DOSE INTENSIFICATION OF MITOXANTRONE IN COMBINATION WITH LEVOFOLINIC ACID, FLUOROURACIL, CYCLOPHOSPHAMIDE AND GRANULOCYTE-COLONY-STIMULATING FACTOR SUPPORT IN ADVANCED UNTREATED BREAST-CANCER PATIENTS - A MULTICENTRIC PHASE-II STUDY OF THE SOUTHERN ITALY ONCOLOGY GROUP

Fifty-five consecutive patients with metastatic breast cancer (Mac) (n =57) were treated with a combination of levofolinic acid (I-FA) 100 mg /m(2) plus 5-fluorouracil (5-FU) 340 mg/m(2) i.v. on day 1-3, cyclopho sphamide (CTX) 600 mg/m(2) i.v. on day 1 and mitoxantrone (DHAD) 12 mg /m(2) i.v. on day 1. DHAD dose was progressively escalated by 2 mg/m(2 )/cycle up to 18 mg/m(2) in the absence of dose-limiting toxicities. G ranulocyte colony stimulating factor (G-CSF) was given s.c. in order t o prevent neutropenia. DHAD dosage could be increased to 18 mg/m(2) in 66 out of 317 cycles of chemotherapy (21%). In most patients the dose -limiting toxicity was represented by myelosuppresion. A statistically significant correlation was found between median white blood cell (WB C) or absolute neutrophil count (ANC) nadir and DHAD dose level. Moreo ver, a statistically significant correlation was observed between the number of chemotherapeutic cycles, nadir ANC and WBC, and the occurren ce of anemia and thrombocytopenia of increasing severity. These data s uggest the occurrence of progressive cumulative bone marrow toxicity. Although patients who reached different DHAD levels showed differences in mean dose intensity, such differences were not statistically signi ficant. No correlation was found between the increase in dose intensit y and type, rate or duration of objective responses. In patients with metastatic breast cancer the overall response rate was 72% (95% CL 57- 84%) with a 18% complete response rate. Median duration of response wa s 12 and 11 months, respectively, for complete and partial responses. Projected median survival of the whole series of patients with Mac was 18 months. These data demonstrate that the combination of 5-FU with I -FA, CTX and DHAD is very active against MBC. G-CSF use allows the inc rease DHAD dosage up to 18 mg/m(2)/cycle, but its use may be linked to the occurrence of sometimes severe cumulative hematological toxicity.