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Journal of Clinical Oncology, Vol 25, No 18 (June 20), 2007: pp. 2580-2585 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.1666 Weekly Infusional High-Dose Fluorouracil (HD-FU), HD-FU Plus Folinic Acid (HD-FU/FA), or HD-FU/FA Plus Biweekly Cisplatin in Advanced Gastric Cancer: Randomized Phase II Trial 40953 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group and the Arbeitsgemeinschaft Internistische Onkologie
From the Caritasklinik St Theresia, Saarbrücken; Kliniken Essen-Mitte, Essen; Universitätsklinikum Essen, Essen; Universitätskrankenhaus Eppendorf, Hamburg; Evangelisches Krankenhaus, Hamm, Germany; UMC St Radboud, Nijmegen; AZ Maastricht, Maastricht; Laurentius Ziekenhuis, Roermond, the Netherlands; Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland; AZ Middelheim, Middelheim; European Organisation for Research and Treatment of Cancer Data Center, Brussels; and UZ Leuven, Leuven, Belgium Address reprint requests to Manfred P. Lutz, MD, Caritasklinik St Theresia, Rheinstr 2, 66113 Saarbrücken, Germany; e-mail: m.lutz{at}caritasklinik.de
Purpose: This multicentric, randomized, two-stage phase II trial evaluated three simplified weekly infusional regimens of fluorouracil (FU) or FU plus folinic acid (FA) and cisplatin (Cis) with the aim to select a regimen for future phase III trials. Patients and Methods: A total of 145 patients with advanced gastric cancer where randomly assigned to weekly FU 3,000 mg/m2/24 hours (HD-FU), FU 2,600 mg/m2/24 hours plus dl-FA 500 mg/m2 or l-FA 250 mg/m2 (HD-FU/FA), or FU 2000 mg/m2/24 hours plus FA plus biweekly Cis 50 mg/m2, each administered for 6 weeks with a 1-week rest. The primary end point was the response rate. Results: Confirmed responses were observed in 6.1% (two of 33) of the eligible patients treated with HD-FU, in 25% (12 of 48, including one complete remission [CR]) with HD-FU/FA, and in 45.7% (21 of 46, including four CRs) with HD-FU/FA/Cis. The HD-FU arm was closed after stage 1 because the required minimum number of responses was not met. The median progression-free survival of all patients in the HD-FU, HD-FU/FA, and HD-FU/FA/Cis arm was 1.9, 4.0, and 6.1 months, respectively. The median overall survival was 7.1, 8.9, and 9.7 months, and the survival rate at 1 year was 24.3%, 30.3%, and 45.3%, respectively. Grade 4 toxicities were rare. The most relevant grade 3/4 toxicities were neutropenia in 1.9%, 5.4%, and 19.6%, and diarrhea in 2.7%, 1.9%, and 3.9% of the cycles in the HD-FU, HD-FU/FA, and HD-/FU/Cis arms, respectively. Conclusion: Weekly infusional FU/FA plus biweekly Cis is effective and safe in patients with gastric cancer.
Adenocarcinoma of the stomach is a leading cause of cancer-related deaths worldwide. Advances in surgical technology led to an increase in R0 resections and to decreased perioperative mortality. Nevertheless, more than 80% of the patients still die as a result of their disease, either because they have an advanced tumor at the time of diagnosis or because of incurable recurrences after resection.1 Perioperative chemotherapy improves the results of surgery alone,2 and palliative chemotherapy has the potential to ameliorate symptoms or prolong survival in metastatic disease. However, the benefit from current treatment options is limited and clearly there is a need for other active and well-tolerated regimens. Several randomized trials demonstrated that fluorouracil (FU) -based chemotherapy significantly improves overall survival (OS) and quality of life in patients with metastatic disease.3-5 The activity of FU may be enhanced further by prolonged infusion or by modulation with folinic acid (FA), as shown by the European Organisation for Research and Treatment of Cancer (EORTC) and others in colorectal cancer.6,7 In addition, because infusional FU is less myelotoxic than the bolus application,6 this type of administration enables the combination with cisplatin (Cis) or other myelosuppressive drugs. In fact, the regimen of continuous infusion of FU in combination with intermittent epirubicin/Cis (ECF) is currently considered as a standard regimen because it increases median survival compared with FU, doxorubicin, methotrexate (FAMTX).8,9 This trial was designed to screen the activity of three different weekly infusional FU regimens, either with modulation by FA or in combination with Cis. None of the three regimens require protracted infusion and thus may be less cumbersome than ECF. In a dose-finding study with FU as single agent, a weekly infusion of 3,000 mg/m2/24 hours was recommended. Preliminary results in six patients with advanced gastric cancer yielded two objective responses, indicating activity of this simple regimen (Wilke et al, unpublished data). If FU is modulated by FA, the recommended dose levels are 500 mg/m2 of FA and 2,600 mg/m2 FU weekly.10,11 This regimen was investigated in 17 patients after failure of first-line chemotherapy, which included FU in 14 of the patients (etoposide, doxorubicin, Cis; FAMTX; etoposide, FA, and FU; and so on). Three patients with partial remission (response rate [RR] of 18%; 95% CI, 0% to 38%) and seven patients with stable diseases (41%; 95% CI, 17% to 64%) were observed in this group with an unfavorable prognosis, and the median survival time was 5 months.12 FU/FA and biweekly Cis was evaluated in a small German multicenter trial.13 Here, the recommended dose of FU was 2,000 mg/m2 and the recommended dose of Cis was 50 mg/m2. The overall RR in 50 patients was 66%. Outpatient treatment was well tolerated using implantable venous access systems and portable pumps. Median time to progression was 8 months and the median survival time was 11 months. Thus, all three regimens are active in gastric cancer, with no clear advantage of one of them. The EORTC GI Group therefore initiated this randomized phase II trial to define a regimen for comparison against a standard arm in a future phase III study. The main goal was to evaluate whether simplified, moderately toxic, and economically favorable FU regimens would be of interest. Initially, the trial was designed as a four-arm study using the three HD-FU–containing regimens (HD-FU, HD-FU/FA, HD-FU/FA/Cis) and FAMTX as a well-established and widely used internal control. The trial was amended and the FAMTX arm was closed after seven patients had been included because it became obvious after the publication of one large phase III trial that FAMTX is inferior to ECF.9 These results were supported by our own experience from a randomized phase III trial (EORTC 40902), in which FAMTX had only modest activity (response rates of 12%) with relevant toxicity (five treatment-related deaths in 133 patients).14 In this article, we present the final report of the EORTC trial 40953 in the 145 patients assigned to the three infusional FU-based regimens.
This was an open, prospective, randomized, multicenter, two-stage, phase II trial. Patients were centrally randomly assigned at the EORTC Data Center (Brussels, Belgium) and stratified according to institution, WHO performance status (0 or 1 v 2) and stage of disease (locally advanced v metastatic) using the minimization technique.
Patient Population
Treatment Chemotherapy was administered for four cycles unless there was documented disease progression, unacceptable toxicity, or patient refusal. Cisplatin was only administered during the first three cycles. Chemotherapy was delayed for at least one week in case of any diarrhea or mucositis at the day of planned treatment, or if granulocytes were less than 1,200/µL, platelets were less than 75,000/µL or hand-foot syndrome more than grade 2 occurred. FU was reduced by 20% if maximum diarrhea/mucositis exceeded grade 2. FU and Cis were reduced by 20% if granulopenia or thrombocytopenia was grade 4. Cisplatin was discontinued if neurotoxicity more than grade 1 or nephrotoxicity more than grade 2 occurred.
Pretreatment Evaluation and Follow-Up
Toxicity and Response Evaluation
Statistical Design RRs were evaluated for all patients with at least one measurable lesion. Although not originally foreseen in the protocol, progression-free survival (PFS) and median survival curves were also calculated using the method of Kaplan and Meier. Overall survival (OS) was defined as the time interval between the date of random assignment and the date of death. PFS was defined as the time interval between the date of random assignment and the date of disease progression or death, whichever occurred first. Response duration was calculated as the time interval between random assignment and date of progression (for responders only). If the event was not observed at the time of last information, the patient was censored at that time point. All eligible patients who started treatment were considered assessable for response. All patients who started treatment were considered assessable for toxicity. OS and PFS analyses included all entered patients.
From January 1996 to August 1999, 145 patients were enrolled by 17 institutions (37 patients to HD-FU, 54 patients to HD-FU/FA, and 54 patients to HD-FU/FA/Cis). The median number of patients treated per institution was nine (range, one to 25 patients); seven centers entered fewer than five patients. After stage 1 of the trial, the HD-FU arm was closed because only two responses had been observed, which did not meet the required minimum of at least four responses in the first 21 eligible patients. Total number of patients in this arm was 37 (33 eligible) because inclusion was not interrupted before interim analysis. Of the 145 patients entered, four did not start protocol treatment (one in the HD-FU/FA arm and three in the HD-FU/FA/Cis arm). Treatment and toxicity information was thus available for 141 patients (37 patients for HD-FU, 53 patients for HD-FU/FA arm, and 51 patients for HD-FU/FA/Cis). Thirty-eight patients in each arm received dl-FA; the remainder received the l-form. The patient characteristics for those who started treatment are listed in Table 1. All patients were white. Age, sex, performance status, histologic subtype, and location of the primary were well balanced, although there was a trend toward more patients having metastatic disease in the HD-FU/FA arm. Half of the patients had had prior surgery.
Eleven patients were considered ineligible (two with HD-FU, four with HD-FU/FA, and five with HD-FU/FA/Cis), mainly because of nonmeasurable disease (two in each arm) and because of incomplete files rendered the eligibility verification impossible (two with HD-FU, one with HD-FU/FA, three with HD-FU/FA/Cis; Fig 1). In total, 127 eligible patients started treatment and were thus assessable for response (33 patients with HD-FU, 48 patients with HD-FU/FA, 46 patients with HD-FU/FA/Cis). The median follow-up was 3.75 years.
Safety and Dose-Intensity In the 141 patients who started chemotherapy, the total number of cycles administered was 67 (median, one; range, one to four) for HD-FU, 144 (median, three; range, one to seven) for HD-FU/FA, and 143 (median, three; range, one ot seven) for HD-FU/FA/Cis. Forty-five patients (31.0%) received one cycle of chemotherapy (20 [54.1%] in HD-FU, 15 [28.3%] in HD-FU/FA, 10 [19.6%] in HD-FU/FA/Cis), 31 patients (21.4%) received two cycles (nine [24.3%] in HD-FU, 11 [20.8%] in HD-FU/FA, 11 [21.6%] in HD-FU/FA/Cis), 26 patients (17.9%) received three cycles (three [8.1%] in HD-FU, 11 [20.8%] in HD-FU/FA, 12 [23.5%] in HD-FU/FA/Cis), and 32 patients (22.1%) completed the four cycles of treatment (20 [54.1%] in HD-FU, 15 [28.3%] in HD-FU/FA, 10 [19.6%] in HD-FU/FA/Cis). Seven patients (4.8%) received more than the four predefined cycles of treatment, with a maximum of seven cycles. The toxicities are listed in Table 2. Severe (grade 3/4) toxicity was rare in all three arms. Grade 3 neutropenia was more frequent with HD-FU/FA/Cis and there was somewhat more frequent nausea and vomiting in this arm. The incidence of alopecia was moderate. Grade 3 neurotoxicity was observed in four patients (7.8%) treated with Cis. There was one treatment-related death in the HD-FU/FA/Cis arm as a result of a bilateral pneumonia probably caused by aspiration.
Toxicity-related dose-reductions and dose delays were reported in seven patients (18.9%) and seven patients (18.9%) in the HD-FU arm, in 19 patients (35.8%) and eight patients (15.1%) in the HD-FU/FA arm, and in 22 patients (43.1%) and 17 patients (33.3%) in the HD-FU/FA/Cis arm, respectively. This resulted in a median relative FU dose-intensity of 89.7% with HD-FU, 84.3% with HD-FU/FA, and 86.8% with HD-FU/FA/Cis. The median relative dose-intensity for Cis in the HD-FU/FA/Cis arm was 77.8%.
Response and Response Duration
PFS and OS The median PFS and the PFS at 1 year, respectively, were 1.9 months (95% CI, 1.6 to 3.3 months) and 8.1% (95% CI, 0% to 16.9%) for HD-FU, 4.0 months (95% CI, 3.1 to 5.5) and 5.6% (95% CI, 0.0% to 11.7%) for HD-FU/FA, and 6.1 months (95% CI, 5.0 to 7.3 months) and 15.1% (95% CI, 5.5% to 24.7%) for HD-FU/FA/Cis. The median OS and survival rates at 1 year were 7.1 months (95% CI, 6.0 to 8.6 months) and 24.3% (95% CI, 10.5% to 38.2%) for HD-FU, 8.9 months (95% CI, 7.1 to 11.9 months) and 30.3% (95% CI, 17.9% to 42.7%) for HD-FU/FA, and 9.7 months (95% CI, 7.6 to 17.4 months) and 45.3% (95% CI, 31.9% to 58.7%) for HD-FU/FA/Cis, respectively. Twenty-five percent of the patients treated with HD-FU/FA/Cis were alive after 2 years (95% CI, 13.3% to 37.3%; Fig 2).
Gastric cancer is considered to be chemotherapy sensitive. FU-based chemotherapy doubles the median survival time in randomized trials when compared with best supportive care.3-5 Older phase II trials with combinations such as etoposide, doxorubicin, and Cis; etoposide, FA, and FU; FAMTX; and 5-day Cis/FU regimens achieved objective response rates of 40% to 50%. Unfortunately, these results could not be confirmed in randomized studies. When compared with FU, doxorubicin, and mitomycin or modifications of FU, doxorubicin, and mitomycin, the response rates rarely exceeded 25% and the median survival times were approximately 7 months.14,16 Moreover, some of these combinations were toxic or could only be administered in specialized centers. Additional developments focused on alternative application schedules of FU in combination with other drugs, such as Cis. Preclinical and clinical evidence in colorectal cancer demonstrated that weekly or biweekly 24- to 48-hour infusion of increased doses of FU or continuous infusion over months could increase its efficacy or overcome FU resistance with a favorable toxicity profile, probably because long-term exposure preferably results in inhibition of thymidylate synthase and thus inhibition of DNA synthesis, whereas the FU bolus application instead promotes incorporation into nascent RNA.6 This effect may be enhanced further by the addition of reduced folates, which are necessary for ternary complex formation of 5-fluorodesoxymonophosphate with thymidylate synthase. Because the protracted infusion is less myelotoxic, combinations of FU with other active but myelosuppressive drugs became feasible. ECF, the current standard in the treatment of advanced gastric cancer, is based on the continuous infusion of FU for months in combination with IV epirubicin and Cis. ECF increased response rates and significantly improved median survival times as compared with FAMTX,8 and was equivalent to MCF, with an overall response rate of 42.4% and median survival time of 9.4 months.17 The results of the present multicentric, randomized, phase II study suggest that another infusion scheme of FU, the weekly infusion of FU during 24 hours, is active when combined with either FA or with FA and Cis, with response rates of 25% and 46%, including complete responses in one of 48 and in four of 49 patients, respectively. Although this is a phase II study and a formal comparison between the three treatment arms was not carried out, the activity results seem to favor the HD-FU/FA/Cis combination as compared with HD-FU/FA, and also with regard to HD-FU, where only two partial responses were observed in 33 patients (6.1%). A trend to longer median survival with HD-FU/FA/Cis is also suggested as compared with HD-FU/FA or HD-FU (9.7 v 8.9 v 7.1 months, respectively). Overall, the activity of HD-FU/FA/Cis in this study is in the same range than that observed with ECF, with an apparently similar median survival. Infusional FU is less toxic than FU administered as a bolus application.6 In our hands, toxicity of either HD-FU/FA or HD-FU/FA/Cis was moderate, with less than 2% with grade 4 myelotoxicity in the HD-FU/FA arm and less than 4% in the HD-FU/FA/Cis arm. We observed three episodes of serious infections in 143 cycles in the 51 patients in the HD-FU/FA/Cis arm, with one death as a result of toxicity after aspiration of gastric contents and resulting pneumonia. With HD-FU/FA/Cis, dose reductions were necessary in 43% of the patients and dose delays were reported in 33%. Again, these results are in the same range than those reported with ECF (41% dose reductions and 32% dose delays, respectively),9 and compare favorably with FAMTX, for which 56% dose reductions and dose delays were reported.14 In summary, our results suggest that the addition of FA and Cis to FU increases its activity in gastric cancer. This has not been shown in this tumor type before. In addition, the increase of activity was not associated with a substantial increase in adverse effects. Moreover, activity and survival results of HD-FU/FA/Cis seem to be in the same range as those achieved with ECF,9 with other infusional FU/Cis regimens,18 or with novel combinations such as FU plus irinotecan,19 oxaliplatin,20 docetaxel,21 or docetaxel/Cis.22,23 We conclude that HD-FU/FA/Cis is safe and active in gastric carcinoma. This simple regimen might be a convenient alternative for patients who cannot or do not want to be treated with more aggressive combination chemotherapy or with protracted infusion of FU over months. Because of its simplicity and moderate toxicity, it might be well suited as a perioperative regimen. Confirmation is necessary from phase III trials.
The author(s) indicated no potential conflicts of interest.
Conception and design: Hansjochen Wilke, D.J. Theo Wagener, Jacques Wils, Eric Van Cutsem Administrative support: Muriel Debois, Ullrich Bethe, Michel Praet Provision of study materials or patients: Manfred P. Lutz, Hansjochen Wilke, D.J. Theo Wagener, Udo Vanhoefer, Krzysztof Jeziorski, Susanna Hegewisch-Becker, Leopold Balleisen, Eric Joosens, Rob L. Jansen, Jacques Wils, Eric Van Cutsem Collection and assembly of data: Hansjochen Wilke, Muriel Debois, Michel Praet Data analysis and interpretation: Manfred P. Lutz, Hansjochen Wilke, Muriel Debois, Ullrich Bethe, Jacques Wils Manuscript writing: Manfred P. Lutz, Hansjochen Wilke, Muriel Debois, Ullrich Bethe, Eric Van Cutsem Final approval of manuscript: Manfred P. Lutz, Hansjochen Wilke, D.J. Theo Wagener, Udo Vanhoefer, Krzysztof Jeziorski, Susanna Hegewisch-Becker, Leopold Balleisen, Eric Joosens, Rob L. Jansen, Muriel Debois, Ullrich Bethe, Michel Praet, Jacques Wils, Eric Van Cutsem
The following investigators participated in the trial: T. Wagener, UMC St Radboud, Nijmegen (NL), 28 patients; M.P. Lutz, Universitätsklinikum Ulm, Ulm (D), 20 patients; J. Wils, Laurentius Ziekenhuis, Roermond (NL), 19 patients; E. Van Cutsem, UZ Leuven, Leuven (B), 18 patients; U. Vanhoefer and A. Harstrick, Universitätsklinikum Essen, Essen (D), 12 patients; K. Jeziorski, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw (PL), eight patients; S. Hegewisch-Becker, Universitätsklinikum Hamburg-Eppendorf, Hamburg (D), eight patients; L.Balleisen, Evangelisches Krankenhaus, Hamm (D), seven patients; R. Mathijs, AZ Middelheim, Middelheim (B), six patients; R.L. Jansen, AZ Maastricht/RTIL, Maastricht (NL), six patients; H.J. Wilke, Kliniken Essen-Mitte, Essen (D), six patients; R. Engelhardt, Klinikum der Albert-Ludwig-Universität Freiburg, Freiburg (D), 4 patients; R. Fuchs and C. Maintz, St Antonius-Hospital, Eschweiler (D), four patients; R. Kleinschmidt, Universitätsklinikum Bonn, Bonn (D), two patients; P. Preusser, Westfälische Wilhelms-Universität Münster (D), two patients; J. Fleeth, Allgemeines Krankenhaus St. Georg, Hamburg (D), one patient; J.L. Van Laethem, Hôpital Erasme, Brussels (B), one patient.
Supported by Grants No. 5U10 CA11488-26 through 5U10 CA11488-33 from the National Cancer Institute (Bethesda, MD). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. M.P.L. and H.W. contributed equally to this publication. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Macdonald JS: Gastric cancer: New therapeutic options. N Engl J Med 355:76-77, 2006 2. Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11-20, 2006 3. Glimelius B, Ekstrom K, Hoffman K, et al: Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8:163-168, 1997[CrossRef][Medline] 4. Pyrhonen S, Kuitunen T, Nyandoto P, et al: Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71:587-591, 1995[Medline] 5. Murad AM, Santiago FF, Petroianu A, et al: Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 72:37-41, 1993[CrossRef][Medline] 6. Kohne CH, Wils J, Lorenz M, et al: Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952. J Clin Oncol 21:3721-3728, 2003 7. Thirion P, Michiels S, Pignon JP, et al: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: An updated meta-analysis. J Clin Oncol 22:3766-3775, 2004 8. Waters JS, Norman A, Cunningham D, et al: Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: Results of a randomized trial. Br J Cancer 80:269-272, 1999[CrossRef][Medline] 9. Webb A, Cunningham D, Scarffe JH, et al: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261-267, 1997 10. Ardalan B, Chua L, Tian EM, et al: A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma. J Clin Oncol 9:625-630, 1991[Abstract] 11. Haas NB, Hines JB, Hudes GR, et al: Phase I trial of 5-fluorouracil by 24-hour infusion weekly. Invest New Drugs 11:181-185, 1993[CrossRef][Medline] 12. Vanhoefer U, Wilke H, Weh HJ, et al: Weekly high-dose 5-fluorouracil and folinic acid as salvage treatment in advanced gastric cancer. Ann Oncol 5:850-851, 1994 13. Wilke H, Vanhoefer U, Fink U: Weekly high-dose FU/folinic acid (HD-FU/FA) and cisplatin (C): A safe and active combination for advanced gastric cancer (GC). Presented at Sec Intern Conf on Biol, Prev and Treatm of GI Malign, Cologne, Germany, February 5, 1995 14. Vanhoefer U, Rougier P, Wilke H, et al: 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. J Clin Oncol 18:2648-2657, 2000 15. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989[Medline] 16. Kelsen D, Atiq OT, Saltz L, et al: FAMTX versus etoposide, doxorubicin, and cisplatin: A random assignment trial in gastric cancer. J Clin Oncol 10:541-548, 1992 17. Ross P, Nicolson M, Cunningham D, et al: Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20:1996-2004, 2002 18. Mitry E, Taieb J, Artru P, et al: Combination of folinic acid, 5-fluorouracil bolus and infusion, and cisplatin (LV5FU2-P regimen) in patients with advanced gastric or gastroesophageal junction carcinoma. Ann Oncol 15:765-769, 2004 19. Moehler M, Eimermacher A, Siebler J, et al: Randomised phase II evaluation of irinotecan plus high-dose 5-fluorouracil and leucovorin (ILF) vs 5-fluorouracil, leucovorin, and etoposide (ELF) in untreated metastatic gastric cancer. Br J Cancer 92:2122-2128, 2005[CrossRef][Medline] 20. Al-Batran SE, Atmaca A, Hegewisch-Becker S, et al: Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. J Clin Oncol 22:658-663, 2004 21. Roth AD, Maibach R, Fazio N, et al: 5-Fluorouracil as protracted continuous intravenous infusion can be added to full-dose docetaxel (Taxotere)-cisplatin in advanced gastric carcinoma: A phase I-II trial. Ann Oncol 15:759-764, 2004 22. Roth AD, Maibach R, Martinelli G, et al: Docetaxel (Taxotere)-cisplatin (TC): an effective drug combination in gastric carcinoma: Swiss Group for Clinical Cancer Res (SAKK), and the European Institute of Oncology (EIO). Ann Oncol 11:301-306, 2000 23. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al: Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: A report of the V325 Study Group. J Clin Oncol 24:4991-4997, 2006 Submitted February 6, 2007; accepted March 29, 2007. Related Correspondence
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
75 years with histologically confirmed, locally advanced, unresectable, and/or metastatic gastric cancer; at least one bidimensionally measurable target lesion; no prior chemotherapy or radiotherapy; WHO performance status 
3,500/µL; platelets 
