Adjuvant Phase III Trial to Compare Intense Dose-dense Adjuvant Treatment With EnPC to Dose Dense, Tailored Therapy With dtEC-dtD for Patients With High-risk Early Breast Cancer (GAIN-2)
The Norton-Simon-Hypothesis on log cell kill suggests that chemotherapy should be given at
maximum dosages at minimum intervals. Combination chemotherapy, which always has to make
compromises regarding the doses of each drug and treatment intervals due to acute as well as
cumulative toxicities, does therefore not comply with this theory. Sequential application of
monotherapies, however, allows very high single agent doses and dose-dense treatment
intervals. Regimens designed according to the Norton-Simon-Hypothesis have shown to be
highly active as adjuvant treatment for early breast cancer. As the number of cycles of each
agent can be restricted to 3, as previously done in the AGO ETC trial by Möbus et al.,
cumulative toxicities do not really occur.
Two large scale trials of dose-dense chemotherapy have proven very high protective activity
against tumor recurrence (AGO ETC (Ref.1) and CALGB 9741 (Ref.2)). Especially the ETC trial
(epirubicin, solvent-based paclitaxel, and cyclophosphamide) showed an impressive superior
DFS and OS in 1284 high-risk breast cancer patients with > 4positive lymph nodes. The doses
used are exceptional at maximum dosage and minimum intervals with epirubicin 150 mg/m²,
Paclitaxel 225 mg/m² and cyclophosphamide 2.5 g/m² given every 2 weeks based on the above
described Norton-Simon-Hypothesis. However, as each drug was given only 3 times at intervals
of 2 weeks, this regimen is feasible and safe with primary support of G-CSF and ESF. The ETC
schedule is today considered standard of care for high-risk breast cancer patients in
However, both trials, ETC and CALGB 9741, compared the dose-dense concept against EC-P q3w
which is nowadays considered to be an inferior regimen compared to EC-P weekly or EC-Doc.
The GAIN trial had a 2x2 factorial design and explored ETC versus EC-TX and ibandronate vs.
observation. The trial closed recruitment after 3023 pts in July 2008. In the Panther trial,
a joint effort of SBG, ABCSG, AGO-B and GBG, the tailored, dose-dense EC-Doc (dtEC-dtD)
regimen was tested against conventional dosed FEC-Doc. Efficacy results are to be awaited,
safety results will be published in 2012.
Nab-paclitaxel (nP) provides a better toxicity profile and a higher efficacy compared to
solvent based taxanes (paclitaxel and docetaxel). It might therefore be the preferred
component in an intense dose-dense regimen. Assuming that the corresponding dose of
nab-paclitaxel to 175 mg/m² paclitaxel is 260 mg/m², an appropriate dose would be 330 mg/m²
nab-paclitaxel to substitute paclitaxel at 225 mg/m². So far, no experience with such a dose
of nab-paclitaxel is available. However, initial experience with 300mg/m² q3w and 150mg/m²
weekly (in 3 out of 4 weeks) showed a good safety profile even when given for a median of 8
cycles (Ref.3). Another pilot study showed a good tolerability of 260 mg/m² nab-paclitaxel
given q2w for 4 cycles (Ref.4+5).
The GAIN-2 trial will allow for comparing the toxicity and effectiveness of a predefined
intense dose-dense regimen (EnPC) vs. a dose-dense regimen with modification of single doses
depending on individual haematological and non-haematological toxicities. The primary aim of
the GAIN-2 trial will be to compare the invasive disease-free survival after adjuvant
chemotherapy with EnPC or dtEC-dtD in patients with primary node-positive or high risk node
negative breast cancer. To explore the maximum dose of nab-paclitaxel in this setting, a
run-in phase with varying doses of nab-paclitaxel is included in the study design.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
invasive disease-free survival (IDFS)
The IDFS is defined as the time period between the registration and the first invasive event. It will be analyzed after the end of the study by referring to data from GBG patient's registry.
Gunter von Minckwitz, Prof.
German Breast Group
Germany: Federal Institute for Drugs and Medical Devices