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Final Results of a Randomized Phase III Trial of Sequential High-Dose Methotrexate, Fluorouracil, and Doxorubicin Versus Etoposide, Leucovorin, and Fluorouracil Versus Infusional Fluorouracil and Cisplatin in Advanced Gastric Cancer: A Trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group

From the Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Essen; Klinikum Krefeld, Krefeld; Klinikum Minden, Minden; Clinic for Hematology and Oncology, Martin-Luther-University, Halle, Germany; Hôpital Ambroise Paré, Paris; Institut Gustave Roussy, Villejuif Cedex; Henri Mondor Hospital, Creteil; Centre Hospitalier Universitaire de Rouen, Rouen-Cedex, France; Servicio de Oncologia Medica, Hospital General de Asturias, Oviedo, Spain; Department of Internal Medicine, University Hospital Gasthuisberg, Leuven; Institut Jules Bordet and European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium; Instituto Portuges de Oncologia, Porto, Portugal; and St Laurentius Ziekenhuis, Roermond, the Netherlands.

Address reprint requests to U. Vanhoefer, MD, Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Hufelandstr 55, 45122 Essen, Germany; email udo.vanhoefer{at}uni-essen.de .

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To compare the efficacy and tolerability of etoposide, leucovorin, and bolus fluorouracil (ELF) or infusional fluorouracil plus cisplatin (FUP) with that of the reference protocol of fluorouracil, doxorubicin, and methotrexate (FAMTX) in advanced gastric cancer.

PATIENTS AND METHODS: A total of 399 patients with advanced adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, and progression-free and overall survival. Only reviewed and confirmed responses were considered. The analysis of remission was based on assessable patients with documented measurable lesions. The intent-to-treat principle, log-rank test, and Cox regression model were used for the statistical analysis of time-to-event end points.

RESULTS: The overall response rate for 245 eligible patients with measurable disease was 9% with ELF, 20% with FUP, and 12% with FAMTX, with no significant differences. One hundred twelve patients were eligible for efficacy in assessable, nonmeasurable disease. No change was observed in 66% of patients treated with ELF, 56% with FUP, and 55% with FAMTX. Two patients achieved a complete tumor regression (one each for ELF and FAMTX). With a median follow-up time of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with FUP, and 6.7 months with FAMTX, respectively, with no significant differences. Nonhematologic and hematologic toxicities of ELF, FUP, and FAMTX were acceptable, with neutropenia being the major toxicity for all three regimens. Seven treatment-related deaths occurred (two with FUP and five with FAMTX).

CONCLUSION: All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as standard treatment for advanced gastric cancer. New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
ADENOCARCINOMA OF the stomach remains one of the leading causes of cancer death worldwide. Complete resection is the only curative therapy for gastric cancer; however, approximately two thirds of patients have locally advanced or metastatic disease at diagnosis.¹ Furthermore, recurrent tumors are observed in up to one half of patients treated by curative intention using standardized surgical techniques.^2-4 These patients have a poor prognosis, with a median survival time of 3 to 5 months.^5-8 Randomized trials demonstrated that fluorouracil (5-FU)–based chemotherapy may improve survival and quality of life in patients with advanced gastric cancer when compared with best supportive care.^5-7

The regimen of 5-FU, doxorubicin, and sequential high-dose methotrexate (FAMTX) produced response rates of 30% to 60% and median survival times between 7 and 9 months in nonrandomized phase II studies.^9,10 In a randomized trial of the European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Cooperative Group, FAMTX showed a superior response rate and survival time in advanced gastric cancer when compared with 5-FU, doxorubicin, and mitomycin (FAM) (41% v 9% [P < .0001] and 42 v 29 weeks [P < .005], respectively).¹¹ No major differences in terms of toxicity were found between the two regimens. Moreover, the hematologic toxicities (eg, thrombocytopenia) seemed to be lower for the FAMTX regimen. Thus, in Europe, FAMTX was considered to be the standard treatment for further clinical studies in nonresectable and metastatic gastric cancer.¹¹ Of importance is that the FAMTX regimen has also been used in a neoadjuvant setting of perioperative chemotherapy in patients with locally advanced gastric cancer.¹² Recently, Webb et al¹³ reported the results of a randomized study that compared epirubicin, cisplatin, and infusional 5-FU (ECF) with the FAMTX regimen. In this study, FAMTX yielded an overall response rate of only 21% (95% confidence interval [CI], 13% to 29%) and a median survival time of 5.7 months.¹³

The regimen of etoposide, folinic acid, and 5-FU (ELF) has been reported to be less toxic than other chemotherapy regimens (eg, FAMTX and FAM) but seemed to have comparable antitumor activity in patients with advanced gastric cancer. As first-line and second-line chemotherapy in metastatic gastric cancer, the original ELF regimen yielded response rates from 27% to 53% and median survival times of 7.1 to 11.5 months in nonrandomized phase II studies.^14-18 Recently, a randomized trial demonstrated that ELF improves survival and quality of life in patients with advanced gastric cancer, when compared with best supportive care.⁶ Two trials investigated ELF in elderly patients or in patients who were unsuitable for cisplatin- or anthracycline-containing regimens (eg, cardiac risk and poor performance status).^14,16 The overall response rates were 48% (95% CI, 13% to 29%) and 32% (95% CI, 19% to 48%), with median survival times of 10.5 and 10.0 months, respectively. The hematologic and nonhematologic toxicities were mild, and no treatment-related deaths occurred in either trial. Increased dose-intensity or modifications of ELF (eg, oral etoposide, tegafur, or granulocyte colony-stimulating factor) did not improve the antitumor efficacy when compared with the original regimen.^19-23

Cisplatin-containing regimens (eg, etoposide, doxorubicin, and cisplatin [EAP] and 5-FU, doxorubicin, and cisplatin) have demonstrated antitumor efficacy in selected patients with advanced gastric cancer (eg, neoadjuvant chemotherapy in locally advanced disease). These regimens, however, were associated with significant toxicities.^24,25 Furthermore, in a small randomized phase II trial in patients with measurable disease, EAP failed to show superior antitumor activity compared with the FAMTX regimen in terms of response rate and median survival time but caused significantly more hematologic toxicities and therapy-induced mortality than FAMTX.²⁶

In an attempt to maintain the antitumor efficacy of cisplatin-containing regimens with less toxicity, a continuous 5-day infusion of 5-FU was combined with cisplatin (FUP). In two large phase II trials, the FUP regimen yielded overall response rates of 41% (95% CI, 28% to 54%) and 43% (95% CI, 30% to 56%), with median survival times of 10.6 and 9.0 months, respectively.^27,28 Unlike EAP and the regimen of 5-FU, doxorubicin, and cisplatin, side effects were generally mild, with neutropenia grades 3 and 4 being the main toxicity in 22% of all cycles.²⁸

Based on this background, the EORTC Gastrointestinal Tract Cancer Cooperative Group conducted a randomized phase III trial to compare the clinical efficacy and tolerability of ELF or FUP with that of FAMTX as first-line chemotherapy in patients with advanced gastric cancer. At the start of this trial in July 1991, the FAMTX regimen was considered to be the reference treatment. This is the final report of the EORTC trial 40902, which involved 54 institutions and 399 patients with nonresectable or metastatic gastric cancer treated with ELF, FUP, or FAMTX chemotherapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Eligibility
The eligibility criteria were as follows: age 75 years; histologically proven adenocarcinoma of the stomach, with locally advanced or metastatic disease; no prior chemotherapy or radiotherapy; World Health Organization (WHO) performance status 2; adequate baseline organ function, defined as WBC count 4,000 cells/µL, platelet count 100,000 cells/µL, serum bilirubin level 30 µmol/L, serum creatinine level 135 µmol/L, serum albumin level 35 g/dL, no severe uncontrolled comorbidities or medical conditions (eg, myocardial infarction in the last 12 months); no brain metastases; no second malignancies; and informed consent.

Stratification and Randomization
Patients were stratified according to institution, tumor extension (locally advanced v metastatic disease), and measurability of disease (bidimensionally measurable disease v assessable but nonmeasurable disease v nonassessable disease). Randomization was performed by the EORTC Data Center, Brussels, Belgium, using the minimization technique.²⁹

Treatment
The FAMTX regimen consisted of methotrexate at a dose of 1,500 mg/m² intravenously (IV) followed 1 hour later by 5-FU at a dose of 1,500 mg/m² IV on day 1 and doxorubicin at a dose of 30 mg/m² IV on day 15.¹⁰ Cycles were repeated every 29 days. Adequate hydration (diuresis 100 mL/h) and alkalinization of the urine were achieved before administration of methotrexate, and leucovorin rescue (30 mg orally every 6 hours for 48 hours) was commenced 24 hours after methotrexate. Plasma levels of methotrexate were monitored at 24 and 48 hours after methotrexate administration, and leucovorin rescue at 30 to 60 mg every 6 hours was administered until the plasma levels were less than 2.5 x 10⁶ mol/L.

The FUP regimen was administered as originally described by Lacave et al²⁷: 5-FU was given as a continuous IV infusion in a dose of 1 g/m²/d for 5 consecutive days, and cisplatin 100 mg/m² was given as a 1-hour infusion with hyperhydration on day 2. The cycles were repeated every 29 days.

The ELF regimen consisted of folinic acid at a dose of 300 mg/m² given as a 10-minute IV infusion, followed immediately by etoposide 120 mg/m² given as a 50-minute IV infusion, followed by bolus 5-FU 500 mg/m² for 3 consecutive days. The cycles were repeated every 22 days.¹⁵ Dose modifications and/or treatment delays were made according to the originally published protocols for FAMTX, ELF, and FUP, respectively.^9,15,27

Pretreatment Evaluation and Follow-Up
Baseline evaluation included a complete medical history and physical examination, complete blood cell count (CBCC), serum chemistry that included electrolytes, liver and renal function tests, ECG, chest x-ray, abdominal ultrasound, and computed tomographic (CT) scan(s) of the measurable target lesion(s). If indicated, endoscopy, bone scan, and x-ray were performed. During the study treatment, patients were monitored before each new cycle of chemotherapy, which included the assessment of clinical toxicities, CBCC, serum chemistry, and physical examinations. ECG, chest x-ray, and measurement of the target lesion(s) by CT scan(s), ultrasound, and/or endoscopic evaluation were additionally performed every two cycles and at the end of treatment. During the follow-up period, patients were evaluated every 3 months after the end of study treatment by physical examination, CBCC, serum chemistry, ECG, chest x-ray, and measurement of the target lesion(s) by CT-scan(s), ultrasound, and/or endoscopic evaluation, in case of tumor response or stable disease, until documented disease progression.

Toxicity and Response Evaluation
Toxicities were evaluated and graded according to WHO criteria. Tumor response was assessed every two cycles of chemotherapy (every 6 weeks for ELF and every 8 weeks for FUP and FAMTX) and at the end of treatment. Complete remission, partial remission, no change, and progressive disease were defined according to the standardized response definitions of the WHO. Tumor responses had to be confirmed by a second evaluation at least four weeks apart. The data files and CT scans of patients who achieved an objective remission were centrally reviewed by a board of the study coordinators. Only patients with bidimensionally measurable disease (eg, hepatic or lung metastases or lymph nodes) were considered assessable for objective remissions. Unconfirmed responses were not considered in the response analysis for objective remissions. Primary tumors were defined as assessable nonmeasurable disease, and responses were only classified as complete remission, stable disease, or progression of disease.

Statistics and Data Analysis
The primary end point of the study was response to treatment. Based on the past experience in the chemotherapy of gastric cancer, the percentage of responses that were considered to be of interest in all three regimens was assumed to be 35%. To detect a difference of 20% (with a power of 80% using a two-sided significance level of 5%) in response rate between any two treatment groups, 400 patients were needed. The analysis of response to treatment was restricted to the eligible patients with measurable disease (bidimensional lesion[s]) and according to the treatment arm in which the patients were randomized. Primary tumors were considered as assessable nonmeasurable lesion(s). To keep an overall alpha error of 5% on each end point and considering that two comparisons were to be performed with FAMTX as the reference treatment arm, the level of significance for both comparisons was 2.5%. Comparison of the response rate between two treatment arms was performed using the ² test, but CIs were calculated using the exact empirical distribution.³⁰ The safety analysis was restricted to the patients who received at least one cycle of the administered chemotherapy. The time-to-event end points were estimated using the method of Kaplan and Meier³¹ and based on the intent-to-treat principle (all randomized patients were analyzed according to the treatment arm in which they were initially randomized). Overall survival was defined as the time interval between the date of randomization and the date of death. Progression-free survival was defined as the time interval between the date of randomization and the date of disease progression or death, whichever occurred first. Duration of response was defined as the time interval between the date of randomization and the date of disease progression for responders only. If the event was not yet observed at the time of last record, the patient was censored at that time point. Both the ELF and the FUP regimens were compared with the FAMTX arm for the different time-to-event end points using the two-sided unstratified log-rank test at a level of 2.5% significance to keep the overall alpha error at 5% on each end point.³² Retrospective stratification in the proportional hazards regression model was used to adjust for confounding variables.³³ The ratio of the instantaneous rate of events and its 95% CI were given for each comparison.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
From July 1991 to April 1995, 399 patients with locally advanced or metastatic gastric cancer from 54 institutions were randomized (ELF, 132 patients; FUP, 134; and FAMTX, 133). Fifteen institutions entered fewer than three patients, and the median number of patients treated per institution was four (range, one to 44 patients). A total of 376 patients (94%) were eligible. Fourteen patients (ELF, six patients; FUP, three; and FAMTX, five) were ineligible because of disease stage (eg, not drained ascites or pleural effusion), incorrect histology, concurrent treatment, abnormal blood chemistry, or other violations of inclusion criteria. For nine other patients (ELF, four; FUP, two; and FAMTX, three), no further information was received after the initial randomization and eligibility criteria could not be proven.

The patient characteristics are listed in Table 1. With exception of performance status, which favored the ELF regimen, all three treatment arms were balanced. Sixty-five patients (16%) had locally advanced disease, and 335 (84%) had metastatic disease. A total of 253 patients (63%) had measurable lesion(s), 116 (29%) had assessable but nonmeasurable lesion(s), and 30 (8%) had nonassessable lesion(s). The detailed tumor sites per treatment arm are listed in Table 2.

The median number of cycles for patients who received treatment was four for the ELF regimen (range, one to eight), four for FUP (range, one to eight), and three for FAMTX (range, one to six). The median treatment duration was 13 weeks in both the ELF and FAMTX arms and 16 weeks for the FUP regimen. The toxicities are listed in Table 3. The major toxicity was myelosuppression. Neutropenia grades 3 and 4 was common and was observed in approximately 40% of all patients (ELF, 39%; FUP, 35%; and FAMTX, 43%). Thrombocytopenia grades 3 and 4 was almost absent for the ELF regimen but occurred in 9% and 5% of patients treated with FUP and FAMTX, respectively. With the exception of nausea/vomiting and mucositis, nonhematologic toxicities were generally mild, and no major differences were observed between the regimens. However, the FUP regimen resulted in more severe nausea/vomiting, which occurred in 26% of patients, and a lower rate of mucositis occurred in the ELF arm. Occurrence of late toxicities was observed in seven patients (5%) treated with ELF (eg, alopecia, prolonged myelosuppression, mucositis, and diarrhea), in 14 (11%) who received FUP (mainly polyneuropathy, ototoxicity, and nephrotoxicity), and in four (3%) treated with FAMTX (eg, nephrotoxicity and prolonged myelosuppression). Thirty-five patients (9%) discontinued study treatment because of toxicity (ELF, three; FUP, 20; and FAMTX, 12), and 20 (5%) refused to continue study treatment (ELF, five; FUP, five; and FAMTX, 10). There were seven treatment-related deaths (FUP, two, and FAMTX, five).

Response to Treatment
The best overall response to treatment for all 245 eligible patients with measurable disease (ELF, 79; FUP, 81; and FAMTX, 85) is presented in Table 4. Seventeen patients with early death (four with toxic death, 10 with disease-related death, and three with early death of unknown cause) and 26 who did not start chemotherapy (eg, because of progression of disease, deterioration, or organ dysfunction) or for whom no sufficient data on treatment and/or tumor response had been received were included in the response analysis. Of note, primary tumors were defined as nonmeasurable disease, and only bidimensionally measurable lesions (eg, hepatic or lung metastasis and lymph nodes) were considered assessable for objective remissions. Reviewed and confirmed tumor responses were observed in 9% of patients (95% CI, 3.5% to 17.5%; seven partial responses) treated with the ELF regimen, 20% of patients (95% CI, 11.5% to 30%; 16 partial responses) with FUP, and 12% of patients (95% CI, 6% to 20.5%; 10 partial responses) with FAMTX. When compared with FAMTX, the differences in tumor response for the ELF and FUP regimens were not statistically significant (P = .73 and .77, respectively, by ² test). Thirty-six (46%), 35 (43%), and 29 patients (34%) achieved no change of disease who were treated with the ELF, FUP, and FAMTX regimens, respectively. The tumor growth control rates were 54.5% (95% CI, 43% to 65.5%) for ELF, 63% (95% CI, 51.5% to 73.5%) for FUP, and 46% (95% CI, 35% to 57%) for FAMTX. The median duration of responses was 8.0 months (95% CI, 6.8 to 10.9 months) for ELF, 7.1 months (95% CI, 6 to 10.1 months) for FUP, and 9.5 months (95% CI, 5.9 to 20.6 months) for FAMTX.

Progression-Free and Overall Survival
The progression-free survival times of the different treatments are listed in Fig 1. The progression-free survival time was 3.3 months (95% CI, 2.9 to 4.1 months) for the ELF regimen, 4.1 months (95% CI, 3.8 to 5.4 months) for FUP, and 3.3 months (95% CI, 2.3 to 4.3 months) for FAMTX. There was no significant difference between the treatments with respect to progression-free survival (P = .89 for ELF v FAMTX and P = .36 for FUP v FAMTX, by log-rank test). The probability at 6 months for progression-free survival was 26% for the ELF regimen (95% CI, 18% to 33%), 36% for the FUP regimen (95% CI, 28% to 45%), and 24% for the FAMTX regimen (95% CI, 17% to 32%).

View larger version (15K): [in this window] [in a new window]   Fig 1. Progression-free survival time for the ELF, FUP, and FAMTX regimens. Abbreviations: O, odds; N, no. of patients.

View larger version (15K): [in this window] [in a new window]   Fig 2. Overall survival time for all patients (N = 399) treated with ELF, FUP, or FAMTX.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

The results of the present large randomized multicenter study demonstrate modest clinical efficacy of all three investigated regimens in advanced gastric cancer, with no significant differences in overall response rate, progression-free survival, or overall survival. The inferior response rates of the investigated regimens may be partially explained by the elimination of case-selection bias, which is commonly observed in nonrandomized trials. Furthermore, previous studies included the primary tumor for analysis of objective remission using CT scanning, endoscopy, or ultrasound technique, which resulted in nonstandardized response definitions and difficulty in interpreting tumor response rates. Thus, in the present trial, only patients with clearly measurable disease (eg, hepatic metastasis or lymph nodes) were considered assessable for objective remissions. Applying strict response criteria (eg, confirmed responses by two investigations at least 4 weeks apart, with external data review), objective tumor remissions were only observed in 9%, 20%, and 12% of patients with measurable metastatic disease treated with ELF, FUP, and FAMTX, respectively. Although the response rate favored the FUP regimen, the difference in tumor response was not statistically significant to the FAMTX regimen. Of importance is that only two of 357 eligible patients with measurable or assessable nonmeasurable disease achieved a complete response.

Previous randomized trials of FAMTX yielded median survival durations of 5.7 to 10.4 months.^11,13 In the present study, the median survival time of the FAMTX regimen was 6.7 months (95% CI, 5.1 to 7.6 months), with no significant differences between the treatment arms with respect to overall survival. The equivalence in treatment efficacy remains when adjusted for different prognostic factors by the Cox proportional hazards regression model (Table 5).

Although the ELF regimen has been reported to be presumably less toxic than other chemotherapy regimens,^14,16,18 in the present study neutropenia grades 3 and 4 was the main toxicity for all three investigated regimens and occurred in approximately 40% of all patients, with no differences between the treatment arms (Table 3). With exception of severe nausea/vomiting, which was more frequent for the FUP regimen, other hematologic and nonhematologic toxicities were infrequent or of mild-to-moderate severity (eg, polyneuropathy or nephrotoxicity) (Table 3). Prophylactic antiemetic treatment was administered according to the individual protocol of each center (category: highly emetic) but did not necessarily contain 5-HT3 receptor antagonists (eg, ondansetron). Thus, the incidence and severity of emesis observed for the FUP regimen might be related to insufficient antiemetic therapy in some cases.

Recently, in a randomized trial for advanced gastric cancer, an infusional 5-FU–based combination chemotherapy with cisplatin and epirubicin (ECF regimen) proved to be significantly superior to the FAMTX regimen in terms of response rate (45% [95% CI, 36% to 54%] v 21% [95% CI, 13% to 29%]) and median survival time (8.9 v 5.7 months, respectively).¹³ Thus, the ECF combination suggested a new reference treatment for further clinical trials in advanced gastric cancer. However, the following should be considered in interpreting these data: (1) overall survival analysis included one third of patients with locally advanced disease, which is commonly associated with improved prognosis; (2) 12 (25%) of 47 ECF-treated patients with locally advanced disease underwent curative surgery after neoadjuvant chemotherapy, which might influence long-time survival; and (3) approximately 40% of patients had adenocarcinoma of the esophagus or esophagogastric junction, which might not necessarily reflect the biologic characteristics of gastric cancer.

Data on leucovorin-modulated high-dose infusional 5-FU (2.0 g/m²/24 h IV infusion) given weekly for 6 weeks in combination with biweekly cisplatin (5-FU_{24 hours}/leucovorin + cisplatin) suggest significant clinical efficacy with acceptable toxicity in locally advanced and metastatic gastric cancer.³⁴ This regimen is currently under clinical investigation by the EORTC Gastrointestinal Tract Cancer Cooperative Group, and the results will be available in the near future. Of importance is that the regimen of FU_{24 hours}/leucovorin + cisplatin provides a higher dose-intensity of 5-FU compared with the investigated regimens of ELF, FAMTX, and FUP. So far, it seems that infusional 5-FU–based combination regimens could be a promising approach in the treatment of gastric cancer.^13,34

Topoisomerase-I interactive agents (eg, irinotecan) and taxanes showed significant antitumor efficacy in advanced gastric cancer, lacking clinical cross-resistance to cisplatin and 5-FU.^35-38 Furthermore, it has been recently reported that the combination of irinotecan and cisplatin has promising antitumor activity with acceptable side effects in patients with gastric cancer.³⁹ However, the role of new drugs, especially their potential in combination therapy, needs to be further clarified in randomized trials.

Based on the data reported herein, we conclude the following: (1) the ELF and FUP regimens have comparable antitumor efficacy in terms of tumor response, progression-free survival, and overall survival time compared with FAMTX; (2) considering remission rate and overall survival as major end points of this study, all three regimens showed modest clinical activity in advanced gastric cancer; and (3) all three regimens were associated with a comparable incidence, type, and degree of toxicity. However, different levels of practicability may favor the ELF regimen, which is essentially an outpatient protocol. Nevertheless, based on their low activity in advanced gastric cancer, none of these regimens can be regarded as standard treatment. It is of major importance to consider new strategies with better clinical efficacy in the treatment of advanced gastric cancer (eg, new drug combinations and analysis of molecular prognostic factors to identify responsive patients).

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following investigators and their centers participated in this study, with randomization of at least five patients: E. van Cutsem, University Hospital Gasthuisberg, Leuven; H. Bleiberg, Institut Jules Bordet, Brussels, Belgium; P. Rougier and M. Ducreux, Institut Gustave Roussy, Villejuif; P. Piedbois, Henri Mondor Hospital, Creteil; B. Paillot, Centre Hospitalier Universitaire de Rouen, Rouen-Cedex, France; H. Wilke and U. Vanhoefer, University of Essen Medical School, Essen; M. Planker, Klinikum Krefeld, Krefeld; H. Schmoll and H. Drobny, Martin-Luther University and Clinic of Kröllwitz, Halle-Saale; H. Bodenstein, Klinikum Minden, Minden; H. Riess, University Clinics Rudolf-Virchow, Berlin; J.H. Hartlapp, University Clinics, Bonn; O. Clemens, Eberhard Karls University, Tübingen; H. König, University Clinics Erlangen, Erlangen; L. Balleisen, Evangelisches Krankenhaus, Hamm; H.E. Reis, Krankenhaus Maria Hilf, Mönchengladbach; W. Dornhoff, Mutterhaus der Borromäerinnen, Trier, Germany; J. Wils, St Laurentius Ziekenhuis, Roermond; F. Erdkamp, De Goodelijke Voorzienigheid Maasland, Sittard; R.L.H. Janssen, Academisch Ziekenhuis, Maastricht; P. Pannebakker, De Wever Ziekenhuis, Heerlen, the Netherlands; J. Guimaraes Dos Santos and E. Sanches Dos Santos, Instituto Portuges de Oncologia, Porto, Portugal; A. Lacave, Hospital General de Asturias, Oviedo; H. Gravalos, Hospital Universitario 12 de Octobre, Madrid; F.L. Wul, Hospital Nuestra Senora del Christal, Orense; L.M.G. Sande, Hospital de León, León; L.M. Antón-Aparicio, Hospital Juan Canalejo, La Coruna; M. Constenla, Hospital Montecelo, Pontevedra, Spain; and F.G. Lejeune, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

	ACKNOWLEDGMENTS

 
Supported by grants no. 5U10 CA11488-20 through 5U10 CA11488-29 from the National Cancer Institute, Bethesda, MD.

	NOTES

 
Presented in part at the Thirty-First Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 20-23, 1995.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

	REFERENCES

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Submitted December 2, 1999; accepted March 8, 2000.

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