Pharmacodynamics of fluorouracil-based induction chemotherapy in advanced head and neck cancer

J Clin Oncol. 1996 May;14(5):1663-71. doi: 10.1200/JCO.1996.14.5.1663.


Purpose and methods: 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.

Conclusion: 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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cisplatin / administration & dosage
  • Female
  • Fluorouracil / blood
  • Fluorouracil / pharmacology*
  • Fluorouracil / therapeutic use
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / metabolism*
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / administration & dosage
  • Leucovorin / administration & dosage
  • Leucovorin / metabolism
  • Male
  • Middle Aged
  • Neoplasms, Squamous Cell / drug therapy*
  • Neoplasms, Squamous Cell / metabolism*
  • Recombinant Proteins
  • Stereoisomerism
  • Tetrahydrofolates / blood


  • Interferon alpha-2
  • Interferon-alpha
  • Recombinant Proteins
  • Tetrahydrofolates
  • Cisplatin
  • Leucovorin
  • 5-methyltetrahydrofolate
  • Fluorouracil