Phase II study of a weekly 8-hour 5-fluorouracil and leucovorin infusion for patients with advanced colorectal cancer: Dose adjusted according to its toxicity

Background: 5-fluorouracil (5-FU) clearly behaves as two different drugs according to the schedules for its administration. A weekly, 8-h 5-FU continuous infusion (CI) regimen may produce a dual effect, because it elicits both a high plasma 5-FU level and also a durable exposure to 5-FU, which may have the advantage of inhibiting both DNA synthesis and RNA activities. The plasma 5-FU level, however, cannot be monitored in most hospitals, so we initiated a pragmatic clinical trial with this weekly 8-h 5-FU CI regimen and adjusted the drug's dose according to the detected toxicity. Methods: The initial dose of 5-FU was 1200 mg/m² and this was escalated by 200 mg/m weekly, provided that no evidence of significant (grade 2 or greater) toxicity became apparent. Twenty-six patients entered the study from June 1998 to March 1999. Results: The median dose of 5-FU delivered was 1600 mg/m². The major symptoms precluding dose escalation were nausea and vomiting. Seven patients demonstrated a partial response (26.9%), 11 patients revealed stable disease (42.3%) and eight exhibited progressive disease (30.8%). Conclusion: This weekly 8-h CI 5-FU protocol with the adjustment of dose according to toxicity was not able to achieve the same 5-FU dose and response rate as in previous studies with pharmacokinetic monitoring of 5-FU levels. However, with the concurrent administration of intensive anti-emetic premedication, it is still possible to achieve adequate plasma 5-FU levels by adjusting the 5-FU dose according to elicited toxicity.