Individual 5-FU dose adaptation in metastatic colorectal cancer: results of a phase II study using a bimonthly pharmacokinetically intensified LV5FU2 regimen

The aim of this phase II study was to determine the efficacy and tolerability of the bimonthly, pharmacokinetically intensified LV5FU2 regimen in the treatment of metastatic colorectal cancers.

A total of 53 patients (23% second-line; 25 male/28 female; mean age 67 years; WHO performance status 0 in 38, 1 in 10 and 2 in 5) were treated in cycle 1 with the standard LV5FU2 regimen (leucovorin 200 mg/m² per day followed by a 5-FU bolus 400 mg/m² per day and a 22-h 5-FU continuous infusion 600 mg/m² per day for two consecutive days every 2 weeks), and the AUC in mg·h/l·m² was calculated. For cycle 2, according to a predefined schedule depending on the cycle-1 AUC value, in the absence of grade 3 toxicity, the 5-FU infusion dose was increased by 150% for AUC ≤5, by 100% for AUC >5–10, by 50% for AUC >10–15, and by 25% for AUC >15–20. 5-FU plasma concentrations were determined using high-performance liquid chromatography. A Bayesian methodology was used to assess individual pharmacokinetic parameters using the NONMEM computer program.

Among the 53 eligible patients, 87% (per-protocol population) received an increased dose in cycle 2 and 72% received the same dose. The median relative dose intensity was 1.28 (range 0.5–1.54) compared with the non-adapted theoretical total 5-FU dose. The objective response rate was 37% (95% CI 23–50%) in the intention-to-treat population and 47% (95% CI 29–65%) in the first-line per-protocol population. The median response duration was 10.4 months. The median progression-free survival (PFS) and overall survival (OS) were, respectively, 7 and 18.6 months. PFS and OS in first-line per-protocol patients were, respectively, 9.2 and 20 months. No deaths were attributed to toxicity of 5-FU despite the high doses administered. Of the 53 patients, 19% experienced gastrointestinal and 30% haematological grade 3/4 toxicities. Hand-foot syndrome was common but mild (grade 3 in one patient).

This strategy could be compared in a phase III trial with the standard LV5FU2 regimen.