Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer

S. M. Swain, M. E. Lippman, E. F. Egan, J. C. Drake, S. M. Steinberg, C. J. Allegra

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Abstract

The efficacy and toxicity of leucovorin 500 mg/m2 administered intravenously (IV) over 30 minutes daily for five days followed in one hour by fluorouracil (5-FU) 375 mg/m2 administered IV daily for five days, each given every 3 weeks, was assessed in 54 previously treated patients with metastatic breast cancer. An overall objective response rate of 24% was achieved (95% confidence interval, 13% to 38%), with an additional 56% of patients maintaining stable disease. Eleven of 12 patients who responded had received previous 5-FU therapy. Toxicity of this regimen included grade 3 diarrhea in 13%, grade 3 or 4 mucositis in 33%, grade 3 or 4 granulocytopenia in 65%, and grade 3 or 4 thrombocytopenia in 19%. Delay of treatment was required for hematologic toxicity in 44 patients. Thirty-eight patients required dose reductions due to toxicity. Biochemical evaluation of tumor biopsy specimens obtained from 17 patients used as their own controls with and without leucovorin was performed. These studies reveal an increased stabilization of the 5-fluorodeoxyuridylate (FdUMP)-thymidylate synthase (TS) folate ternary complex with the addition of leucovorin. There was a 71% ± 14% occupancy or inhibition of the enzyme with the use of both 5-FU and leucovorin, v 30% ± 13% for 5-FU alone (P2 > .037). The percent TS bound in responding patients was substantially higher than in those patients with progressive disease. Finally, the mean total tumor TS pre-therapy in seven patients was 31 fmol/mg compared with a mean of 81 fmol/mg in these same seven patients 24 hours after therapy. This 2.6-fold increase suggests that there is an induction of the enzyme, TS, with 5-FU treatment.

Original languageEnglish (US)
Pages (from-to)890-899
Number of pages10
JournalJournal of Clinical Oncology
Volume7
Issue number7
DOIs
StatePublished - Jan 1 1989

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Swain, S. M., Lippman, M. E., Egan, E. F., Drake, J. C., Steinberg, S. M., & Allegra, C. J. (1989). Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. Journal of Clinical Oncology, 7(7), 890-899. https://doi.org/10.1200/JCO.1989.7.7.890