A randomized phase III trial with dose-dense sequential chemotherapy with epirubicin/paclitaxel/Cyclophosphamide-Methotrexate-Fluorouracil (CMF) vs epirubicin/CMF/docetaxel or paclitaxel as adjuvant chemotherapy in high-risk patients with operable breast cancer.

Group B will be treated with epirubicin [110 mg/m2 intravenous infusion (IV)] every 2 weeks for 3 cycles followed by 3 cycles of CMF (cyclophosphamide; 840 mg/m2 IV , methotrexate; 57 mg/m2 IV and fluorouracil; 840 mg/m2 IV) every 2 weeks followed 3 weeks later by 9 weekly cycles of Docetaxel; 35 mg/m2 IV . The cumulative dose of docetaxel is 315 mg/m2. The duration of E-CMF-docetaxel chemotherapy would be identical to that of E-T-CMF (22 weeks). Group C will be treated with epirubicin (110 mg/m2 IV) every 2 weeks for 3 cycles followed by 3 cycles of CMF (cyclophosphamide; 840 mg/m2 IV, methotrexate; 57 mg/m2 IV and fluorouracil; 840 mg/m2 IV) every 2 weeks followed 3 weeks later by 9 weekly cycles of Paclitaxel 80mg/m2 IV. The cumulative dose of Paclitaxel is 720mg/m2. The duration of E-CMF-paclitaxel chemotherapy would be identical to that of E-T-CMF (22 weeks). Filgrastim 5 micrograms/kg will be given on days 2-7 of each cycle in group A and during the intensified phase of EPI and CMF treatment (all cycles of EPI/CMF) in groups B and C. Ondansetron + Dexamethazone is recommended as antiemetic treatment in all patients. It is anticipated by the protocol that when trastuzumab will be licensed for the adjuvant treatment of high-risk operable breast cancer with human epidermal growth factor receptor 2 (HER-2) overexpression or HER-2 gene amplification, all such patients entered the study will be eligible to receive trastuzumab 8 mg/kg loading dose followed by 6 mg/m2 q3 weeks for 1 year after the completion of chemotherapy. In these patients hormonal treatment with tamoxifen or anastrazole will be started concurrently with initiation of treatment with trastuzumab. All premenopausal patients with receptor positive status will receive tamoxifen 20 mg by mouth (p.o.) daily for 5 years and goserelin (zoladex) 10.8 mg p.o. every 3 months for 2 years. All postmenopausal patients with receptor positive status will be treated with anastrazole 1mg daily for 5 years. Radiotherapy (RT) is required for all patients (pre- or post -menopausal), providing that they had either a partial mastectomy or tumor size > 5cm and /or more than 4 positive lymph nodes, irrespectively the type of surgery (conservative or radical).