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Patients with high-risk breast cancer may benefit from dose-escalated chemotherapy. We studied toxicity and therapeutic efficacy of sequential high-dose therapy consisting of two cycles of ifosfamide 12,000 mg/m2, carboplatin 900 mg/m2, and epirubicin 180 mg/m2 (ICE) with peripheral blood stem cell support. Ninety-one patients with advanced breast cancer were included. Fifty-one patients with stage II/III disease and 10 or more tumor-positive axillary lymph nodes received high-dose therapy as adjuvant treatment; the remaining 40 patients were treated for metastatic disease. Peripheral blood stem cells were collected following granulocyte colony-stimulating factor-supported induction chemotherapy. In 68 patients, induction chemotherapy included two cycles of ifosfamide 7,500 mg/m2 and epirubicin 120 mg/m2, while 23 patients received one cycle of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 135 mg/m2, ifosfamide 6,000 mg/m2, and epirubicin 90 mg/m2. One hundred ninety-two cycles of ICE were supported with a median of 3.5 x 10(6) CD34+ cells/kg body weight (range, 1.7 to 38 x 10(6) CD34+ cells/kg body weight), which resulted in rapid hematologic reconstitution with recovery times, for a median neutrophil count of 0.5 x 10(9)/L of 13 days (range, 6 to 20 days) and for a median platelet count greater than 20 x 10(9)L of 9 days (range, 5 to 24 days). Seven patients received only one cycle of ICE because of progressive disease (in two patients with metastatic disease), central nervous system toxicity (one patient), cardiac toxicity (one patient), severe enterocolitis (one patient), development of human leukocyte antigen antibodies (one patient), and wish to withdraw from the study (one patient). Seventeen patients with metastatic disease received an additional high-dose cycle consisting of the non-cross-resistant agents thiotepa 600 mg/m2, etoposide 1,500 mg/m2, and paclitaxel 165 mg/m2. In patients treated adjuvantly, the probability of disease-free survival was 64% at 47 months, which compares favorably with results of conventional treatment protocols, with a 47% event-free probability at the same time period. The probability of progression-free survival in patients with metastatic disease was 18% at 44 months. In conclusion, sequential high-dose therapy with peripheral blood stem cell support in patients with high-risk breast cancer can be administered safely and offers a potential benefit in the adjuvant setting.

The plasminogen activator system plays a key role in the proteolysis of malignant tumours. In 155 patients with primary breast cancer levels from PAI-1 and uPA were measured in cytosol with monoclonal antibodies and by an enzyme-linked immunosorbent assay. 35 tumour tissue samples form benign breast were also examined. Malignant tumours contain higher levels of PAI-1 (8.6 ng/mg) than benign tumours (1.28 ng/mg) (p < 0.01). Also the median level of uPA was significantly higher (p < 0.01) in malignant tissue (2.38 ng/mg) in comparison to benign disease (0.54 ng/mg). No correlation was found between the proteases and the classical prognostic parameters like axillary lymph node involvement, tumour size and menopausal status. However, a significant correlation (p < 0.01) was found in tumours with lymphangiosis carcinomatosa, negative hormone receptors, grade III tumour cells and high S-phase fractions (> 5%). After a median follow-up of 46 months we found that high levels of PAI-1 correlated with short DFS (p = 0.0005) and OAS (p = 0.003). However, in the Cox multivariate regression analysis only PAI-1 was significantly independent for OAS and could therefore give additional information. We conclude that levels from PAI-1 antigen measured in cytosol of primary breast cancer is an independent prognostic parameter to identify patients with high and low risk for relapse and for individualised treatment.