Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer.
OBJECTIVE
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.


METHODS
Eight hundred sixteen patients were randomized to receive either UFT (300 mg/m(2)/d) and LV (75 or 90 mg/d) for 28 days every 35 days or IV bolus 5-FU (425 mg/m(2)/d) and LV (20 mg/m(2)/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.


CONCLUSIONS
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.
Douillard
Jean-Yves
JY
Centre René Gauducheau, Nantes, France. jy-douillard@nantes.fnclcc.fr
Hoff
Paulo M
PM
Skillings
Jamey R
JR
Eisenberg
Peter
P
Davidson
Neville
N
Harper
Peter
P
Vincent
Mark D
MD
Lembersky
Barry C
BC
Thompson
Seth
S
Maniero
Antonella
A
Benner
Steven E
SE
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011788:Quality of Life; D015996:Survival Rate; D005641:Tegafur / Q000008:administration & dosage; D014481:United States / Q000453:epidemiology; D014498:Uracil / Q000008:administration & dosage
D005641:Tegafur; D014498:Uracil; D002955:Leucovorin; D005472:Fluorouracil