Granulocyte-Macrophage Colony-Stimulating Factor Treatment Before Doxorubicin and Cyclophosphamide Chemotherapy Priming in Women With Early-Stage Breast Cancer

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Abstract
PURPOSE: To determine if inhibition of stem-cell activity induced by granulocyte-macrophage colony-stimulating factor ([GM-CSF]; Sargramostim; Immunex Corporation, Seattle, WA) withdrawal or priming protects hematopoietic stem cells from the cytotoxic effects of adjuvant chemotherapy for early-stage breast cancer. PATIENTS AND METHODS: Serial blood counts were performed in 20 women with early-stage breast cancer receiving four courses of cyclophosphamide and doxorubicin chemotherapy. By a double-blind, placebo-controlled, balanced randomization, subjects received GM-CSF priming on days 5 to 1 for courses 1 and 3 or courses 2 and 4. RESULTS: Compared with before priming, after priming the times to neutrophil nadir (12.8 ± 2.5 days v 14.8 ± 1.5 days, respectively; P = .0001) and platelet nadir (mean ± SD, 10.1 ± 1.9 days v 11.1 ± 2.2 days, P < .05) were shorter, indicating a shift of cytotoxicity to later progenitors. The neutrophil nadir was similar with and without priming (mean ± SD, 490 ± 310/μL v 550 ± 350/μL, respectively; P = .2); however, on day 16 the mean neutrophil count was higher (mean ± SD, 1030 ± 580/μL v 690 ± 370/μL, P = .004), and the proportion of patients with a neutrophil count less than 500/μL was lower after priming than before (six of 35 or 17.1% v 12 of 34 or 35.3%, respectively; P = .04). The platelet nadir was higher (mean ± SD, 166,000 ± 51,000/μL after priming v 151,000 ± 45,000/μL before priming, P = .007), and the duration of thrombocytopenia, ie, a platelet count less than 150,000/μL, was shorter (1.5 ± 2.1 days v 2.8 ± 2.9 days, P = .0025) after priming. Episodes of fever and neutropenia were not observed. CONCLUSIONS: GM-CSF priming from days 5 to 1 before doxorubicin and cyclophosphamide chemotherapy was associated with an earlier neutrophil and platelet nadir. On day 16, a higher mean neutrophil count and a lower proportion of patients with severe (< 500/μL) neutropenia were observed. Beneficial effects on the severity and duration of thrombocytopenia were also noted. These observations support the hypothesis that GM-CSF priming protects hematopoietic progenitors from the cytotoxic effects of chemotherapy.