A phase I trial of 5-day chronomodulated infusion of 5-fluorouracil and 1-folinic acid in patients with metastatic colorectal cancer

A phase II study of irinotecan plus chronomodulated oxaliplatin, 5-fluorouracil and folinic acid in advanced colorectal cancer patients

“…The schedule we applied in this study is based on the following: (a) L-OHP 20 mg m 2 day À1 plus 5-FU 600 mg m 2 day À1 and FA 150 mg m 2 day À1 by chronomodulated infusion were the starting doses in the 3-weekly FFL schedule used in our phase III trials (Lévi et al, 1994(Lévi et al, , 1997; (b) we previously conducted a phase II study where CPT-11, 180 mg m À2 on day 1 in 1 h by a 6-h chronomodulated infusion, was combined to chronomodulated 5-FU and FA from day 2 to day 5 . To increase the activity of this last combination, L-OHP at the dose of 20 mg m 2 die À1 (days 2 -5), was added to the previous CPT-11 (day 1) plus the 4-day (days 2 -5) 5-FUFA chronomodulated infusion every 3 weeks.…”

“…Circadian changes in drug pharmacokinetics, target tissue susceptibility, bone marrow DNA synthesis, 5-FU metabolic and catabolic enzymatic activity (thymidylate phosphorylase and dehydropyrimidine dehydrogenase) and oral/rectal epithelium during night hours vs light hours are some of the explanations of these differences. Concerning drug activity 5-FU dose-intensity seems to be related to drug activity and this could influence survival (Lévi et al, 1999;Garufi et al, 1997).The combination of CPT-11 and L-OHP without 5-FU was also investigated in phase I and II studies, which showed the activity of these drugs in patients heavily pretreated with 5-FU-based regimen (Scheiteuer et al, 1999;Wassermann et al, 1999). Haematologic toxicity has been commonly observed; grade 3 -4 (G3 -4) neutropenia occurred in 20 -33% of patients even though concomitant granulocyte colony-stimulating factor (G-CSF) administration.…”

“…It was demonstrated in phase III trials that the combination of L-OHP plus 5-FU and FA delivered by chronomodulated infusion, the FFL regimen, provides more activity and a better toxicity profile when compared to the flat infusion of the same drugs with a five-fold greater mucositis rate due to 5-FU and the double of peripheral neurotoxicity due to L-OHP in the constant infusion regimen (Lévi et al, 1994(Lévi et al, , 1997. Circadian changes in drug pharmacokinetics, target tissue susceptibility, bone marrow DNA synthesis, 5-FU metabolic and catabolic enzymatic activity (thymidylate phosphorylase and dehydropyrimidine dehydrogenase) and oral/rectal epithelium during night hours vs light hours are some of the explanations of these differences.…”

“…Circadian changes in drug pharmacokinetics, target tissue susceptibility, bone marrow DNA synthesis, 5-FU metabolic and catabolic enzymatic activity (thymidylate phosphorylase and dehydropyrimidine dehydrogenase) and oral/rectal epithelium during night hours vs light hours are some of the explanations of these differences. Concerning drug activity 5-FU dose-intensity seems to be related to drug activity and this could influence survival (Lévi et al, 1999;Garufi et al, 1997).…”

The contribution of circadian rhythms to cancer formation and mortality

“…Several clinical trials have been performed in an attempt to highlight the potential advantages of chronotherapy versus conventional drug administration, particularly using the antimetabolite 5-fluorouracil in the treatment of colorectal cancer. A phase I trial of 5-fluorouracil administered with 1-folic acid utilized programmable pumps to deliver five days of timed infusions, lasting from 10pm to 10am and peaking at 4am, to several groups of patients with metastatic colorectal cancer (Garufi et al, 1997). The doses were increased with each group given this treatment to determine the maximum tolerated dose, and the timed treatment revealed low toxicity and promisingly high efficacy rates for both previously treated and untreated patients (Garufi et al, 1997).…”