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 > 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.
Bjarnason
G A
GA
Division of Medical Oncology, Toronto Bayview Regional Cancer Center, Ontario, Canada.
Kerr
I G
IG
Doyle
N
N
Macdonald
M
M
Sone
M
M
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007260:Infusion Pumps; D002955:Leucovorin / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged
D002955:Leucovorin; D005472:Fluorouracil