3.1. Chemotherapy regimen

Several polychemotherapy regimens are accepted as adjuvant chemotherapy regimen with strong evidence in patients with early stage breast cancer. The preferred regimens vary according to characteristics of disease, patients' comorbidities, patients' preferences, age, prescribing doctor, institution, or country.

Early Breast Cancer Trialists' Collaborative Group (EBCTCG) reports a meta-analysis periodically to review the data on adjuvant treatment of breast cancer. The previous data supported the adjuvant chemotherapy particularly cyclophosphamide, methotrexate and fluorouracil (CMF), anthracyclines and taxane compared with no treatment in adjuvant setting.

Trials with CMF-treated controls revealed that standard 4 AC and standard CMF were equivalent (P = 067), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4 AC [e.g., CAF or cyclophosphamide & epirubicin & fluorouracil (CEF)] were superior to standard CMF (RR 0.78, P = 0.0004) [45]. However, NSABP B-36 randomized phase III trial compared six cycles of FEC-100 with four cycles of standard AC in pts. with T1- 3 N0 breast cancer [46]. Primary and secondary endpoint analyses at 8 years did not reveal any significant differences in DFS, OS, recurrence free interval (RFI), or distant RFI, although patients and tumor characteristics were equally distributed between the two groups (<50 years old: 40%, lumpectomy: 68%, and hormone positivity: 65%). Overall, Grade 3 and 4 expected toxicities were more frequent in the FEC arm. Thus, international guidelines excluded six cycles of FEC-100 from adjuvant breast cancer treatment recommendations.

In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0.86, SE 0.04, twosided significance P = 0.0005) [45].

In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumor diameter or differentiation, ER status, or adjuvant tamoxifen. Hence, largely independently of age (up to at least 70 years) or the tumor characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality about one-third.

Thus, based on these strong evidences, AC followed by a taxane (either triweekly docetaxel, paclitaxel or two weekly or weekly paclitaxel) is now usually preferred regimen in most cases in whom adjuvant chemotherapy is indicated.

Nonanthracycline-based chemotherapy regimens should be preferred in certain patients with lower risk disease (node-negative), cardiac contraindication, advanced age, previous chest wall irradiation or patients who do not accept the risks of anthracycline-based therapy. In these patients, four cycles of docetaxel and cyclophosphamide (TC) are most preferred regimen.

When adjuvant chemotherapy is indicated in HR+ HER2-negative early breast cancer, taxane is mostly added to anthracycline-based regimen based on scientific data. However, patients who cannot receive taxane due to risks of allergic reactions or peripheral neuropathy, CMF can be administered instead of anthracycline or taxane- based regimens.

Dose-dense chemotherapy plays a controversial role in the adjuvant treatment of breast cancer patients. Whereas meta-analyses persistently describe a significant superiority for dose-dense treatment, the results of large phase III trials remain contradictory [47]. Some of these trials showed important differences between the dose-dense and conventional groups regarding number of cycles, type of drug, and total dose. Other trials are accepted and interpreted as dose-dense but present a mixture of dose-dense and conventional schedules.

Goldvaser et al. performed a systemic review and meta-analysis of clinical trials in which patients with early stage breast cancer were treated with adjuvant dose-dense chemotherapy [48]. Dose-dense treatment significantly improved DFS (HR 0.85, P < 0.001) and OS (HR 0.86, P = 0.008). A significantly greater relative magnitude of benefit was observed in premenopausal women and those with nodal involvement, but there was no influence of hormone receptor status on results. Adjuvant dose-dense regimens improve breast cancer outcomes. It remains uncertain whether the observed benefit reflects the impact of dose density or the inferiority of paclitaxel every 3 weeks as a control group.

Although a direct head-to-head comparison is missing, intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddETC) or four cycles each of dose-dense epirubicin/cyclophosphamide followed by paclitaxel are the preferred adjuvant regimens for patients at risk. Patients with four positive lymph nodes should preferentially be treated with iddETC.

However, in EBCTCG meta-analyses, information was lacking about tumor gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both.
