Abstract
Purpose
Intrahepatic cholangiocarcinoma usually presents late in the clinical course and has a poor prognosis. No effective systemic therapy is currently available. This study aimed to determine the efficacy and toxicity of the ECF regimen (epirubicin, cisplatin. and 24-h continuous infusion of 5-FU) in advanced intrahepatic cholangiocarcinoma.
Patients and method
On day 1, epirubicin 50 mg/m2 and cisplatin 60 mg/m2 were administered i.v., repeated every 21 days. 5-FU (200 mg/m2/day was given continuous i.v. via an ambulatory infusion pump throughout the treatment course. A total of 24 patients (15 men and nine women) with advanced intrahepatic cholangiocarcinoma between August 1996 and April 2002 were enrolled in this study.
Results
Of the 20 evaluable patients, two had partial response (10%) and nine had stable disease (45%), including two minor response. Grade 3/4 neutropenia was observed in six patients, while grade 3/4 thrombocytopenia was seen in five patients. There was no neutropenic infection or thrombocytopenic bleeding during any of the cycles of chemotherapy.
Conclusion
ECF regimen is well-tolerated but is not an effective treatment for advanced intrahepatic cholangiocarcinoma. Newer clinical trials with combination drugs should be developed.
Keywords: Intrahepatic cholangiocarcinoma, ECF regimen
Introduction
Cholangiocarcinoma is an uncommon cancer, with an incidence of 2% of all reported cancers. It can be classified into an intrahepatic or extrahepatic tumor (proximal, middle, and distal bile duct tumor) according to location (Fong et al. 2001). Although intrahepatic cholangiocarcinoma is the second most common primary malignancy of liver, only about 10% of all cholangiocarcinomas in western countries are of the intrahepatic type. In contrast, intrahepatic cholangiocarcinoma has a higher incidence in Asian countries, accounting for 10–20% of cholangiocarcinomas in Japan (Okuda et al. 1977; Liver cancer study group of Japan 1987), and 23–29% in Korea (Seo et al. 1995; Ahn et al. 1997).
Because intrahepatic cholangiocarcinomas are usually asymptomatic in the earlier stage, most patients present with advanced disease. It may be confused with hepatocellular carcinoma (HCC) or metastatic cancer of unknown primary origin on radiologic imaging because it presents as a hepatic mass, although serum α-FP or CEA levels may be normal. Lymph node involvement and metastasis to adjacent organs are more common in intrahepatic than in extrahepatic cholangiocarcinoma (Nakajima et al. 1988). Conventional surgery including hepatic resection is considered to be the most effective treatment, but many cases are inoperable at the time of diagnosis.
Data on chemotherapy and radiotherapy in intrahepatic cholangiocarcinoma is limited. The most commonly used chemotherapeutic agent is 5-FU, but this agent has a response rate of only 10% (Davis et al. 1974; Falkson et al. 1984). A number of small trials of combination regimen, including 5-FU, cisplatin, mitomycin and/or leucovorin, have been reported with response rates varying from 20–30% (Raderer et al. 1999; Ducreux et al. 1998; Chen et al. 1998). Ellis et al. reported that the combination of epirubicin, cisplatin, and protracted infusion of 5-FU (ECF regimen), which showed good response rate in patients with advanced stomach cancer, may be effective in treating biliary tract cancer. While they reported response rates of about 40%, they included those with cancer and hepato-pancreatic cancer patients as well as those with cholangiocarcinoma.
In this study, we tried to determine the effectiveness and toxicity of an ECF regimen only in patients with advanced or metastatic intrahepatic cholangiocarcinoma.
Patients and method
Patients
Twenty-four patients with advanced or metastatic intrahepatic cholangiocarcinoma were entered into this study between August 1996 and April 2002. Inclusion criteria were as follows; (1) adenocarcinoma of the intrahepatic bile duct confirmed by histological or cytological examination; (2) performance status of 0–2 on the Eastern Cooperative Oncology Group (ECOG) scale; (3) 20–75 years of age; (4) bi-dimensionally measurable lesion, with a metastatic lesion or lymphadenopathy greater than 10 mm; (5) adequate bone marrow reserve (WBC count >4,000/μl, platelet count >100,000/ μl); (6) normal cardiac function; (7) normal renal function (serum creatinine <1.5 times the upper normal limit); (8) adequate hepatic function (AST and ALT <2.5 times the upper normal limit, and total bilirubin <1.5 times the upper normal limit; patients with obstructive jaundice should have undertaken internal or external biliary drainage before enrollment); and (9) estimated life expectancy of at least 12 weeks at the time of enrollment. Patients with recurrent disease after surgery or having history of treatment with 5-FU were also included. Patients with extrahepatic cholangiocarcinoma, gall bladder cancer, and ampulla of Vater cancer were not included in this study. All included patients and/or legal representatives signed informed consent forms.
Treatment schedule
All patients received chemotherapy according to the following schedule: epirubicin 50 mg/m2 intravenous (i.v) on day 1, cisplatin 60 mg/m2 i.v on day 1, each given every 21 days, and 5-FU 200 mg/m2/day was given a continuous i.v infusion via ambulatory infusion pump throughout the treatment course. All three chemotherapeutic agents were administered via an indwelling catheter placed in the subclavian vein. Patients changed their 5-FU infusion bags once weekly at an outpatient unit. Appropriate pre- and post-treatment i.v. hydration was given along with cisplatin.
Prior to every treatment, we recorded patient history and performed physical examination, CBC, blood chemistry, and urine analysis. If the white cell count was <2,000 μl or the platelet count was <70,000 μl, treatment with epirubicin and cisplatin was delayed for 1 week or until myelosuppression had resolved. If there were two episodes of treatment delay or an episode of neutropenic infection, we decreased the dose of epirubicin and cisplatin by 25%. If grade 3/4 hematologic toxicity developed following dose reduction, treatment was stopped. In addition, the dose of cisplatin was modified based on the serum creatinine value. That is, if serum creatinine was <1.5 mg/dl, a full dose of cisplatin was given. 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 not administered. If severe hand-foot syndrome or mucositis developed during protracted infusion of 5-FU, infusion of 5-FU was stopped and pyridoxine was administered. If these symptoms improved, infusion with 5-FU was restarted. If other grade 3/4 non-hematologic toxicities developed, treatment was delayed until symptoms were resolved and the dose reduction was not carried out.
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 CT scans were performed and repeated after two treatment cycles. Response to treatment was assessed according to WHO criteria. Complete response (CR) was defined as the disappearance of all known disease for at least 4 weeks. Partial response (PR) was defined as a greater than or equal to 50% decrease in the sum of the products of the tumor’s longest dimension and its widest perpendicular dimension for at least 4 weeks, without the appearance of new lesions or progression of any other lesion. Progressive disease (PD) was defined as a >25% increase in one or more of the measurable lesions or the appearance of new lesion. Stable disease (SD) was defined as a less than 50% decrease or less than 25% increase in the size of the measurable disease, without the appearance of new lesions. Before each cycle, patients were assessed for toxicity according to NCI criteria
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 to death or last follow-up. All data were analyzed by the Kaplan-Meier method using SPSS program (version 11.0).
Result
Clinical characteristics
A total of 24 patients (15 men and nine women) were enrolled in this study. Median age was 53 years (range, 46–75 years). All patients had stage IV intrahepatic cholangiocarcinoma (nine stage IVA and 15 stage IVB), according to AJCC cancer staging system (4th edn. 1997). Abdominal pain and jaundice (16/24 patients) were the most common initial clinical symptoms, and moderate differentiated adenocarcinoma was the most common histologic finding (Table 1). Of 24 patients, 21 (87.5%) had not been treated previously, two (8.3%) patients had been treated with 5-FU, and one (4.2%) patient had undergone surgery 3 years ago.
Table 1.
Patients’ characteristics
| No | Percent | ||
|---|---|---|---|
| Age (median) | 53 | (40–75) | |
| Sex | Male | 15 | |
| Female | 9 | ||
| Chief | Abdominal pain | 11 | 45.8 |
| Complaint | Jaundice | 5 | 20.8 |
| Indigestion | 3 | 12.5 | |
| Weight loss | 1 | 4.2 | |
| Palpable mass | 2 | 8.3 | |
| Pitting edema | 1 | 4.2 | |
| Hematochezia | 1 | 4.2 | |
| Grade | Well | 2 | 8.3 |
| Moderate | 19 | 79.2 | |
| Poorly | 3 | 12.5 | |
| T | 3 | 4 | 16.7 |
| 4 | 20 | 83.3 | |
| N | 0 | 2 | 8.3 |
| 1 | 18 | 75 | |
| 2 | 4 | 16.7 | |
| M | 0 | 9 | 37.5 |
| 1 | 15 | 62.5 | |
| Stage | IVA | 9 | 37.5 |
| IVB | 15 | 62.5 | |
| Previous | None | 21 | 87.5 |
| Therapy | Chemoradiation | 2 | 8.3 |
| Surgery | 1 | 4.2 |
Treatment response
Of the 24 patients enrolled, two patients were lost to follow-up after first cycle because they refused all anti-cancer therapy, and two patients could not be evaluated for response. The total number of cycles were 69, and the median number of cycle was three (range, 2–9). The overall response rate was 10% (Table 2). Of the 20 evaluable patients, two had PR (10%) and nine had SD (45%). In two of the nine patients with SD, tumor size decreased 31.5% and 33.3%, respectively, although this was not the criteria of PR. The clinical characteristics of patients who had responses are listed in Table 3. Median time to progression was 59 days (25–198 days) and median survival was 149 days (57–334 days) (Fig. 1).
Table 2.
Response to chemotherapy
| No (%) | |
|---|---|
| Evaluable patient | 20 |
| Response | |
| PR | 2(10) |
| SD | 9(45) |
| PD | 9(45) |
| Time to progression | 59 days |
| Survival | 149 days |
Table 3.
Clinical characteristics in responders
| No | Response | Age/Sex | Grade | Stage | Prior therapy | Cycle no | Survivala | TTPa |
|---|---|---|---|---|---|---|---|---|
| 1 | PR | 53/M | Moderate | IVB | None | 6 | 215 | 126 |
| 2 | PR | 66/M | Moderate | IVA | None | 4 | 149 | 135 |
| 3 | MR | 53/M | Moderate | IVA | None | 6 | 334 | 142 |
| 4 | MR | 53/M | Moderate | IVA | None | 5 | 175 | 85 |
a Days
Fig. 1.
Survival curve
Toxicity
There was no dose modification due to toxicity during any of the cycles of chemotherapy. In three patients, treatment was delayed for 1 week due to non-recovery from bone marrow suppression. Grade 3/4 neutropenia was observed in six patients, while grade 3/4 thrombocytopenia was seen in five patients (Table 4). There was no neutropenic infection or thrombocytopenic bleeding.
Table 4.
Toxicity profile
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
|---|---|---|---|---|
| Hematologic | ||||
| Anemia | 5 | 8 | 3 | 0 |
| Leukopenia | 8 | 6 | 4 | 2 |
| Thrombocytopenia | 6 | 1 | 4 | 1 |
| Non-hematologic | ||||
| Nausea | 10 | 7 | 6 | 0 |
| Vomiting | 9 | 5 | 1 | 1 |
| Mucositis | 2 | 2 | 2 | 0 |
| Neuropathy | 4 | 1 | 0 | 0 |
| Diarrhea | 4 | 2 | 0 | 0 |
The most common non-hematologic toxicities were nausea and vomiting; six patients developed grade 3/4 nausea, and two developed grade 3/4 vomiting. Grade 3 mucositis was observed in only one patient and no hand-foot syndrome was noted. No deaths occurred during any of the cycles of chemotherapy.
Discussion
No effective standard therapy is yet available for advanced biliary tract cancer. However, several phase II clinical trials have studied the combination of 5-FU, cisplatin, and mitomycin for these cancers (Table 5). Raderer et al. reported that combination chemotherapy with 5-FU (400 mg/m2, D1–4), leucovorin (200 mg/m2, D1–4), and mitomycin (8 mg/m2, D1) showed 25% response rate with a median survival of 9.5 months in 20 patients with advanced biliary tract cancer (Raderer et al. 1999). In another trial, 24% response rate was observed in 25 patients with biliary tract cancer treated with continuous i.v infusion of 5-FU (1,000 mg/m2, D1–5) and cisplatin (100 mg/m2, D2) (Ducreux et al. 1998). In a trial in 19 patients with biliary cancer, combination of 5-FU (2,600 mg/m2) and leucovorin (150 mg) given weekly for 4 weeks, followed by 2 weeks of rest, resulted in a response rate of 33%, along with mild toxicity (Chen et al. 1998). The ECF regimen, consisting of epirubicin and cisplatin every 21days, along with a protracted infusion of 5-FU, showed a 71% response rate in gastro-esophageal cancer and a 41% response rate in hepato-biliary cancer (Findlay et al. 1994; Ellis et al.1995). Using the same regimen, we observed a response rate of only 10% (2/20). We believe that our lower response is due to the inclusion of only patients with intrahepatic cholangiocarcinoma. In contrast, other clinical trials on biliary track cancer also included patients with ampulla of Vater cancer, gall bladder cancer, extrahepatic cholangiocarcinoma, and even HCC. Of the eight responders to the ECF regimen by Ellis et al., six were patients with gall bladder and ampulla of Vater cancer.
Table 5.
Systemic chemotherapy for biliary tract cancers [BTC biliary tract cancers (including intrahepatic, hilar, extrahepatic cholangiocarcinoma), GB gallbladder cancer, AV ampulla of Vater cancer, ADR adriamycin, STZ streptozocin, MMC mitomycin c, LV leucovorin]
| Regimen | No. of cases | Partial response (%) | ||
|---|---|---|---|---|
| Falkson et al. 1984 | 5-FU | BTC | 12 | 1 (8%) |
| 5-FU/STZ | 10 | 0 (0%) | ||
| 5-FU/MeCCNU | 12 | 2 (17%) | ||
| Harvey et al. 1984 | 5-FU/ADR/MMC | BTC | 17 | 4 (23.5%) |
| Ellis et al. 1995 | 5-FU/cisplatin/epirubicin | BTC | 12 | 2 (17%) |
| GB | 9 | 3 (33.3%) | ||
| AV | 4 | 3 (75%) | ||
| Patt et al. 1996 | 5-FU/IFN-a | BTC | 25 | 9 (36%) |
| GB | 10 | 2 (20%) | ||
| Chen et al. 1998 | 5-FU/LV | BTC | 14 | 6 (43%) |
| GB | 6 | |||
| Ducreux et al. 1998 | 5-FU/cisplatin | BTC | 25 | 6 (24%) |
| Raderer et al. 1999 | 5-FU/LV/MMC | BTC | 20 | 5 (25%) |
| Gemcitabine | 19 | 3 (16%) | ||
| Patt et al. 2001 | cisplatin/IFN-2b/ADR/5-FU | BTC | 22 | 2 (9%) |
| GB | 19 | 6 (31.5%) |
Cholangiocarcinoma is known to respond poorly to chemotherapy. In a phase II clinical trial of the PIAF regimen (cisplatin, IFN-alpha 2b, adriamycin, and 5-FU) for biliary tract cancer, the response rate was 35.5% for patients with gall bladder cancer but only 9.5% for patients with cholangiocarcinoma (Patt et al. 2001). The poor response of cholangiocarcinoma may be due to the relative resistance to chemotherapeutic agents. For example, using the succinate dehydrogenase inhibition assay to investigate resistance to chemotherapeutic agents (adriamycin, cisplatin, and mitomycin) in primary liver cancer, the resistance rate was found to be 50.9% for HCC and 77.7% for intrahepatic cholangiocarcinoma (Shimada et al. 1996). Dihydropyrimidine dehydrogenase (DPD) is known to catabolize 5-FU in liver and tumor tissues. The different effectiveness of 5-FU in various tumors is thus thought to be based on the different DPD enzymatic activity in host tissue. Using DPD activity to evaluate 5-FU resistance in HCC, cholangiocarcinoma, normal tissue adjacent to HCC, colorectal cancer and normal liver tissue, DPD activity in cholangiocarcinoma was shown to be 140±34 unit/mg protein, which is higher than that in colorectal cancer (58±45 unit/mg protein), normal tissue adjacent to tumor (105±50 unit/mg protein) or normal control tissue (93±24 unit/mg protein) (Ikeguchi et al. 2001). These findings suggest that the non-responsiveness of cholangiocarcinoma to 5-FU may be due to the increased DPD activity present in these tumors. In addition, it has been suggested that overexpression of bcl-2, anti-apoptotic protein, may be related to the resistance to chemotherapy in cholangiocarcinoma (Ito et al. 2000).
In agreement with previous findings (Ellis et al. 1995), the ECF regimen was well tolerated. No serious toxicity was noted and no dose reduction was needed. In addition, no hand-foot syndrome was observed in our study, perhaps due to a small number of cycles of chemotherapy given in our study.
Newer chemotherapeutic agents, including oxaliplatin, carboplatin, irinotecan, and docetaxel are currently being investigated in cholangiocarcinoma, but no substantial improvement in response and survival rate have yet been reported thus far compared to those of previous trials (Adjei et al. 2000; Sanz-Altamira et al. 1998). One phase II trial with a single agent, gemcitabine, has a reported response rate of 30% in cholangiocarcinoma, compared with a 5% response rate in HCC (Kubicka et al. 2001). Based on this result, further study of combination chemotherapy with gemcitabine is warranted.
Recently, hepatic arterial chemotherapy through an implanted port system has been developed as one of treatment options for cholangiocarcinoma (Arai et al. 1997). In comparison with intravenous chemotherapy, it has the advantages that chemotherapeutic agents can be delivered into the tumor tissue at higher concentration and fewer side effects. However, this approach is regional therapy rather than systemic therapy. It has not been clearly elucidated that this regional approach has advantages over systemic chemotherapy because distant metastasis is more common in intrahepatic cholangiocarcinoma than in other biliary tract cancers, and catheter-related complications have been frequently reported.
Tanaka et al. reported that the combination of intra-arterial hepatic chemotherapy (epirubicin and cisplatin) and systemic infusion of 5-FU was effective in intrahepatic cholangiocarcinoma, with a response rate of 45% (Tanaka et al. 2002). Although the study was limited, due to the small number of cases, this combined regimen appeared to be feasible and safe. Further studies are warranted to determine the efficacy of this combined treatment modality.
In conclusion, the ECF regimen was well tolerated, but it was not very effective in intrahepatic cholangiocarcinoma. New clinical trials with a combination chemotherapy should be developed for the treatment of hepatobiliary cancer, especially in intrahepatic cholangiocarcinoma.
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