• A: To compare the disease-free survival after adjuvant chemotherapy with "ETC" (Arm A1) or "EC-TX" (Arm A2) in patients with primary node-positive breast cancer.
  
• B: To compare the disease-free survival with (Arm B1) or without ibandronate (Arm B2) treatment for 2 years in patients with primary node-positive breast cancer
  

• To compare overall survival between arms A1 vs. A2 and B1 vs. B2
  
• To evaluate the compliance in arms A1 vs. A2 and in B1
  
• To compare the safety between arms A1 vs. A2 and B1 vs. B2
  
• To assess the rate of responders to erythropoesis stimulating factors in arm A1 and A2
  
• To compare the incidence of secondary primaries between arms A1 vs. A2
  
• To compare the event-free survival in subgroups of hormone sensitive and insensitive disease and in groups with 1-3, 4-9 or 10+ involved nodes between arms A1 vs. A2 and B1 vs. B2
  
• Tertiary objectives:
  
• To determine prognostic factors like TS or TP and others on tumor tissue collected from primary surgery and to correlate them with study treatment effect
  

Currently several strategies are under investigation to further improve adjuvant treatment of early node-positive breast cancer. These are combination treatment of drugs with synergistic mode of action, dose-dense application of cytotoxic drugs, dose-intensification and the use of new, non-cytotoxic approaches.

In the recent AGO-study, a dose-dense and dose-intensified sequence of Epirubicin - Paclitaxel - Cyclophosphamide has shown superior efficacy compared to a conventionally dosed sequence of Epirubicin / Cyclophosphamid and Paclitaxel and was therefore chosen as standard treatment in this study.

The experimental arm of EC-TX combines several of the above mentioned strategies: the combination of EC will be administered every 2 weeks as a dose-dense regimen, the combination of TX can also be considered as dose-dense due to the weekly application of paclitaxel. Furthermore there is clinical evidence, that a combination of capecitabine and Paclitaxel provide synergistic effects with improved tumour response. A randomized phase III study could demonstrate a survival benefit of a combination of capecitabine with Docetaxel in patients with metastatic breast cancer. This synergistic effect is probably based on the preclinical observed taxane-mediated up-regulation of thymidine phosphorylase in the tumour cell, which give drive to an increased transformation of capecitabine to its active form 5-Fluorouracil. Apart from this synergy, the EC-TX regimen includes now 4 highly active compounds for the treatment of breast cancer. The total doses of Epirubicin and Paclitaxel are identical in both arms. The dosage of Cyclophosphamide is lower in the experimental arm, which is preferred due to the induction of leukaemia at higher doses of Cyclophosphamide. The duration of both arms with 18 and 20 weeks is nearly similar.

The 2 by 2 factorial design of the trial provides the additional possibility to explore the efficacy of a bisphosphonate as another strategy to further improve the prognosis of node positive breast cancer. As the mechanism of action of cytotoxic drugs and bisphosphonates appear to be independent the factorial design is an adequate statistical model for this trial. Up to now only limited information is available on the potential role of bisphosphonates in this setting and they have all been generated by using the 1st generation bisphosphonate Clodronate. 3rd generation bisphosphonates like ibandronate are much more active, less toxic and their application is more convenient (which is of high importance regarding the long duration of treatment).

Primary aims of this trial are to improve disease-free survival by using the EC-TX regimen and by using ibandronate as adjuvant treatment for 2 years.