Failure of GM-CSF to permit dose-escalation in an every other week dose-intensive regimen for advanced breast cancer

In an attempt to improve dose intensity and therapeutic effectiveness in breast cancer, GM-CSF was incorporated into a multi-drug every other week chemotherapy regimen that had been previously reported to have promising activity, but whose dose-limiting toxicity was neutropenia. A Phase I-II study in patients with locally advanced or metastatic breast cancer was initiated using GM-CSF and a 5-drug chemotherapy regimen employing oral cyclophosphamide daily for 7 days and doxorubicin, vincristine, methotrexate, 5-fluorouracil, and leucovorin IV every 2 weeks for 10 courses. In the first 8 patients, GM-CSF in escalating doses (1–20 μg/kg s.c. per day) was given on days 8–13 of each 2 week cycle. In the last 12 patients, GM-CSF was given on days 3–14 of each cycle in an attempt to improve its effectiveness by prolonging treatment duration. The regimen was poorly tolerated. Only 10 patients completed all 10 courses of treatment, and most of those required dose delays and/or reductions. GM-CSF failed to reduce neutropenia when given by either schedule. Furthermore, thrombocytopenia was severe and progressive, especially with the more prolonged GM-CSF schedule in which the mean lowest nadir platelet count was 15,000/μsl. Anemia, fatigue, mucositis, and neutropenic fevers were also common, and dose escalations were not possible in any patient. Central venous catheter complications were also common. Complete or partial remissions were observed in 15 of 20 patients, but response durations were brief. GM-CSF in two different schedules failed to ameliorate myelosuppression when used in combination with this multiple drug, every other week regimen. Neutropenia and, especially, thrombocytopenia remained dose limiting.