“…To date, the three-drug chronotherapy regimen with 5-FU, LV and oxaliplatin used by Levi et al [23]is apparently one of the most active regimens in metastatic colorectal cancer with a response rate, validated in multicenter phase III randomized studies, over 50% [23, 30, 31]. In this three-drug regimen, on the basis of preclinical observations, 5-FU and LV were administered as a sinusoidally modulated infusion for 12 h between 10 p.m. and 10 a.m., with peak flow rates at 4 a.m. A similar infusion schedule was used by Bjarnason et al [22], but 5-FU+LV were infused over 14 days and only 62.5% of the total daily dose were administered over 7 h around the infusion peak which occurred at 3–4 a.m. However, these studies did not define if a sinusoidal modulation of drug delivery, which requires rather sophisticated infusion pumps, was really important in reducing 5-FU toxicities; furthermore, they also did not determine the relative importance of the timing and of the intermittency of 5-FU delivery.…”