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.

Inclusion Criteria:

• Primary epithelial invasive carcinoma of the breast pT1-4, pM0
• Histopathological proof of axillary lymph node metastases (pN1-3) or high risk pN0/NX, defined as: 'pT ≥ 2 or histopathological grade 3 or age ≤ 35 or negative hormone receptor status'
• Complete resection the primary tumor with margins of resection free of invasive carcinoma not more than 6 weeks ago
• Females ≥ 18 years of age
• Performance Status ≤ 2 on Eastern Cooperative Oncology Group (ECOG) Scale
• Adequate bone marrow reserve: leucocytes ≥ 3.0 x 10^9/l and platelets ≥ 100 x 10^9/l
• Bilirubin within one fold of the reference laboratory's normal range, aspartate aminotransferase (ASAT) (serum glutamate oxalacetate transaminase, SGOT), alanine aminotransferase (ALAT) (serum glutamate pyruvate transaminase, SGPT) and alkaline phosphatase (AP) within 1,5 fold of the reference laboratory's normal range for patients
• Intention of regular follow-up visits for the duration of the study
• Ability to understand the nature of the study and to give written informed consent

Exclusion Criteria:

• Inflammatory breast cancer
• Previous or concomitant cytotoxic or other systemic antineoplastic treatment which is not part of or allowed within this study
• History of treatment or disease affecting bone metabolism (e.g., Paget's disease, primary hyperparathyroidism)
• Prior treatment with bisphosphonates within the last 6 months
• Severe renal insufficiency as evidenced by creatinine clearance < 30 ml/min as calculated using the Cockcroft-Gault formula
• Second primary malignancy (except in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin)
• Cardiomyopathy with impaired ventricular function (New York Heart Association Functional Classification Class (NYHA) > II), cardiac arrythmias influencing left ventricular ejection fraction (LVEF) and requiring medication, history of myocardial infarction or angina pectoris within the last 6 months, or arterial hypertension not being controlled by medication
• Any known hypersensitivity against docetaxel, epirubicin, cyclophosphamide, fluorouracil, gemcitabine or any other medication included in the study protocol
• Use of any investigational agent within 3 weeks prior to inclusion
• Patients in pregnancy or breast feeding (in premenopausal women anticonception has to be assured: intra uterine devices, surgical methods of sterilization, or, in hormone unsensitive tumors only, oral, subcutaneous or transvaginal hormonal, non estrogen containing contraceptives)
• Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures.
• Recent (within 6 weeks) or planned dental or jaw surgery (e.g.. extraction, implants)