Modified-irinotecan/fluorouracil/levoleucovorin therapy as ambulatory treatment for metastatic colorectal cancer: results of phase I and II studies.

Background: Combined therapy with irinotecan/fluorouracil/levoleucovorin (calcium levofolinate) [IFL] has lost its position as the standard regimen for metastatic colorectal cancer because its toxicity and effectiveness have become controversial.

Objective: To (i) identify the optimal regimen for IFL therapy in terms of irinotecan dosage, and (ii) determine the maximum tolerated dose and efficacy of the modified-IFL regimen in patients with histologically confirmed advanced colorectal cancer.

Methods: In a phase I study, nine patients with advanced colorectal cancer received IFL treatment modified such that irinotecan was administered every 2 weeks, as opposed to the more toxic once-weekly administration. The study evaluated three escalating dose levels of irinotecan (100, 125 and 150 mg/m(2)). Each treatment cycle consisted of irinotecan on days 1 and 15; fluorouracil 600 mg/m(2) on days 1, 8, 15 and 22; and levoleucovorin 250 mg/m(2) on days 1, 8, 15 and 22. Data from the phase I study were used to determine the recommended dose of irinotecan for the phase II study. The latter study evaluated the effectiveness (overall response rate, median time to disease progression and median survival time) and tolerability of this modified-IFL therapy as ambulatory treatment in 22 patients with advanced colorectal cancer.

Results: The dose-limiting toxicity of irinotecan was grade 3 neutropenia, which occurred in three patients at dose level 2 (125 mg/m(2)); furthermore, a fourth patient developed grade 4 neutropenia at this dose level. Therefore, 125 mg/m(2) was considered to be the maximum tolerated dose, and the dose of irinotecan for the phase II study was set at 100 mg/m(2). Fourteen patients achieved partial response using this modified-IFL regimen, and the overall response rate was 63.6% (95% CI 43.5, 83.7). The median time to progression was 197 days (range 111-283 days) and the median survival time was 414 days (95% CI 116, 712). Toxicities were acceptable and manageable.

Conclusions: Modified-IFL therapy is a practical, effective and tolerable option for ambulatory treatment of advanced colorectal cancer.