title: Phase I trial of low-dose, prolonged continuous infusion fluorouracil plus interferon-alfa: evidence for enhanced fluorouracil toxicity without pharmacokinetic perturbation.
abstract: OBJECTIVE
  To determine the maximum-tolerable dose (MTD) of fluorouracil (5-FU) administered as a low-dose, prolonged continuous intravenous infusion (PCI) plus interferon-alfa (IFN-alpha) that would permit treatment for at least 28 consecutive days, and to determine the effect of IFN-alpha on 5-FU pharmacokinetics.
  
  
  METHODS
  Twenty-six assessable patients with advanced cancer received low-dose PCI 5-FU (150, 200, 250, and 300 mg/m2/d) plus IFN-alpha, 5 x 10(6) IU/m2 administered subcutaneously (SC) at hour 48 of the 5-FU infusion, then thrice weekly thereafter in cohorts of at least three patients. Treatment continued until treatment-limiting toxicity (TLT) developed, such as mucositis, diarrhea, or fatigue. Escalation to the next 5-FU dose level occurred if none of three or zero to two of six patients developed TLT before day 28. Quantitation of plasma 5-FU concentration by high-performance liquid chromatography was performed in 15 patients. Data were standardized using the Cosinor method and compared before and after IFN-alpha administration using the paired t test.
  
  
  RESULTS
  The mean number of days of continuous 5-FU therapy for patients receiving 150, 200, 250, and 300 mg/m2/d of 5-FU plus IFN alfa-2a (IFN-alpha 2a) was 75, 54, 37, and 22 days, respectively. The MTD of PCI 5-FU by our criteria that could be combined with IFN-alpha was 250 mg/m2/d. Comparison of the standardized pharmacokinetic data showed no significant effect of IFN-alpha on plasma 5-FU concentration, and no alteration of the normal circadian variation in plasma 5-FU concentration that was evident before IFN-alpha administration. Objective response occurred in patients with adenocarcinoma of the pancreas (n = 3), kidney (n = 2), and lung (n = 1).
  
  
  CONCLUSIONS
  IFN-alpha substantially enhanced the gastrointestinal toxicity of low-dose PCI 5-FU without affecting 5-FU pharmacokinetics, contrary to previous reports using alternative 5-FU schedules in which IFN-alpha-related enhancement of 5-FU toxicity was attributable to reduced 5-FU clearance. Our findings suggest that under certain conditions, mechanisms other than altered 5-FU pharmacokinetics may be responsible for the ability of IFN-alpha to enhance the toxic effects of 5-FU.
authors.affiliation: Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY 10467.
authors.forename: J A
authors.initials: JA
authors.lastname: Sparano
authors.forename: S
authors.initials: S
authors.lastname: Wadler
authors.forename: R B
authors.initials: RB
authors.lastname: Diasio
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.forename: Z
authors.initials: Z
authors.lastname: Lu
authors.forename: E L
authors.initials: EL
authors.lastname: Schwartz
authors.forename: A
authors.initials: A
authors.lastname: Einzig
authors.forename: P H
authors.initials: PH
authors.lastname: Wiernik
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D016896:Treatment Outcome
chemical_list: D016898:Interferon-alpha; D005472:Fluorouracil