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Chronotherapy with 5‐fluorouracil and folinic acid in advanced colorectal carcinoma
Author(s) -
Adler Sigrid,
Lang Susanne,
Langenmayer Irmgard,
EiblEibesfeldt Bernolf,
Rump Waltraud,
Emmerich Bertold,
Hallek Michael
Publication year - 1994
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(19940615)73:12<2905::aid-cncr2820731206>3.0.co;2-j
Subject(s) - medicine , folinic acid , mucositis , fluorouracil , toxicity , gastroenterology , colorectal cancer , chronotherapy (sleep phase) , chemotherapy , cancer , pharmacology , morning
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/m 2 /day) and FA (20 mg/m 2 /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 0h00‐7h00, and the remaining 25% from 7h00‐24h00. Treatment courses were repeated after 28 days. Dose escalations of 250 mg/m 2 /day of 5‐FU and 10 mg/m 2 /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/m 2 /day of 5‐FU and 30 mg/m 2 /day of FA in five, and 1000 mg/m 2 /day of 5‐FU and 40 mg/m 2 /day of FA in two patients, respectively. One patient tolerated 1000 mg/m 2 /day of 5‐FU and 40 mg/m 2 /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. Conclusion. 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. Cancer 1994; 73:2905–12.