A dose intensity study of FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy and Escherichia coli-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) in advanced breast cancer patients

J. A. O'shaughnessy, A. M. Denicoff, D. J. Venzon, D. Danforth, L. J. Pierce, J. N. Frame, A. Bastian, B. Ghosh, B. Goldspiel, L. Miller, F. A. Dorr, P. Keegan, N. Ben-bamch, H. Mrose, M. Noone, K. H. Cowan

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Abstract

Background: It has been demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) can ameliorate chemotherapy-induced neutropenia. The extent to which GM-CSF can increase the actual delivered dose intensity of combination chemotherapy over multiple cycles of therapy to patients with advanced breast cancer has not been well defined. We conducted a phase I/II study of dose-intensive FLAC chemotherapy (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) in combination with GM-CSF in patients with locally advanced and metastatic breast cancer to study the acute and cumulative toxicities, anti-tumor activity and dose-intensity achievable with this regimen. Methods: Eighty-one patients with newly diagnosed stages LTB, in and IV breast cancer who were previously untreated with chemotherapy and who had measurable disease received multiple cycles of FLAC chemotherapy plus E. coli-derived GM-CSF administered every three weeks. Results: FLAC plus GM-CSF as associated with significant cumulative hematologic toxicity. Ninety-eight percent of patients developed grade 4 neutropenia; 29% of all cycles administered required hospitalization for fever and neutropenia; 41% and 22% of cycles required red blood cell and platelet transfusions, respectively. Other significant toxicities with E. coli-derived GM-CSF included mild to moderate first dose effects (hypotension, dyspnea, abdominal cramping) in 30% of patients; late occurring anaphylactoid reactions in 11% of patients; and vascular thromboses. The average delivered dose intensities over all cycles were cyclophosphamide, 210 mg/m2/week; doxorubicin, 14.8 mg/m2/week and 5-fluorouracil, 342 mg/m2/week. The overall clinical response rates were 100% and 83% for LABC and metastatic patients, respectively. There were 23% (6/26) pathologic CR's in the LABC patients given neoadjuvant FLAC and 22% (12/54) clinical CR's in the stage IV patients. The median survival of the LABC patients has not been reached (>26 months) and is 30 months for the stage IV patients. Colusions: The administration of multiple cycles of FLAC plus E. coli-derived GM-CSF therapy is associated with cumulative, dose-limiting myelosuppression, especially thrombocytopenia, as well as significant clinical toxicity. A modest increase in FLAC dose intensity over the starting doses was achievable with the addition of GM-CSF. FLAC chemotherapy has substantial antitumor activity in the treatment of advanced breast cancer. The potential usefulness of FLAC plus GM-CSF must be balanced by its considerable cost and alteration in patients' quality of life due to toxicity. Combination hematopoietic growth factor strategies may be able to reduce the toxicity of FLAC and to allow further increase dose intensity.

Original languageEnglish (US)
Pages (from-to)709-716
Number of pages8
JournalAnnals of Oncology
Volume5
Issue number8
DOIs
StatePublished - Oct 1994

Keywords

  • Breast cancer
  • Dose intensity
  • GM-CSF

ASJC Scopus subject areas

  • Hematology
  • Oncology

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    O'shaughnessy, J. A., Denicoff, A. M., Venzon, D. J., Danforth, D., Pierce, L. J., Frame, J. N., Bastian, A., Ghosh, B., Goldspiel, B., Miller, L., Dorr, F. A., Keegan, P., Ben-bamch, N., Mrose, H., Noone, M., & Cowan, K. H. (1994). A dose intensity study of FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy and Escherichia coli-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) in advanced breast cancer patients. Annals of Oncology, 5(8), 709-716. https://doi.org/10.1093/oxfordjournals.annonc.a058975