A Study to Compare ETC vs. EC-TX and Ibandronate vs. Observation in Patients With Node-positive Primary Breast Cancer (GAIN)
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Study type: Interventional
Phase: Phase 3

Summary: 
      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 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.
    

Detailed description: 
      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.
    

Intervention name(s): Epirubicine; Cyclophosphamide; Taxol; Xeloda; Ibandronat
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Epirbubicne is given; Cyclophosphamide is given; Taxol is given; Xeloda is given; Ibandronat is given
Intervention MeSH terms: Cyclophosphamide; Epirubicin
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: dose dense sequence; dose dense combination; node positive disease