© The Author 2007. Published by Oxford University Press.
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Adjuvant Treatment of High-Risk, Radically Resected Gastric Cancer Patients With 5-Fluorouracil, Leucovorin, Cisplatin, and Epidoxorubicin in a Randomized Controlled Trial
On behalf of the Italian Group for the Study of Digestive Tract Cancer
Affiliations of authors: Universita' Politecnica delle Marche, Ancona, Italy (SC); Azienda Ospedaliera "Ospedali Riuniti" di Bergamo, Bergamo, Italy (RL, GDB); Universita' Cattolica del Sacro Cuore, Roma, Italy (CB, AC); Istituto Humanitas, Milano, Italy (As, CC); Azienda Ospedaliera "Ospedale S Salvatore," Pesaro, Italy (VC); Azienda Ospedaliera S Gerardo, Monza, Italy (OB); Azienda Ospedaliera Le Molinette, Torino, Italy (SB); Azienda Ospedaliera S Paolo, Milano, Italy (LF, EA); Azienda Ospedaliera "Ospedale Poma," Mantova, Italy (EA); GISCAD Centre (SR), Clinical Trials Unit and Cancer Clinical Research Laboratory (VT, IF), Mario Negri Institute, Milano, Italy
Correspondence to: Stefano Cascinu, MD, Clinica di Oncologia Medica, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona; Universita' Politecnica delle Marche, Via Conca 60020 Ancona, Italy (e-mail: cascinu{at}yahoo.com).
Background: Promising findings obtained using a weekly regimen of 5-fluorouracil (5-FU), epidoxorubicin, leucovorin (LV), and cisplatin (PELFw) to treat locally advanced and metastatic gastric cancer prompted the Italian Group for the Study of Digestive Tract Cancer (GISCAD) to investigate the efficacy of this regimen as adjuvant treatment for high-risk radically resected gastric cancer patients.
Methods: From January 1998 to January 2003, 400 gastric cancer patients at high risk for recurrence including patients with serosal invasion (stage pT3 N0) and/or lymph node metastasis (stage pT2 or pT3 N1, N2, or N3), were enrolled in a trial of adjuvant chemotherapies; 201 patients were randomly assigned to receive the PELFw regimen, consisting of eight weekly administrations of cisplatin (40 mg/m2), LV (250 mg/m2), epidoxorubicin (35 mg/m2), 5-FU (500 mg/m2), and glutathione (1.5 g/m2) with the support of filgrastim, and 196 patients were assigned to a regimen consisting of six monthly administrations of a 5-day course of 5-FU (375 mg/m2 daily) and LV (20 mg/m2 daily, 5-FU/LV). Disease-free and overall survival were estimated and compared between arms using hazard ratios (HRs) and Kaplan–Meier estimates. All statistical tests were two-sided.
Results: The 5-year survival rates were 52% in the PELFw arm and 50% in the 5-FU/LV arm. Compared with the 5-FU/LV regimen, the PELFw regimen did not reduce the risk of death (HR = 0.95, 95% confidence interval [CI] = 0.70 to 1.29) or relapse (HR = 0.98, 95% CI = 0.75 to 1.29). Less than 10% of patients in either arm experienced a grade 3 or 4 toxic episode. Neutropenia (occurring more often in the PELFw arm) and diarrhea and mucositis (more prevalent in the 5-FU/LV arm) were the most common serious side effects. Nevertheless, only 19 patients (9.4%) completed the treatment in the PELFw arm and 85 (43%) patients completed the treatment in the 5-FU/LV arm.
Conclusions: Our study found no benefit from an intensive weekly chemotherapy in gastric cancer. The extent of toxicity experienced by the patients in the adjuvant setting suggests that, in gastric cancer, chemotherapy may be more safely administered preoperatively.
| CONTEXT and CAVEATS Prior knowledge The relative effectiveness of promising adjuvant chemotherapies for gastric cancer patients who have had surgery and are at high risk of recurrence was largely unknown. Study design This was a randomized trial comparing two treatment arms. Contribution This trial showed that a regimen consisting of cisplatin, leucovorin, epidoxorubicin, 5-fluorouracil, and glutathione was not more effective in prolonging survival of gastric cancer patients than a previously used regimen based on 5-fluorouracil and leucovorin. Implications Additional strategies that may include preoperative therapies that do not have the side effects associated with postoperative chemotherapy will be needed to treat gastric cancer patients who are at high risk. Limitations It was not feasible to include a control arm in this trial, and an unexpectedly high survival rate in both treatment arms, possibly due to the high quality of the gastric surgery that was performed, limited the statistical power of the study to detect differences in outcomes.
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Manuscript received July 29, 2006; revised February 1, 2007; accepted March 8, 2007.
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J Natl Cancer Inst 2007 99: 1345-1346.
J Natl Cancer Inst 2007 99: 580-582.
J Natl Cancer Inst 2007 99: 577.
J Natl Cancer Inst 2007 99: 577.
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