A Phase III Trial to Compare ETC vs, EC-TX and Ibandronate vs. Observation in Patients With Node-positive Primary Breast Cancer (GAIN)
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.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment
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.
US-law not applicable
Volker Möbus, Prof. Dr.
Städtische Kliniken Frankfurt a.M.-Höchst, Gotenstr. 6-8, 65929 Frankfurt, Germany
Germany: Federal Institute for Drugs and Medical Devices