Biweekly irinotecan or raltitrexed plus 6S-leucovorin and bolus 5-fluorouracil in advanced colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase II-III randomized trial

Purpose: The aim of this randomised trial was to evaluate the activity and toxicity of a biweekly regimen including 6S-leucovorin-modulated 5-fluorouracil (LFA-5-FU), combined with either irinotecan (CPT-11 + LFA 5-FU) or raltitrexed (Tomudex®) (TOM + LFA 5-FU), in advanced colorectal cancer patients, and to make a preliminary comparison of both these experimental regimens with a biweekly administration of LFA-5-FU modulated by methotrexate (MTX + LFA-5-FU). Patients and methods: One hundred fifty-nine patients with advanced colorectal carcinoma previously untreated for the metastatic disease (34 of them previously exposed to adjuvant 5-FU) were randomly allocated to receive: CPT-11, 200 mg/m 2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m 2 i.v. infusion and 5-FU, 850 mg/m 2 s i.v. bolus (arm A); TOM, 3 mg/m 2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m 2 i.v. infusion and 5-FU, 1050 mg/m 2 i.v. bolus (arm B); or MTX, 750 mg/m 2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m 2 i.v. infusion and 5-FU, 800 mg/m 2 i.v. bolus (arm C). Courses were repeated every two weeks in all arms of the trial. Response rate (RR) was evaluated after every four courses. The sample size was defined to have an 80% power to detect a 35% RR for each experimental treatment, and to show a difference of at least 4% in RR with the standard treatment if the true difference is 15% or more. Results. The RRs were: 34% (95% confidence interval (95% CI): 21%-48%) in arm A, including 3 complete responses (CRs) and 15 partial responses (PRs), 24% (95% CI: 14%-38%) in arm B, including 2 CRs and 11 PRs, and 24% (95% CI: 14%-38%), with 2 CRs and 11 PRs. in arm C. After a median follow-up time of 62 (range 18-108) weeks, the median time to progression was 38, 25, and 27 weeks for arm A, B, and C, respectively. With 94 patients still alive, the one-year probability of survival was 61%, 54%, and 59%, respectively. WHO grade 3 or 4 neutropenia and diarrhoea affected 46% and 16%, respectively, of patients treated with CPT-11 + LFA-5-FU. Median relative dose intensity over eight cycles (DI 8 ) was 78% for CPT-11 and 82% for 5-FU. Severe toxicities of TOM + LFA 5-FU were neutropenia (16%) and diarrhoea (16%), but median relative DI 8 was 93% for TOM, and 82% for 5-FU. Conclusions: CPT-11 + LFA-5-FU compares favorably in term of activity and toxicity with other combination regimens including CPT-11 and continuous infusional 5-FU. The hypothesis of a RR 15% higher than the MTX + LFA-5-FU treatment can not be ruled out after this interim analysis. The TOM + LFA 5-FU regimen showed a RR and a toxicity profile very close to the MTX + LFA-5-FU combination, and dose not deserve further evaluation in advanced colorectal cancer patients.