Adverse effect on bone marrow protection of prechemotherapy granulocyte colony-stimulating factor support

Abstract

Background: Increased proliferation of endogenous bone marrow progenitor cells in response to the administration of hematopoietic growth factors, followed by reduced cell cycling or entrance of the cells into a quiescent state upon withdrawal of the growth factors, may have clinically relevant effects on the tolerance of the hematopoietic system to subsequent myelotoxic treatments. Purpose: We investigated the ability of granulocyte colony- stimulating factor (G-CSF) to protect progenitor cells in the bone marrow of cancer patients from the toxic effects of subsequent treatments with chemotherapeutic agents. Methods: Thirty-six patients with histologically documented, locally advanced or metastatic breast cancer were randomly assigned to receive doxorubicin once every 3 weeks at a dose of 75 mg/m2 and cyclophosphamide at a dose of 1000 mg/m2, with G-CSF administered either before and after chemotherapy (18 patients) or after chemotherapy only (18 patients). For prechemotherapy administration of G-CSF, recombinant human methionyl (r-met Hu) G-CSF was administered subcutaneously to patients twice per day for 5 days at a dose of 5 μg/kg, with the last dose given 48 hours before the start of chemotherapy. For postchemotherapy administration of G- CSF, r-met Hu G-CSF was administered subcutaneously to patients once per day for 7 days at a dose of 5 μg/kg, with the first dose given 24 hours after chemotherapy. Results: The incidence or the duration of grade 4 neutropenia was not reduced in all patients by the use of prechemotherapy G-CSF; the incidence over all cycles of chemotherapy was 74% for patients treated with prechemotherapy and postchemotherapy G-CSF and 66% for patients treated with postchemotherapy G-CSF only (two-sided P, adjusted for dose = .21) and the median duration in both treatment arms was 3 days (two-sided P = .19). Unexpectedly, the incidence of grades 3 and 4 thrombocytopenia was much greater in patients who received prechemotherapy G-CSF compared with those who did not (54% versus 6%, respectively, over all chemotherapy cycles; two- sided P, adjusted for dose