabine single (2200 mg/m2, D1, 15) (7). In a trial with 23 patients with cholangiocarcinoma, i.v. infusion of gemcitabine for 30 min weekly for 3 weeks, followed by 1 week of rest, resulted in a response rate of 30%, along with mild toxicity (8).
Cisplatin is known to act synergistically with gemcitabine and combination chemotherapy with these two drugs has proved effective in the treatment of metastatic lung cancer and bladder cancer, with response rates of 33–49% (10,11) This combination was also shown to be highly effective in 11 advanced gallbladder cancer cases (12). Recently, some clinical trials with a combination of gemcitabine and cisplatin for biliary cancer, including gallbladder cancer, were reported (13,14). In these trials, the overall response rates were 33% and 57%, although all the patients had no previous chemotherapy. We therefore tested the efficacy and toxicity of gemcitabine and cisplatin combination chemotherapy in advanced intrahepatic cholangiocarcinoma as second-line treatment. Clinical trials of this combination for cholangiocarcinoma have not been conducted because of the low incidence of these tumors, in addition to the advanced age and poor performance status of patients with these tumors (15). In our study, all four patients were in their fifties and had a performance status of ECOG 2 or 3 and all four had progressive disease after previous chemotherapy. Although this trial was limited, our results were very promising. Two patients showed PR and one patient showed a minor response.
Gemcitabine displays minimal toxicity even in elderly patients as a single agent (16) and 75 mg/m2 of cisplatin has acceptable toxicity. The toxicity of this regimen was very mild and all patients tolerated it well during all cycles of chemotherapy in our study. No patient experienced severe anorexia, nausea or vomiting. No grade IV toxicity developed. Hospital days for day 1 chemotherapy were 3 days because of pre-and post-hydration for cisplatin, but chemotherapy on day 8 was administered at the outpatient department.
Newer chemotherapeutic agents, including oxaliplatin, carboplatin, irinotecan and docetaxel, are being investigated in the treatment of cholangiocarcinoma, but substantial improvements in response and survival rate have not yet been reported (17,18).
In conclusion, combination chemotherapy with gemcitabine and cisplatin seems to be a very promising regimen with tolerable toxicity in intrahepatic cholangiocarcinoma. This result was assessed from retrospective case reports as second-line treatment. Based on our results, phase II clinical trials of combination chemotherapy with gemcitabine and cisplatin in different dose as first-line treatment are ongoing.
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References |
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