Simultaneous Study of Gemcitabine-Docetaxel Combination Adjuvant Treatment, as Well as Extended Bisphosphonate and Surveillance-Trial

This is an open-label, multicenter, 2x2 factorial design, randomized controlled, Phase III study comparing the disease free survival after randomisation in patients treated with 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC)-chemotherapy, followed by 3 cycles of Docetaxel(Doc)-chemotherapy versus 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC), followed by 3 cycles of Gemcitabine-Docetaxel(DocGemzar)-chemotherapy, and to compare the disease free survival after randomisation in patients treated with 2 years of Zoledronate versus 5 years of Zoledronate in patients with early primary breast cancer. Patients will be required to have histopathological proof of axillary lymph node metastases (pN1-3) or high risk node negative, defined as: 'pT≥2 or histopathological grade 3, or age ≤ 35 or negative hormone receptor', but are not allowed to have evidence of distant disease. Patients will have to be entered into the study no later than 6 weeks after complete resection of the primary tumor. No other antineoplastic treatment other than surgical treatment, the defined cytotoxic and endocrine treatment and radiotherapy will be allowed prior to study entry and during the course of the study.

After surgery, leading to R0 resection of the invasive and intraductal components of the primary tumor, patients will be randomized to one of the following treatments:

First randomization

AA: 3 cycles of 5-Fluorouracil 500 mg/m² i.v. body surface area and Epirubicin 100 mg/m² i.v. and Cyclophosphamide 500 mg/m² i.v., (FEC100), each administered on day 1, repeated on day 22, subsequently followed by 3 cycles of Docetaxel 75 mg/m² body surface area i.v. (Doc), and Gemcitabine 1000 mg/m² i.v. (30 min infusion) (Gemzar), administered on day 1, followed by Gemcitabine 1000 mg/m² i.v. (30 min infusion) on day 8, repeated on day 22

AB: 3 cycles of 5-Fluorouracil 500 mg/m² i.v. body surface area and Epirubicin 100 mg/m² i.v. and Cyclophosphamide 500 mg/m² i.v., (FEC100), each administered on day 1, repeated on day 22, subsequently followed by 3 cycles of Docetaxel 100 mg/m² body surface area i.v. (Doc), administered on day 1, repeated on day 22

Second randomization B

BA: Zoledronic acid 4 mg i.v., every 3 months for the duration of two years, subsequently followed by zoledronic acid 4 mg i.v., every 6 months for the duration of additional three years

BB: Zoledronic acid 4 mg i.v., every 3 months for the duration of two years

During the zoledronic acid treatment period, patients will receive 500 mg Calcium p.o. qid and 400 i.E. Vitamin D p.o. qid.

Patients with positive hormone receptor status (≥ 10 % positively stained cells for estrogen and/or progesterone) of the primary tumor will receive Tamoxifen treatment 20 mg p.o. per day for 2 years, after the end of chemotherapy. Subsequent to chemotherapy, postmenopausal patients with positive hormone receptor status will be treated with Anastrozole (Arimidex®) 1 mg p.o. for additional 3 years, premenopausal patients will continue Tamoxifen treatment for additional 3 years. In addition to tamoxifen, all patients with positive hormone receptor status of the primary tumor and under the age of 40 or restart of menstrual bleeding within 6 months after the completion of cytostatic treatment or with premenopausal hormone levels as defined below will receive Goserelin (Zoladex®) 3.6 mg subcutaneously every 4 weeks over a period of 2 years following chemotherapy. Premenopausal endocrine status will be assumed, if the following serum levels are met: Luteinizing hormone (LH) < 20 mIE/ml, follicle stimulating hormone (FSH) < 20 mIE/ml and estradiol (E2) > 20 pg/ml. Endocrine therapy will start after the end of chemotherapy.

All patients with breast conserving therapy or more than 3 axillary lymph node metastases or in the following cases after mastectomy:

* T3/T4-carcinoma * T2-carcinoma > 3 cm * multicentric tumor growth * lymphangiosis carcinomatosa or vessel involvement * involvement of the pectoralis fascia or a safety margin < 5 mm.

will receive adjuvant radiotherapy.