RANDOMIZED PHASE-II NONCOMPARATIVE TRIAL OF ORAL AND INTRAVENOUS DOXIFLURIDINE PLUS LEVO-LEUCOVORIN IN UNTREATED PATIENTS WITH ADVANCED COLORECTAL-CARCINOMA

BACKGROUND. Doxifluridine (5-dFUR) is a fluoropyrimidine derivative th at has been shown to be active on a Variety of solid tumors. The clini cal use of intravenous (i.v.) 5-dFUR as a bolus injection or short ter m infusion has been limited because of its unpredictable severe neurot oxicity. Unlike fluorouracil (5-FU), 5-dFUR is effective when administ ered orally. METHODS. This randomized, parallel-group, Phase II trial of two schedules of 5-dFUR was conducted between April 1993 and Septem ber 1994. A total of 130 previously untreated patients with locally ad vanced or metastatic colorectal carcinoma were randomized to receive o ral levo-leucovorin (1-leucovorin) 25 mg/dose followed by oral 5-dFUR 750 mg/m(2) twice daily for 4 days every 12 days (arm A) or i.v. 1-leu covorin 25 mg/dose followed by i.v. 5-dFUR 3000 mg/m(2) for 5 days eve ry 21 days (arm B). RESULTS. The two treatment arms were well balanced in terms of age, sex, and disease extension. Metastases were present in more than 90% of the total population, with the liver being the mos t common site. A median of 7 oral courses (range, 1-15) and 5 intraven ous courses (range, 1-9) were administered. Intent-to-treat analysis r ate of the randomized patients revealed a response rate of 15% (95% co nfidence interval [CI], 7-26) in arm A and 41% (95% CI, 29-54) in arm B. However, 7 cases in arm A and 12 in arm B were inadequately treated , and the response rates, according to standard analysis, were respect ively 17% (95% CI, 8-28) and 51% (95% CI, 37-65). The median time to t reatment failure was 4 months (range, 1-23) and 7 months (range, 1-9), respectively, for the two groups; median survival was 11 months (rang e, 1-24) in both groups. National Cancer Institute Grade 3 and 4 diarr hea were observed in 25% of the orally treated patients and in 18% of those receiving i.v. treatment. Stomatitis was reported mainly in arm B (15%). Mild and moderate neurotoxicity was observed in 6% of the pat ients in both arms; no severe neurotoxicity was reported. CONCLUSIONS. 5-dFUR with 1-leucovorin, administered either orally or intravenously , produces response rates that are similar to those offered by the reg imens containing 5-FU that are usually used to treat advanced colorect al carcinoma. This study documents the good tolerance of the i.v. sche dule administered as a 1-hour infusion; furthermore, oral administrati on seems to be promising and feasible as a home treatment. (C) 1996 Am erican Cancer Society.