Infusions of fluorouracil and leucovorin: Effects of the timing and semi-intermittency of drug delivery

Preclinical and clinical studies have demonstrated that the circadian modul ation of 5-FU delivery may reduce toxicities and improve antitumor activity . However, the relative importance of the timing of 5-FU delivery has not b een clinically addressed. The aims of this study were to determine the toxi cities, the maximum tolerable doses and the activity of a regimen with 5-fl uorouracil (5-FU) and leucovorin (LV) administered as a 14-day continuous i nfusion according to a flat or three different chronomodulated rhythms in p atients with metastatic gastrointestinal carcinomas. A total of 113 patient s entered the study and their characteristics were comparable among the fou r groups. Toxicities included mainly stomatitis and diarrhea, and a reduced toxicity was observed in all the three chronogroups that allowed the deliv ery of higher dose intensities. Response rates were not significantly diffe rent among the four groups. These results suggest that a reduction in 5-FULV toxicity and an increase in 5-FU dose intensity can be obtained by a non sinusoidally circadian modulated infusion. However, the reduction in toxici ty observed seems to be dependent mainly on the quasi-intermittency and not on the timing of 5-FU+LV delivery.