1 Département de Médecine, Institut Gustave Roussy, Villejuif; 2 Service dHépato-Gastro-Entérologie, Hôpital A. Paré, Boulogne, France
Received 9 October 2001; revised 1 February 2002; accepted 26 February 2002
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Unresectable biliary tract carcinoma (BTC) is associated with a very poor prognosis. To improve efficacy and tolerance of the 5-fluorouracil (5-FU)/cisplatin combination in BTC, we designed a new therapeutic schedule, the LV5FU2-P regimen.
Patients and methods:
Twenty-nine patients with advanced or metastatic BTC were prospectively enrolled in the study. The treatment (LV5FU2-P regimen) consisted of a biweekly administration of a 2-h infusion of leucovorin 200 mg/m2, a 400 mg/m2 bolus of 5-FU followed by a 22-h continuous infusion of 600 mg/m2 5-FU on two consecutive days and cisplatin 50 mg/m2 on day 2. Clinical symptoms, performance and weight changes were monitored.
Results:
Objective responses were observed in 10 patients (34%) (95% confidence interval 23% to 45%) including one complete response and nine partial responses (stabilization 38%, progression 28%). Median progression-free survival and overall survival were 6.5 and 9.5 months, respectively. Weight gain was observed in 45% of patients and performance status improved in 60%. One patient had a grade 4 thrombocytopenia, and grade 3 toxicity occurred in 41% of patients. There were no treatment-related deaths.
Conclusions:
This study, one of the largest phase II trials performed for this disease, shows that the LV5FU2-P regimen is an active and well-tolerated chemotherapy for advanced and metastatic BTC.
Key words: biliary tract carcinoma, chemotherapy, cisplatin, 5-fluorouracil
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Pre-treatment evaluation included a clinical examination, tumor markers (carcinoembryonic antigen and CA 19-9), an abdominal computed tomography (CT) scan and a thoracic CT scan if lung metastases were suspected. Body weight, performance status and clinical symptoms such as jaundice, pain or anorexia were also recorded before beginning therapy.
Treatment schedule
The treatment consisted of a 2-h infusion of leucovorin at a dosage of 200 mg/m2, a 400 mg/m2 bolus of 5-FU followed by a 22-h continuous infusion of 5-FU 600 mg/m2 on two consecutive days as described previously [13]; then a 30-min infusion of CDDP 50 mg/m2 on day 2, preceded and followed by hydration. All patients were given prophylactic antiemetic treatment consisting of 5-hydroxytryptamine type 3 receptor antagonists and prednisolone. Treatment was repeated every 2 weeks if the neutrophil count was >1500/mm3, the platelet count >100 000/ mm3 and serum creatinine <120 µmol/l. Patients who responded or had a stable disease (SD) received the full treatment for at least 6 months. CDDP administration during subsequent courses depended on the patients condition. Treatment was discontinued in cases of disease progression, repeated grade 3/4 toxicity, or patient refusal. Second-line chemotherapy was permitted if the investigator considered it warranted.
Assessment of response and clinical benefit
All patients had bidimensionally measurable lesions for response evaluation. Bone metastases and pleural and peritoneal effusions were not considered as evaluable metastatic sites but were taken into account for progression. Response to treatment was evaluated every four cycles by helicoidal CT scan, or earlier in the case of clinical suspicion of progression. WHO criteria were used for response and response duration [17]: a complete response (CR) was defined as a 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 two largest perpendicular diameters of measurable lesions for at least 4 weeks; SD was defined as a 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 two diameters of at least one tumor, or the appearance of a new lesion. All objective responses had to be confirmed by a second evaluation 48 weeks later. Body weight, performance status and symptoms were also recorded at each cycle.
Toxicity evaluation
Toxicity was recorded according to the National Cancer Institute criteria. Complete blood and platelet counts were performed every week to assess hematological toxicity. Physical examination, a full blood count and a serum creatinine assay were performed before each cycle. Patients were questioned specifically about nausea and vomiting, mucositis, diarrhea, malaise, anorexia, neurotoxicity and ototoxicity. All patients who had received at least one course of chemotherapy were evaluated for toxicity.
Statistical analysis
The end point of this phase II trial was the overall response to the LV5FU2-P regimen. The study was conducted employing a two-stage Simon design [18]. The sample size was calculated to reject a 10% response rate in favor of a target response rate of 30%, with a significance level of 0.05 and a power of 80%. In the initial stage, a total of 10 evaluable patients were to be entered and evaluated for response. If there was less than one response, accrual was to be terminated. If more than one response was observed in the first stage, then 19 additional patients were to be entered in the second stage to achieve a total of 29 evaluable patients. Further assessment of the regimen was felt to be warranted if more than six responses were observed in the 29 patients. Results are expressed as means ± standard deviation or range, as appropriate. Follow-up started from the outset of treatment. The censoring event for response was the start of disease progression. The censoring event for survival was the date of death. Survival curves were plotted with Splus 4.5 software, using the KaplanMeier method.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
Clinical benefit
Out of 20 patients with an initial WHO performance status of >0, 12 (60%) had an improvement of their performance status during therapy. Weight gain was observed in 13 patients (45%) during treatment and symptoms such as pain, ascites, anorexia and jaundice improved in 13 of 18 (72%) initially symptomatic patients. The median time for improvement of symptoms was 1 month.
Toxicity
Toxicity data were available for all patients (Table 2). A total of 271 cycles, with a median of nine cycles per patient (range 220), were administered. No treatment-related deaths were observed. Grade 3/4 toxicity occurred in 13 patients (45%). Hematological toxicity was the most common severe toxicity followed by gastrointestinal side-effects. White blood cell grade 3 toxicity was observed in five patients (17%) and did not require hospitalization. Two grade 3 and one grade 4 thrombocytopenia were observed without any associated bleeding event. A 25% reduction of the 5-FU bolus was necessary in six patients, with no further hematological toxicity observed. Nausea and vomiting was a frequent side-effect despite systematic prophylaxis. It occurred in 19 patients, usually starting within 3 h after the beginning of treatment and persisting for a few days. Grade 3 nausea/vomiting occurred in only 10% of patients, all of whom were able to continue treatment with a reinforcement of their antiemetic treatment.
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The prognosis of patients with advanced or metastatic BTC remains extremely poor, with median survival not exceeding 6 months [19]. In operable diseases, surgery and even hepatic transplantation have given disappointing results [20]. Although interesting new palliative therapeutic approaches have recently been published in advanced and metastatic diseases, such as biliary drainage with a carboplatin-coated tube [21], systemic chemotherapy remains one standard of care for eligible patients. Glimelius et al. [22] showed that chemotherapy can add to both quantity and quality of life in advanced pancreatic cancer and BTC. However, the low frequency of these tumors has resulted in a lack of data concerning their sensitivity to chemotherapeutic regimens. Actually, only a few phase II trials and no large randomized phase III trials have been performed. Single-agent chemotherapy has yielded disappointing results in advanced BTC, with objective response rates ranging from 5% to 20%. Even new drugs such as paclitaxel or gemcitabine, used as single agents, have shown response rates ranging from 0% to 16% and median survivals of 6 months [23, 24]. Studies comparing 5-FU alone with polychemotherapy combining 5-FU, doxorubicin and mitomycin, have shown an increased toxicity for a similar efficacy in the combination therapy group [8, 25]. A recent phase II study investigated the efficacy of combined 5-FU and interferon
-2b and reported an interesting objective response rate of 34% but poor tolerance [26]. Two recent publications showed that 5-FU modulation with leucovorin seems to be well tolerated in advanced BTC with response rates of 33% and 17%, but rather short median overall survivals of 6 and 7 months [27, 28]. Regimens combining 5-FU and platin analogs were more promising with response rates ranging from 21% to 40% and are now one of the standards in the treatment of advanced BTC [1113]. However, toxicity has been significant with the different schedules tested, with either CDDP or carboplatin, and needs to be improved. In a previous publication, our team observed a 24% response rate with a 5-day 5-FU/CDDP regimen, but with 40% of patients having grade 3/4 hematological toxicity and 25% having grade 3 nausea/vomiting [12]. Severe (grade 4) hematological toxicity was observed in eight of 25 patients and severe alopecia was frequent with the ECF regimen [11]. Finally, the 5-FU, leucovorin and carboplatin combination tested by Sanz-Altamira et al. [13] showed 57% of patients having febrile neutropenia. A better therapeutic index was obtained with a less-toxic schedule of folinic acid-modulated 5-FU and CDDP, as in the LV5FU2-P regimen. In two cases this regimen was efficient enough to allow, after major response, a complete surgical resection of the tumor, which was initially unresectable.
During the past decade many new cytotoxic drugs have become available, and are currently being tested in many orphan neoplasias such as BTC. As compared with regimens including newly developed and expensive drugs, the LV5FU2-P regimen is rather less costly. In future, chemotherapeutic regimens including expensive new drugs for BTC should thus provide significant improvement in efficacy and toxicity to be relevant in terms of cost-effectiveness and to gain wide acceptance from physicians.
The LV5FU2-P regimen therefore appears to be well-tolerated and to provide good palliation, and seems to be a less toxic alternative therapeutic option in the management of patients with inoperable BTC.
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Evander A, Fredlund P, Hoevels J. Evaluation of aggressive surgery for carcinoma of the extra hepatic bile duct. Ann Surg 1980; 191: 2329.[ISI][Medline]
3. Levin B. Gallbladder carcinoma. Ann Oncol 1999; 10: 129130.
4. Klempnauer J, Ridder GJ, Werner M. What constitutes long-term survival after surgery for hilar cholangiocarcinoma? Cancer 1997; 79: 2634.[ISI][Medline]
5. Nakeeb A, Pitt HA, Sohn TA. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224: 463475.[ISI][Medline]
6. Reding R, Buard JL, Lebeau G, Launois B. Surgical management of 552 carcinomas of the extrahepatic bile ducts (gallbladder and periampullary tumors excluded). Results of the French Surgical Association Survey. Ann Surg 1991; 213: 236241.[ISI][Medline]
7. Okada S, Ishii H, Nose H. A phase II study of cisplatin in patients with biliary tract carcinoma. Oncology 1994; 51: 515517.[ISI][Medline]
8. Falkson G, MacIntyre JM, Moertel CG. Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer 1984; 54: 965969.[ISI][Medline]
9. Taal BG, Audisio RA, Bleiberg H. Phase II trial of mitomycin C (MMC) in advanced gallbladder and biliary tree carcinoma. An EORTC Gastrointestinal Tract Cancer Cooperative Group Study. Ann Oncol 1993; 4: 607609.[Abstract]
10. Johnston PG, Geoffrey F, Drake J. The cellular interaction of 5-fluorouracil and cisplatin in an human colon carcinoma cell line. Eur J Cancer 1996; 32: 21482154.
11. Ellis PA, Norman A, Hill A. Epirubicin, cisplatin and infusional 5-fluorouracil (5-FU) (ECF) in hepatobiliary tumours. Eur J Cancer 1995; 31A: 15941598.
12. Ducreux M, Rougier P, Fandi A. Effective treatment of advanced biliary tract carcinoma using 5-fluorouracil continuous infusion with cisplatin. Ann Oncol 1998; 9: 653656.[Abstract]
13. Sanz-Altamira P, Ferrante K, Jenkins R. A phase II trial of 5-FU, leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma. Cancer 1998; 82: 23212325.[ISI][Medline]
14. de Gramont A, Bosset JF, Milan C. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 1997; 15: 808815.[Abstract]
15. Louvet C, de Gramont A, Beerblock K. Hydroxyurea, leucovorin, 5FU and cisplatin (HLFP regimen): high response rate and low toxicity in advanced gastric cancer. Proc Am Soc Clin Oncol 1994; 13: (Abstr 579).
16. Raymond E, de Gramont A, Louvet C. Clinical benefit with cisplatin, hydroxyurea and 5-fluorouracil/leucovorin in advanced pancreatic carcinoma. Eur J Cancer 1997; 33: 696697.[ISI][Medline]
17. Miller AB, Hoogstratten B, Staquet M. Reporting results of cancer treatment. Cancer 1981; 47: 25072514.
18. Simon R. Optimal two-stage designs for Phase II clinical trials in oncology. Control Clin Trials 1989; 10: 110[ISI][Medline]
19. Morganti AG, Trodella L, Valentini V. Combined modality treatment in unresectable extrahepatic biliary carcinoma. Int J Radiat Oncol Biol Phys 2000; 46: 913919.[ISI][Medline]
20. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 2000; 69: 16331637.[ISI][Medline]
21. Mezawa S, Homma H, Sato T. A study of carboplatin-coated tube for the unresectable cholangiocarcinoma. Hepatology 2000; 32: 916923.[ISI][Medline]
22. Glimelius B, Hoffman K, Sjoden PO. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996; 7: 593600.[Abstract]
23. Jones DV, Lozano R, Hoque A. Phase II study of paclitaxel therapy for unresectable biliary tree carcinomas. J Clin Oncol 1996; 14: 23062310.[Abstract]
24. Raderer M, Hejna MH, Valencak JB. Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer. Oncology 1999; 56: 177180.[ISI][Medline]
25. Takada T, Kato H, Matsushiro T. Comparison of 5-fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic-biliary carcinomas. Oncology 1994; 51: 396400.[ISI][Medline]
26. Patt YZ, Jones DV, Hoque A. Phase II trial of intravenous flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer. J Clin Oncol 1996; 14: 23112315.[Abstract]
27. Choi CW, Choi IK, Seo JH. Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas. Am J Clin Oncol 2000; 23: 425428.[ISI][Medline]
28. Chen JS, Jan YY, Lin YC. Weekly 24 h infusion of high-dose 5-fluorouracil and leucovorin in patients with biliary tract carcinomas. Anticancer Drugs 1998; 9: 393397.[ISI][Medline]