Annals of Oncology 15:765-769, 2004
© 2004 European Society for Medical Oncology
Combination of folinic acid, 5-fluorouracil bolus and infusion, and cisplatin (LV5FU2-P regimen) in patients with advanced gastric or gastroesophageal junction carcinoma
1 Hepato-Gastroenterology and Digestive Oncology, CHU Ambroise Paré, AP-HP, Boulogne; 2 Department of Medicine, Institut Gustave Roussy, Villejuif; 3 Department of Internal Medicine, CHU Ambroise Paré, AH-HP, Boulogne, France
Received 20 August 2003; revised 19 December 2003; accepted 21 January 2004
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ABSTRACT |
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Background:
Combination chemotherapy with continuous 5-fluorouracil (5-FU) and cisplatin in a monthly regimen is one of the standard treatments for advanced gastric carcinoma. This study evaluated the new LV5FU2-P regimen, designed to improve efficacy and tolerance of the 5-FU plus cisplatin combination.
Patients and methods:
Forty-three patients with advanced or metastatic gastroesophageal junction or gastric carcinoma were prospectively included in the study. They were treated every 14 days with cisplatin 50 mg/m2 on day 2 plus folinic acid 200 mg/m2/day as a 2-h intravenous (i.v.) infusion on days 1 and 2, plus bolus 5-FU 400 mg/m2/day on days 1 and 2, plus continuous 5-FU 600 mg/m2/day as a 22-h i.v. infusion on days 1 and 2. Ten patients received a simplified regimen (folinic acid 40 mg/m2 day 1 + bolus 5-FU 400 mg/m2 day 1 + continuous 5-FU 2400 mg/m2 on days 1 and 2 with cisplatin 50 mg/m2 on day 2).
Results:
All the patients were assessable for response and 42 for toxicity. One patient achieved a complete response and 15 a partial response, for an overall response rate of 37.2% [95% confidence interval (CI) 22.1% to 52.3%]. The median progression-free survival was 7.2 months (95% CI 5.4–10.9) and the overall survival was 13.3 months (95% CI 10.1–16.4). There were no treatment-related deaths. Hematological and gastrointestinal toxicities were the most common severe toxicities.
Conclusions:
LV5FU2-P is an active and well tolerated regimen in the treatment of advanced gastroesophageal junction or gastric carcinomas. It warrants evaluation comparatively with other active regimens.
Key words: antineoplastic combined chemotherapy, cisplatin, fluorouracil, stomach neoplasms
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Introduction |
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TopABSTRACTIntroductionPatients and methodsResultsDiscussionREFERENCES |
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In advanced gastric cancer, three randomized trials have demonstrated that chemotherapy can add to both quantity and quality of life [1–3]. Combination chemotherapy regimens with the most effective drugs have been developed and compared in phase III trials, but, to date, there is no real standard chemotherapy regimen for advanced gastric cancer. The ECF [protracted venous infusion 5-fluorouracil (5-FU) + epirubicin + cisplatin] [4] and FUP (continuous 5-FU + cisplatin) [5] regimens have demonstrated efficacy and are considered as reference regimens.
5-FU as a single agent has demonstrated significant activity with bolus and infusional schedules. In particular, the LV5FU2 regimen (de Gramont regimen) is effective for advanced gastric cancer in poor-prognosis patients [6]. The FUP regimen was compared with the FAMTX (5-fluorouracil, doxorubicin and methotrexate) and ELF (etoposide, leucovorin and 5-fluorouracil) regimens in a large phase III trial [7]. An objective response rate of 20%, with a median progression-free survival (PFS) of 4.1 months and an overall survival (OS) of 7.2 months, was reported for patients treated with the FUP regimen. Severe vomiting and severe neutropenia occurred in 26% and 35%, respectively, with two treatment-related deaths for patients treated with the FUP regimen, and there was no difference between the FAMTX, ELF and FUP regimens [7]. The preliminary results of a phase III trial suggest that the DCF regimen (docetaxel + cisplatin + 5-FU) is superior to the FUP regimen in terms of response rate and time to progression [8].
In order to improve the efficacy and tolerance of 5-FU + cisplatin combination chemotherapy, new regimens have been developed. The combination of weekly high-dose 5-FU/leucovorin (AIO regimen) plus cisplatin was evaluated in a randomized phase II trial (EORTC 40953 trial); the objective response rate was 39%, the median PFS 6 months and the median OS 9.7 months, with a low incidence of severe toxicity [9]. We designed a new regimen based on improved dosage and scheduling of both 5-FU and cisplatin, combining the LV5FU2 regimen and fractionated cisplatin. The bimonthly combination of LV5FU2 and cisplatin 50 mg/m2 is feasible and well tolerated [10], and has also been evaluated for pancreatic and biliary tract carcinomas [11, 12]. This study was conducted in two centers to assess the feasibility, tolerance and efficacy of the LV5FU2-P regimen in the treatment of locally advanced or metastatic gastric cancer.
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Patients and methods |
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Eligibility criteria
Eligibility criteria were as follow: histologically proven gastric or gastroesophageal junction adenocarcinoma; locally advanced or metastatic and inoperable disease; an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; life expectancy of at least 3 months; age between 18 and 80 years; no brain metastases; adequate bone marrow function (hemoglobin >10 g/dl, neutrophils count >1500/mm3, platelet count >100 000/mm3); serum creatinine level <120 µmol/l; no other active malignancy; no concurrent uncontrolled medical illness; bidimensionally measurable lesions.
Between December 1996 and November 2001, all the patients with advanced gastric or gastroesophageal junction cancer referred to our institutions [Hôpital Ambroise Paré (HAP) and Institut Gustave Roussy (IGR)] for medical treatment were considered for this study. The study was conducted in accordance with the Declaration of Helsinki, and the study protocol was reviewed and approved by an institutional review board. All participating patients were required to give written informed consent.
Treatment schedule
The treatment consisted of a 2-h infusion of leucovorin at a dosage of 200 mg/m2, followed by a 400 mg/m2 bolus of 5-FU, followed by a 22-h continuous infusion of 600 mg/m2 of 5-FU on days 1 and 2 with a 30-min infusion of cisplatin 50 mg/m2 on day 2, preceded and followed by hydration (classical regimen). The most recently treated patients received a simplified regimen: leucovorin 40 mg/m2 intravenously over 10 min, followed by a 400 mg/m2 bolus of 5-FU, followed by a 46-h continuous infusion of 2400 mg/m2 of 5-FU with a 30-min infusion of cisplatin 50 mg/m2 on day 2, preceded and followed by hydration. All the patients were given prophylactic antiemetic treatment consisting of 5HT3 antagonists and prednisolone. A central venous catheter was used for all patients.
Treatment was repeated every 2 weeks if the neutrophils count was >1500/mm3, the platelet count >100 000/mm3 and serum creatinine <120 µmol/l. Treatment was discontinued in cases of disease progression, repeated grade 3–4 toxicity or patient refusal. A second-line chemotherapy was permitted if the investigator considered it to be warranted.
Assessment of response
Pretreatment evaluation included a physical examination, tumor marker (carcinoembryonic antigen and CA 19-9) levels, an abdominal computed tomography (CT) scan and a thoracic CT scan if lung metastases were suspected. Laboratory tests were required within 7 days and measurements of disease were required within 14 days of the start of therapy. Body weight, performance status and symptoms were recorded at each cycle. Antitumoral efficacy according to the WHO criteria [13] was evaluated by helicoidal CT scan every four cycles, or earlier in case of clinical suspicion of progression. A complete response (CR) was defined as a complete disappearance of all assessable disease; a partial response (PR) was defined as a decrease of 
50% in the sum of the products of the two largest perpendicular diameters of measurable lesions for at least 4 weeks; stable disease (SD) was defined as a decrease of <50% or an increase of <25% in the sum of the products of the two largest perpendicular diameters of measurable lesions; and progressive disease (PD) was defined as an increase of >25% in the sum of the products of the two largest perpendicular 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 weeks later.
Toxicity evaluation
Toxicity was evaluated before each cycle according to WHO criteria. Complete blood and platelet counts were performed every week to assess hematological toxicity. Physical examination, a full blood count and serum creatinine assay were performed before each cycle. Patients were questioned specifically about nausea and vomiting, mucositis, diarrhea, malaise, anorexia, neurotoxicity and ototoxicity.
Statistical analysis
The end point of this trial was the objective response rate. The sample size was calculated to reject a 20% response rate in favor of a target response rate of 35% with a type I error of 5% and a power of 80% . The target enrolment was estimated to be 42 patients. Secondary objectives were the determination of PFS and OS. Categorical data were examined using the 
2-test with Fisher’s exact test used when appropriate. All survival functions were computed using the Kaplan–Meier method [14] and were measured from the start of chemotherapy. A Cox regression was performed to estimate factors associated with survival in multivariate analysis. All statistical tests were performed at the 0.05 level. The computations were performed using the Stata Statistical software (Stata Corporation, College Station, TX, USA).
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Results |
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Patient characteristics
Forty-three consecutive patients treated at the IGR (n = 14) or at HAP (n = 29) were prospectively included in this study. The median age was 60 years (range 26–79). Patients’ characteristics are summarized in Table 1. All but six patients had metastatic disease.
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Treatment
Thirty-three patients (76.7%) were treated according to the classical regimen, whereas the last 10 patients treated (23.3%) received the simplified regimen. A total of 311 cycles of chemotherapy were administered, with a median of six cycles per patient (range one to 14).
Toxicity
Forty-two patients were assessable for toxicity. One patient was not assessable because the charts were not completed correctly. There was no dose reduction or treatment stoppage for toxicity for this patient.
Non-hematological and hematological toxicities are described in Table 2. There were no treatment-related deaths. Grade 3 toxicity occurred in 14 patients (33.3%) and grade 4 in six patients (14.3%). Hematological toxicity was the most common severe toxicity, with grade 3–4 neutropenia in 18 patients (42.9%). Two patients (4.8%) had febrile neutropenia. One patient (2.4%) had grade 3 thrombocytopenia. Nausea and vomiting were a frequent side effect, despite systematic prophylaxis, but grade 3 vomiting occurred in only seven (16.7%) patients. Adverse reactions necessitated a dose reduction in 17 patients (39.5%) and cessation of treatment in three patients (7%) (after the 4th, 5th and 13th cycles, respectively). There was no difference between the two LV5FU2-P regimens for severe (grades 3 and 4) toxicity (Table 3). Adverse reactions necessitated a dose reduction in 13 patients (39.4%), and cessation of treatment in one patient (3%) treated with the classical LV5FU2-P regimen and in four (40%) and two (20%) patients treated with the modified LV5FU2-P regimen.
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Antitumoral activity and survival
All patients were assessable for response, according to WHO criteria, and survival. One patient (2.3%) with a gastric tumor achieved a confirmed CR and 15 patients (34.9%) a confirmed PR, for an overall objective response rate of 37.2% [95% confidence interval (CI) 22.1% to 52.3%) (Table 4). The median duration of response was 5.3 months (range 1.2–35.1 months). The objective response rate was 41.9% in patients with performance status 0–1, compared with 25% in patients with performance status 2 (P = 0.3). There was no significant difference in the objective response rate between patients with locally advanced disease (33.3%) and patients with metastatic disease (37.8%) (P = 0.8), nor between patients with one metastatic site (47.1%) and those with two or more metastatic sites (30%) (P = 0.3). The objective response rate for patients treated with the simplified regimen (30%) was not different from that observed for patients treated with the classical regimen (39.4%) (P = 0.7) (Table 4).
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Median PFS and OS were 7.2 months (95% CI 5.4–10.9) and 13.3 months (95% CI 10.1–16.4), respectively. The 1-year survival rate was 57.7% (95% CI 41–71.2%).
One patient with an initially non-resectable locally advanced gastroesophageal junction carcinoma was operated for cure after four cycles of chemotherapy. He died 28 months later after progression. Four patients with locally advanced gastric cancer (linitis in two cases), considered as non-resectable during a first surgical exploration, had an objective response and were re-operated after six to 12 cycles of chemotherapy. A complete resection (R0 resection) was possible in three cases, and one patient had an R1 resection. This latter patient received an adjuvant radiochemotherapy combination, whereas the LV5FU2-P regimen was continued for six cycles in another patient. None of these patients has progressed, and their survival ranged from 5 to 37 months at the last follow-up.
Prognostic factors of survival
Presence of liver metastases was the only adverse prognostic factor associated with PFS in univariate or multivariate analysis (hazard ratio 2.5; 95% CI 1.3–4.9). Performance status and presence of liver metastases were the only adverse prognostic factors associated with OS in univariate and multivariate analyses. In multivariate analysis, the hazard ratio associated with performance status 2 was 3 (95% CI 1.38–6.44) compared with performance status 0–1 (P = 0.005). The hazard ratio was 3.1 (95% CI 1.3–7.3) for patients with liver metastases (P = 0.008).
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Discussion |
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TopABSTRACTIntroductionPatients and methodsResultsDiscussionREFERENCES |
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The 5-FU plus cisplatin combination is one of the reference treatments for advanced gastric cancer. The FUP combination has been evaluated in phase II [15] and III [5, 7, 16] trials. The EORTC trial showed that the FUP regimen’s efficacy was comparable to that of FAMTX [7], and the Korean trial showed that a modified ECF regimen did not show any advantage over FUP regimen in terms of response, survival and toxicity profiles [16]. Since the toxicity, and particularly the gastrointestinal toxicity, of the FUP regimen is important, less toxic 5-FU plus cisplatin regimens would be useful. An hypothesis to reduce the gastrointestinal toxicity was to divide up the cisplatin administration, and this had led to the evaluation of the LV5FU2-P regimen, where the dose of cisplatin is given in two 50 mg/m2 perfusions twice a month [10].
The current results showed that the LV5FU2-P and simplified LV5FU2-P regimens are active in patients with advanced gastroesophageal junction, gastric carcinoma and gastric linitis, with manageable gastrointestinal and hematological toxicity. The results compare favorably with those of previous 5-FU plus cisplatin regimens. Those regimens have not been directly compared in a randomized trial, and comparisons have to be read with caution, but gastrointestinal toxicity of the LV5FU2-P regimen seems to be much less than what has been observed with the FUP regimen [7, 15]. Tumoral response and survival also compare favorably with the results of recent infusional 5-FU/folinic acid plus cisplatin regimens. An EORTC randomized phase II trial showed high efficacy (37% of objective response rate with an OS of 9.7 months) with a low incidence of severe toxicity in patients with advanced gastric cancer treated with the AIO + cisplatin combination [9]. The HLFP regimen (LV5FU2 + hydroxyurea + cisplatin 80 mg/m2 every 28 days) is active, with an objective response rate of 62% and a median survival of 11 months, but severe emesis is frequent with this dose of cisplatin [17].
The simplified LV5FU2 regimen [18] seems to be as efficient, and may be less toxic than the classical LV5FU2, although the regimens have never been compared directly. With only one 5-FU bolus and a longer continuous 5-FU perfusion duration, this regimen is more convenient for the patients, and may increase the quality of life. This is probably also true for the LV5FU2-P regimen, and is the reason we used the simplified LV5FU2-P to treat our most recent patients. Tolerance did not differ between the two regimens in our study, but there were more severe nausea and vomiting with the classical regimen (21.9% versus 0%), and more severe hand–foot syndrome and severe thrombocytopenia with the simplified regimen (10% versus 0%). Tumoral response and survival were not different between the classical and simplified regimens, but the comparison between the two regimens should be considered with caution, since only 10 patients were given the simplified regimen. The OS of 13.3 months observed in this study is better than what has been reported with the FUP [7] or the AIO + cisplatin regimens [9]. This may be partly explained by a better efficacy of the LV5FU2-P regimen, but also by differences in patient characteristics, use of second-line regimens or the proportion of patients operated after chemotherapy.
In a previous report, patients with cancer of the gastroesophageal junction had a significantly better response rate than those with distal gastric cancer with a non-significant trend for a better survival (11 versus 8 months: p = 0.3), and linitis was considered as less chemosensitive [15]. This was not observed in the present study. Site-specific response and survival rates were not different, and the only adverse prognostic factors for survival were performance status and the presence of liver metastases. Similar results have been recently reported by Louvet et al. [17]. Owing to the small number of patients included in our study, it is, however, debatable how meaningful the observed predictive factors are.
In conclusion, LV5FU2-P is safe and effective for advanced gastroesophageal junction and gastric adenocarcinoma, as well as for gastric linitis. This regimen appears to be less toxic than the classic FUP regimen. Its simplified version seems to be as efficient, and may be more convenient for the patients. Further evaluation in phase II–III trials is needed to confirm these results.
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FOOTNOTES |
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* Correspondence to: Dr E. Mitry, Hépato-Gastroentérologie, CHU Ambroise Paré, 9 avenue Charles de Gaulle, F-92100 Boulogne-Billancourt, France. Tel: +33-1-49-09-58-79; Fax: +33-1-49-09-45-08; E-mail: emmanuel.mitry{at}apr.ap-hop-paris.fr
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REFERENCES |
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