title: Pharmacodynamics of fluorouracil-based induction chemotherapy in advanced head and neck cancer.
abstract: OBJECTIVE
  To optimize the biochemical modulation of fluorouracil (5-FU), we administered the pure I-stereoisomer of leucovorin (LV) as a 132-hour continuous intravenous infusion (CIV) with cisplatin 100 mg/m2, 5-FU 640 mg/m2/d as a 120-hour CIV, and interferon alfa-2b (IFN) at 2 MU/m2/d for 6 days for three cycles (I-PFL-IFN). Pharmacologic parameters included morning (AM) and afternoon (PM) plasma concentrations of 5-FU, LV and its active metabolite 5-methyl tetrahydrofolate (MTHF), and dihydropyrimidine dehydrogenase (DPD) activity in peripheral mononuclear cells.
  
  
  RESULTS
  Eighty-nine patients were treated (86 stage IV). Neutropenia and mucositis were the most common toxicities. Sixty-six percent achieved a complete remission (CR). There was a trend for higher PM versus AM 5-FU concentrations (median, 1.64 v 1.51 mumoles/L; P = .08), but not for LV plus MTHF (P = .66). The mean +/- SD DPD activity was 0.21 +/- 0.14 nmol/min/mg and did not correlate with plasma concentrations of 5-FU or LV plus MTHF or clinical toxicities. Higher PM 5-FU concentrations correlated with worse leukopenia (P = .04) and severity of mucositis (P = .04). PM 5-FU concentration was higher in women than in men (P = .07), with no apparent difference in severity of toxicities. The maximum 5-FU concentration was higher in CR than non-CR patients (median, 2.01 v 1.54 mumoles/L; P = .02) and higher in women than men who achieved a CR (median, 2.77 v 1.91 mumoles/L; P = .03). No correlation of CR with dose-intensity was found.
  
  
  CONCLUSIONS
  L-PFL-IFN is active in stage IV head and neck cancer. 5-FU concentration is a significant predictor of toxicity. In women, optimization of response outcome requires a higher 5-FU concentration. Individualized 5-FU dosing to obtain higher 5-FU plasma concentrations may be indicated.
authors.affiliation: Department of Medicine, University of Chicago, IL 60637-1470, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Vokes
authors.forename: R
authors.initials: R
authors.lastname: Mick
authors.forename: M S
authors.initials: MS
authors.lastname: Kies
authors.forename: M E
authors.initials: ME
authors.lastname: Dolan
authors.forename: D
authors.initials: D
authors.lastname: Malone
authors.forename: I
authors.initials: I
authors.lastname: Athanasiadis
authors.forename: D J
authors.initials: DJ
authors.lastname: Haraf
authors.forename: M
authors.initials: M
authors.lastname: Kozloff
authors.forename: R R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D002955:Leucovorin / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism*; D011994:Recombinant Proteins; D013237:Stereoisomerism; D013763:Tetrahydrofolates / Q000097:blood
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013763:Tetrahydrofolates; D002945:Cisplatin; D002955:Leucovorin; C005984:5-methyltetrahydrofolate; D005472:Fluorouracil