Circadian patterning of continuous floxuridine infusion reduces toxicity and allows higher dose intensity in patients with widespread cancer.

Abstract

Continuous long-term 5-fluoro-2'-deoxyuridine (floxuridine; FUDR) infusion frequently causes severe and dose-limiting gastrointestinal toxicity when administered at a constant rate at commonly prescribed dose levels. In preclinical studies, a circadian infusion pattern peaking late in the daily activity phase was better tolerated and had superior antitumor activity than a constant infusion against a transplanted tumor. Based upon these data and upon other chronobiological cytokinetic and pharmacologic considerations, we compared a circadian patterned variable rate infusion with a maximal flow rate in the late afternoon/early evening and minimum flow rate during the early morning hours to a constant rate infusion in 54 patients with widespread cancer. All FUDR infusions were administered using an implanted drug pump. In a pilot crossover study and a second randomized trial, patients with metastatic malignancies treated with equal dose intensities experienced less frequent and less severe diarrhea, nausea, and vomiting following variable rate infusion. In a third study, the dose intensity of variable rate infusion was escalated stepwise to determine the maximum-tolerated dose. Patients receiving time-modified FUDR infusion tolerated an average of 1.45-fold more drug per unit time while evincing minimal toxicity. FUDR infusion was found to have activity against progressive metastatic renal cell cancer (RCC). Increased dose intensity achieved by optimal circadian shaping may improve the therapeutic index of infusional FUDR and may help control malignancies that are refractory to conventional chemotherapy.