Chronotherapy with 5-fluorouracil and folinic acid in advanced colorectal carcinoma. Results of a chronopharmacologic phase I trial.
BACKGROUND
Chronotherapy with antineoplastic drugs is a rather new strategy of reducing cytotoxic side effects. Because the circadian timing of 5-fluorouracil (5-FU) was reported to result in a higher efficacy and lower toxicity, the authors conducted a chronopharmacologic Phase I trial with 5-FU and folinic acid (FA).


METHODS
Eight patients with advanced colorectal cancer received 5-FU (initial dose of 500 mg/m2/day) and FA (20 mg/m2/day) as a continuous intravenous infusion over 5 consecutive days. Using a portable, ambulatory drug delivery system, 75% of the daily dose of 5-FU and FA were given from Oh00-7h00, and the remaining 25% from 7h00-24h00. Treatment courses were repeated after 28 days. Dose escalations of 250 mg/m2/day of 5-FU and 10 mg/m2/day of FA per course were performed in the absence of any toxicity greater than WHO (World Health Organization) grade 2.


RESULTS
Dose-limiting toxicity WHO grade 3 was observed at a dose of 750 mg/m2/day of 5-FU and 30 mg/m2/day of FA in five, and 1000 mg/m2/day of 5-FU and 40 mg/m2/day of FA in two patients, respectively. One patient tolerated 1000 mg/m2/day of 5-FU and 40 mg/m2/day of FA, but the treatment was stopped before further dose escalation because of rapid disease progression. Mucositis was the dose-limiting toxicity in seven patients and diarrhea in two. Disease stabilization occurred in three patients and disease progression in five. Compared with conventional Phase I/II trials using a 5-day infusion regimen, the maximal tolerated dose of 5-FU and FA was slightly higher but significantly lower than in a chronotherapeutic trial that used a different, sinusoidal mode of drug application.


CONCLUSIONS
Based on these results, the authors feel justified to caution that the circadian timing of 5-FU plus FA may not always allow the safe application of high dose levels. Future Phase I/II studies need to define whether specific drug delivery systems or schedules are necessary for chronotherapy with 5-FU and FA in patients with colorectal carcinoma.
Adler
S
S
Medizinische Klinik, Universität München, Germany.
Lang
S
S
Langenmayer
I
I
Eibl-Eibesfeldt
B
B
Rump
W
W
Emmerich
B
B
Hallek
M
M
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002940:Circadian Rhythm; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; 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