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Annals of Oncology 14:1142-1147, 2003
© 2003 European Society for Medical Oncology

Original Paper

Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction

G. F. Fleming1,2,+, R. L. Schilsky1,2, L. P. Schumm2, A. Meyerson3, A. M. Hong3, N. J. Vogelzang1,2 and M. J. Ratain1,2,4

1 Department of Medicine, University of Chicago Medical Center; 2 University of Chicago Cancer Research Center; 3 University of Chicago Pritzker School of Medicine; 4 University of Chicago Committee on Clinical Pharmacology, Chicago, IL, USA

Received 24 September 2002; revised 28 February 2003; accepted 26 March 2003

Background:

Patients with hepatic or renal dysfunction are often treated with 5-fluorouracil (5-FU), but there are few data to confirm the safety of this practice.

Patients and methods:

Patients with solid tumors were eligible if they were able to fit into one of three organ dysfunction cohorts: I, creatinine >1.5 but <=3.0 mg/dl and normal bilirubin; II, bilirubin >1.5 but <5.0 mg/dl with normal creatinine; or III, bilirubin >=5.0 mg/dl with normal creatinine. 5-FU doses were escalated separately within each of the three cohorts. Leucovorin (LV) dosage was fixed at 500 mg/m2. 5-FU was given as a 24-h infusion at 1000, 1800 or 2600 mg/m2, and plasma concentrations were measured every 3 h during the first two infusions for each patient.

Results:

Sixty-four patients were treated. Toxicities did not appear to be related to organ dysfunction cohort. A weekly dose of of 5-FU 2600 mg/m2 produced dose-limiting toxicity (DLT) in six of 20 evaluable patients.These DLTs included grade 3 fatigue (n = 3), grade 2 neutropenia precluding weekly dosing (n = 1), grade 3 thrombocytopenia (n = 1) and grade 3 mental status changes (n = 1). There was no relationship between serum bilirubin or serum creatinine and 5-FU clearance.

Conclusions:

Patients with elevated bilirubin may be safely started on a weekly regimen of 5-FU 2600 mg/m2 with leucovorin 500 mg/m2 as a 24-h continuous infusion.

Key words: 5-fluorouracil, hepatic dysfunction, leucovorin, pharmacokinetics, 24-h infusion


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