Circadian rhythm-modulated (CRM) chemotherapy of metastatic breast cancer with mitoxantrone, 5-fluorouracil, and folinic acid: preliminary results of a phase I trial.

A phase I feasibility trial with a 5-day schedule of circadian rhythm-modulated mitoxantrone (MIT), 5-fluorouracil (5-FU, 600 mg/m2/day), and folinic acid (FA, 300 mg/m2/day) was performed in patients with metastatic breast cancer. The MIT dose was escalated from 2 to 2.5 and 2.75 mg/m2/day in consecutive groups of six patients. All three drugs were infused intravenously with a multichannel ambulatory pump. Maximal delivery rate was programmed at 4.00 hours for 5-FU and FA and at 16.00 hours for MIT. Eighteen women with advanced metastatic breast cancer were included in the trial between April 1991 and July 1993. Seventeen of 18 patients had received previous chemotherapy, which contained anthracyling for 16 of them. Tolerability of the first treatment course was assessed 10 and 21 days after course onset. Neutropenia was dose dependent and the most frequent toxicity (grade 3: 4 patients; grade 4: 7 patients), yet only a single hospitalization was required for fever and neutropenia. A single patient exhibited grade 3 mucositis. No grade 3 or 4 diarrhea, nausea, or vomiting was encountered. This chronomodulated infusion of MIT, 5-FU, and FA showed acceptable toxicity in heavily pretreated patients. For the phase II evaluation of the antitumor activity of this circadian schedule, a dose of 2.75 mg/m2/day of MIT is recommended using a monthly regimen. Further dose escalation may be performed in patients without bone metastasis and good performance status.