PHASE-I STUDY OF 5-FLUOROURACIL AND LEUCOVORIN BY A 14-DAY CIRCADIAN INFUSION IN METASTATIC ADENOCARCINOMA PATIENTS

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 greater-than-or-equal-to 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 11 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.