An increase in the dose of chemotherapy enhances the response of many experimental and clinical cancers, but the extent of dose escalation is often limited by myelosuppression. In preliminary trials, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has augmented leukocyte numbers and function, but the optimal dose is not established. We treated 16 adults who had inoperable or metastatic sarcomas with escalating doses of rhGM-CSF before and immediately after a first cycle of chemotherapy (cycle 1) to assess hematologic response and toxicity. A second cycle of chemotherapy (cycle 2) was given without rhGM-CSF. RhGM-CSF was tolerated well at doses of 4 to 32 micrograms per kilogram of body weight per day. At 64 micrograms per kilogram per day, edema and thrombi around a central venous catheter developed in two of four patients. Leukocyte and granulocyte counts increased significantly during the rhGM-CSF infusion. Neutropenia after cycle 1 was significantly less severe and shorter in duration than after cycle 2 (P less than 0.01). Mean total leukocyte and platelet nadirs were 1.0 and 101 x 10(9) per liter for cycle 1 and 0.45 and 44 x 10(9) per liter for cycle 2 (P less than 0.01), and the median intervals from day 1 of chemotherapy to neutrophil recovery (greater than 0.500 x 10(9) per liter) were 15 and 19 days, respectively (P less than 0.01). The duration of neutropenia was 3.5 days with cycle 1 and 7.4 days with cycle 2 (P less than 0.01). We conclude that rhGM-CSF is tolerated well at doses up to 32 micrograms per kilogram per day and is biologically active in leukopenic patients. It merits further evaluation for the prevention of morbidity from chemotherapy.
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Dana-Farber Cancer Institute, Boston, MA 02115.
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