Infusions of Fluorouracil and Leucovorin: Effects of the Timing and Semi-Intermittency of Drug Delivery

Abstract

Preclinical and clinical studies have demonstrated that the circadian modulation of 5-FU delivery may reduce toxicities and improve antitumor activity. However, the relative importance of the timing of 5-FU delivery has not been clinically addressed. The aims of this study were to determine the toxicities, the maximum tolerable doses and the activity of a regimen with 5-fluorouracil (5-FU) and leucovorin (LV) administered as a 14-day continuous infusion according to a flat or three different chronomodulated rhythms in patients with metastatic gastrointestinal carcinomas. A total of 113 patients entered the study and their characteristics were comparable among the four groups. Toxicities included mainly stomatitis and diarrhea, and a reduced toxicity was observed in all the three chronogroups that allowed the delivery of higher dose intensities. Response rates were not significantly different among the four groups. These results suggest that a reduction in 5-FU+LV toxicity and an increase in 5-FU dose intensity can be obtained by a nonsinusoidally circadian modulated infusion. However, the reduction in toxicity observed seems to be dependent mainly on the quasi-intermittency and not on the timing of 5-FU+LV delivery.

Tumor Growth Rate Determines the Timing of Optimal Chronomodulated Treatment Schedules

“…Our model is consistent with these findings, and indicates that higher total doses of chronomodulated drug can be tolerated and are needed to achieve the same anti-tumor efficacy. These theoretical results are in agreement with clinical trials that showed consistent higher tolerance for chronomodulated compared to constant infusion [4], even when given at non-optimal times [24]. Lesser toxicity is independent from the circadian rhythms, i.e.…”

Efficacy and safety of chronomodulated chemotherapy for patients with metastatic colorectal cancer: a systematic review and meta‐analysis

“…Another explanation is that ORR may be influenced by drug flow rate instead of setting peak delivery . Chrono‐chemotherapy of 5‐FU follows a peak delivery time of 4:00 a.m . This shows drug flow rate may be a robust determinant for ORR.…”

Circadian variation of dihydropyrimidine dehydrogenase mRNA expression in leukocytes and serum cortisol levels in patients with advanced gastrointestinal carcinomas compared to healthy controls

“…Taken together, data on human circadian DPD expression and activity pattern are circumstantial. Nevertheless, extensive studies comparing different regimens of 5-FU cancer chemotherapy have shown a significantly better tolerability of 5-FU when it was administered in a chronomodulated manner (Levi et al 1997;Falcone et al 1999;Giacchetti et al 2000). Probably mechanisms different from circadian DPD rhythms are responsible for the better tolerability of chronomodulated 5-FU chemotherapy.…”