Randomized C omparative S tudy o f T egafur/Uracil a nd O ral Leucovorin V ersus P arenteral F luorouracil a nd L eucovorin in P atients W ith P reviously U ntreated M etastatic Colorectal C ancer

Purpose: This phase III study compared the time to progression (TTP) of an oral regimen of dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine composed of a fixed combination of tegafur and uracil in a 1:4 molar ratio (UFT) and leucovorin (LV) to intravenous (IV) fluorouracil (5-FU) and LV in previously untreated metastatic colorectal carcinoma (CRC) patients. Secondary end points were survival, tumor response, safety, and quality of life. Patients and Methods: Between May 1996 and July 1997, 380 patients were randomized to receive either UFT (300 mg/m 2 /d) and LV (90 mg/d), administered for 28 days every 35 days, or 5-FU (425 mg/m 2 /d) and LV (20 mg/m 2 /d), given IV for 5 days every 35 days. Results: No statistically significant difference in TTP was observed between treatments. With 320 events assessed, the median TTP was 3.4 months (95% Confidence interval [CI], 2.6 to 3.8) on UFT/LV and 3.3 months (95% CI, 2.5 to 3.7) on 5-FU/LV (P .591, stratified log-rank test). There were no statistically significant differences in survival, tumor response, duration of response, and time to response. Substantial safety benefits were observed in patients treated with UFT/LV. They experienced significantly less stomatitis/ mucositis (P < .001) and myelosuppression, resulting in fewer episodes of febrile neutropenia (P < .001) and less documented infection (P .04). Concomitant medication usage was significantly greater on 5-FU/LV (P .010). With respect to quality of life, after correcting for baseline imbalances, there were no significant differences between treatments for any scale, except diarrhea. Conclusion: The oral UFT/LV regimen failed to achieve improved TTP; however, the study confirms significant safety improvements compared with bolus IV 5-FU/LV for the first-line treatment of metastatic CRC. J Clin Oncol 20:3617-3627. © 2002 by American Society of Clinical Oncology.