Originally published as JCO Early Release 10.1200/JCO.2002.04.123 on July 9 2002

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Multicenter Phase III Study of Uracil/Tegafur and Oral Leucovorin Versus Fluorouracil and Leucovorin in Patients With Previously Untreated Metastatic Colorectal Cancer

From the Centre René Gauducheau, Nantes, France; University of Texas, M.D. Anderson Cancer Center, Houston, TX; Nova Scotia Cancer Center, Halifax, Canada; California Healthcare, Greenbrae, CA; North Middlesex and Guy’s Hospital, London, United Kingdom; London Regional Cancer Center, London, Canada; University of Pittsburgh Cancer Center, Pittsburgh, PA; and Bristol-Myers Squibb Company, Wallingford, CT.

Address reprint requests to Prof Jean-Yves Douillard, Centre René Gauducheau, Site Hospitalier Nord, Bld J. Monod, 44805 Saint Herblain Cedex, France; email: jy-douillard{at}nantes.fnclcc.fr

PURPOSE: This phase III study was designed to demonstrate equivalence in survival of oral uracil/tegafur (UFT) and oral leucovorin (LV) to conventional intravenous (IV) fluorouracil (5-FU) and LV in previously untreated metastatic colorectal carcinoma. Safety was also compared.

PATIENTS AND METHODS: Eight hundred sixteen patients were randomized to receive either UFT (300 mg/m²/d) and LV (75 or 90 mg/d) for 28 days every 35 days or IV bolus 5-FU (425 mg/m²/d) and LV (20 mg/m²/d) for 5 days every 28 days.

RESULTS: UFT/LV produced survival comparable to the IV 5-FU/LV regimen. Median survival was 12.4 months (95% confidence interval [CI], 11.2 to 13.6 months) with UFT/LV and 13.4 months (95% CI, 11.6 to 15.4 months) with 5-FU/LV (P = .630). The hazard ratio for survival was 0.964 (95.6% CI, 0.826 to 1.125), supporting equivalent survival. The overall response rate did not differ between treatment arms (UFT/LV, 11.7%; 5-FU/LV, 14.5%; P = .232). Median time to progression favored 5-FU/LV (UFT/LV, 3.5 months; 5-FU/LV, 3.8 months; P = .011), but tumor assessment schedules differed between arms. UFT/LV significantly improved safety compared with 5-FU/LV. Diarrhea, nausea and vomiting, and stomatitis and mucositis were significantly less frequent with UFT/LV, as was myelosuppression. Patients treated with UFT/LV had fewer episodes of febrile neutropenia (P < .001) and documented infections (P < .05). Increased bilirubin, without other liver function abnormalities, was observed more often with UFT/LV (P < .001). Concomitant medications were more frequent with 5-FU/LV, including use of antibiotics, growth factors, and antiemetics.

CONCLUSION: UFT/LV provided a safer, more convenient oral alternative to a standard bolus IV 5-FU/LV regimen for metastatic colorectal cancer while producing equivalent survival.

This article was published ahead of print at www.jco.org.

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