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 st rategy of reducing cytotoxic side effects. Because the circadian timin g 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 ove r 5 consecutive days. Using a portable, ambulatory drug delivery syste m, 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 af ter 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 g reater than WHO (World Health Organization) grade 2. Results. Dose-lim iting toxicity WHO grade 3 was observed at a dose of 750 mg/m(2)/day o f 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 to lerated 1000 mg/m(2)/day of 5-FU and 40 mg/m(2)/day of FA, but the tre atment was stopped before further dose escalation because of rapid dis ease progression. Mucositis was the dose-limiting toxicity in seven pa tients and diarrhea in two. Disease stabilization occurred in three pa tients and disease progression in five. Compared with conventional Pha se I/II trials using a 5-day infusion regimen, the maximal tolerated d ose of 5-FU and FA was slightly higher but significantly lower than in a chronotherapeutic trial that used a different, sinusoidal mode of d rug 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 s chedules are necessary for chronotherapy with 5-FU and FA in patients with colorectal carcinoma.