Phase I study of 5-fluorouracil and leucovorin by a 14-day circadian infusion in metastatic adenocarcinoma patients

Abstract

Initial experimental and clinical studies have indicated that 5-fluorouracil (5-FU) toxicity can be reduced by delivering 5-FU at around 4 a.m. More recent data have suggested that the toxicity might be reduced even more with delivery at around 9-10 p.m. The current study determined the maximum tolerated dose (MTD) for 5-FU and leucovorin (LV) delivered as a continuous circadian infusion over 14 days every 28 days, with the peak of the infusion occurring at around 3-4 a.m. The peak drug delivery was shifted to 9-10 p.m. in all patients developing toxicity of > or = grade II (Eastern Cooperative Oncology Group) to determine if this timing further reduced toxicity and enabled increased dose intensity. A total of 14 patients with metastatic adenocarcinoma received an admixture of 5-FU and LV via a programmable portable infusion pump, with 62.5% of the 24-h dose being given over 7 h around the infusion peak. The starting dose level of 5-FU (200 mg/m2 daily) and LV (5 mg/m2 daily) was that established as the highest tolerable dose rate in a previously reported phase I study using a 14-day flat infusion of 5-FU and LV. The LV dose was first escalated to 20 mg/m2 daily, followed by escalations of the 5-FU dose. A total of 51 courses were evaluable for toxicity. The dose-limiting toxicity was oral mucositis and hand-foot syndrome. More dose intensity could be delivered using a circadian infusion peaking at around 3-4 a.m. than was possible with a flat infusion of these drugs. Toxicity was reduced even further with peak drug delivery at around 9-10 p.m. The recommended dose for phase II studies using this schedule is 250 mg/m2 5-FU daily and 20 mg/m2 LV daily with the peak of the infusion occurring at 9-10 p.m. This is a 300% and 25% higher dose for LV and 5-FU, respectively, than was found to be safe for a flat infusion.

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

“…Therefore, these data suggest that adapting 5-FU delivery to circadian rhythms could improve or worsen 5-FU toxicity and efficacy according to the circadian delivery rhythm used. Several clinical trials have demonstrated that 5- or 14-day schedules of chronomodulated 5-FU-based chemotherapy are less toxic, enable 5-FU dose intensity escalations by approximately 25% and significantly improve antitumor activity [20, 21, 22, 23]. 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].…”

“…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.…”

“…Preclinical and more recent clinical data have demonstrated that the circadian modulation of 5-FU delivery reduces 5-FU-induced toxicities and allows 5-FU dose escalations [19, 20, 21, 22]. In particular, in regimens including CI 5-FU and LV, chronotherapy has allowed 5-FU dose intensity escalations of approximately 25% [20, 23]; furthermore, antitumor activity has also been improved and chronomodulated 5-FU+LV+oxaliplatin have demonstrated improved activity when compared with the non-chronomodulated schedule, with response rates over 50% [20, 23].…”

“…In particular, in regimens including CI 5-FU and LV, chronotherapy has allowed 5-FU dose intensity escalations of approximately 25% [20, 23]; furthermore, antitumor activity has also been improved and chronomodulated 5-FU+LV+oxaliplatin have demonstrated improved activity when compared with the non-chronomodulated schedule, with response rates over 50% [20, 23]. However the best chronoinfusion schedule has not yet been determined: based on preclinical studies most trials have used a sinusoidally modulated infusion of 5-FU and LV for 12 h between 10 p.m. and 10 a.m., with peak flow rates at 4 a.m., but some studies suggest that different chronoinfusion rhythms might be even less toxic [22]. Furthermore, many different chronoinfusion rhythms have not yet been evaluated clinically, and it is unknown if they can also reduce or perhaps increase toxicity.…”

Biochemical Modulation of Fluoropyrimidines: Preclinical and Clinical Studies

“…Circadian rhythms are suggested by reduced toxicity profiles with the best tolerance for 5-FU peak levels at 9-10 p.m. [5]. Deactivation takes place mainly, but not exclusively, in the liver.…”