Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma

J. Taïeb1,+, E. Mitry2, V. Boige1, P. Artru2, J. Ezenfis1, T. Lecomte2, M. C. Clavero-Fabri2, J. N. Vaillant2, P. Rougier2 and M. Ducreux1

1 Département de Médecine, Institut Gustave Roussy, Villejuif; 2 Service d’Hépato-Gastro-Entérologie, Hôpital A. Paré, Boulogne, France

Received 9 October 2001; revised 1 February 2002; accepted 26 February 2002


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

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
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Biliary tract carcinoma (BTC) is uncommon. Five-year survival rates for all stages, including resectable diseases, is ~10% for both gall-bladder carcinoma and cholangiocarcinoma [1, 2]. Although surgery alone remains the only potentially curative treatment, ~80% of patients are not eligible for such therapy [3]. Moreover, even when surgery has been performed, 5-year survival is still only ~20%. New multimodality therapeutic strategies are thus needed to improve long-term survival in this setting [46]. Numerous single-agent chemotherapies have been tested in BTC including cisplatin (CDDP), which is not efficient alone [7], and 5-fluorouracil (5-FU), with objective response rates ranging from 10% to 25% [8, 9]. Synergy of action between 5-FU and CDDP has been well described and can be optimal when CDDP is administered after 5-FU [10]. The combination of 5-FU and CDDP has been tested in BTC as a 5-day regimen or in the ECF schedule with epiadriamycin and continuous 5-FU [11, 12]. Response rates with these schedules were 24% and 32%, respectively. The 5-day schedule is actually one of the standards of care for BTC in France and some other European countries. Recently, a 5-FU/carboplatin combination chemotherapy was tested with a 21% rate of objective responses. However, severe toxicity frequently occurs with these regimens, with grade 3/4 toxicity encountered in 40–70% of patients including frequent febrile neutropenia [13]. In order to improve the efficacy and tolerance of 5-FU/CDDP combination chemotherapy, we designed a new regimen based on improved dosage and scheduling of both drugs, combining the LV5FU2 (de Gramont) regimen and fractionated CDDP. This regimen has been developed at our institution based on the following data: the LV5FU2 regimen has been shown to have a better therapeutic ratio than the 5-day NCCTG-Mayo Clinic regimen in advanced colorectal cancer [14] and CDDP seems to be as efficient and may be less toxic in fractionated administration schedules. Moreover, in other conditions, such as advanced gastric and pancreatic cancers, the 5-day 5-FU/CDDP regimen is routinely used but some authors have already shown that the LV5FU2 regimen combined with CDDP is efficient and better tolerated [15, 16].


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility criteria
Eligibility criteria were as follows: pathologically proven BTC; performance status 0, 1 or 2 (WHO criteria); life expectancy of >2 months; age between 18 and 76 years; absence of central nervous system metastasis; initial evaluation <2 weeks before therapy; normal renal function; neutrophil count >1500/mm3; and platelet count >100 000/mm3. Between February 1997 and June 2000, all patients with advanced BTC referred to our institution for medical treatment were considered for this study. The protocol was reviewed and approved by an institutional review board. All participating patients were required to give written informed consent.

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 patient’s 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 4–8 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 Kaplan–Meier method.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Between February 1997 and June 2000, 29 patients with advanced BTC were referred to our two institutions for medical treatment, all but one had metastatic disease, and were prospectively included in the study. Their characteristics are summarized in Table 1. Fifteen patients had undergone abdominal surgery, eight in a curative intent (they relapsed 6–12 months later), six in a palliative intent and one in an explorative intent. One patient had an adjuvant radio-chemotherapy after curative surgery and this patient relapsed 7 months later with a diffuse intrahepatic cholangiocarcinoma. Four patients had received a previous chemotherapy regimen; one patient had been included in a prospective trial evaluating high dose 5-FU in cholangiocarcinoma; one had received novantrone for two cycles before coming to our institutions; one had received the LV5FU2 regimen without CDDP for four cycles; and one had received the ECF regimen for two cycles. All these regimens were stopped at least 4 weeks before the beginning of the LV5FU2-P regimen. Toxicity and response were assessed in all patients.


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Table 1.  Patient pretreatment characteristics
 
Response to treatment and survival
The overall response rate was 34% (95% confidence interval 23% to 45%), including one CR and nine PRs. Stable disease was observed in 11 patients (38%) and PD in nine patients (28%). The median progression-free survival was 6.5 months. The median overall survival was 9.5 months and the 1-year survival was 50 ± 10% (Figure 1). In two patients with complete or major objective responses, subsequent curative surgery was performed. The first patient was a 72-year-old woman with T4N2M0 gall bladder adenocarcinoma which was unresectable at prior surgery. She had a PR at the first evaluation (four cycles) and a CR after 12 cycles of LV5FU2-P. Surgery confirmed the macroscopic CR and few adenocarcinomatous cells were found at the pathological examination. An adjuvant chemo-radiotherapy was performed (45 Gy plus continuous 5-FU) and the patient remains free of disease 3 years after diagnosis. The second patient was a 47-year-old man in whom the initial laparoscopic examination found very extensive T4N2M1 (hepatic metastasis) cholangiocarcinoma that was not resectable. He received 14 cycles of the LV5FU2-P regimen and achieved a major objective response. A second-look surgery was performed and a significant decrease in tumor size, as compared with the first surgical exploration, was observed. An extensive hepatectomy was performed. He received 6 months of adjuvant intra-arterial hepatic chemotherapy with mitomycin and with concomitant systemic LV5FU2. The patient is still alive and free of disease 30 months after diagnosis.



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Figure 1. Overall and progression-free survival.

 
Thirteen patients received second-line chemotherapy, gemcitabine was used in 10 patients, 5-FU and gemcitabine in two and epirubicin plus mitomycin in one. One patient was irradiated after 3 months of chemotherapy.

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 2–20), 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.


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Table 2.  Treatment-related toxicity (number of patients per grade)
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
With an overall response rate of 34% (including one CR), manageable hematological and gastrointestinal toxicity, no treatment-related deaths and only three patients (10%) hospitalized for treatment-related toxicity, our results compare very favorably with those of previous 5-FU/CDDP combination schedules, although a comparison between two phase II studies remains limited. Only one grade 4 event, a 25% rate of grade 3 hematological toxicity and a 10% rate of grade 3 nausea/vomiting were observed. Moreover, a substantial symptomatic effect was achieved. Sixty percent of patients experienced significant improvement of their performance status and 45% gained weight during therapy. These symptomatic effects generally appeared during the first month of treatment. The LV5U2-P regimen was delivered with 5-FU infusors, and patients had to be hospitalized for only 24 h every 2 weeks for CDDP infusion.

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 {alpha}-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
 
+ Correspondence to: Dr J. Taïeb, Service d’Hépatogastro-entérologie, Groupe Hospitalier Pitié Salpétrière, 47–89 Boulevard de l’Hôpital, 75013 Paris, France. Tel: +33-1-4216-1041; Fax. +33-1-4216-1425; E-mail: service.hepato-gastro@psl.ap-hop-paris.fr Back


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 Results
 Discussion
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