Combination chemotherapy (rather than single-agent sequential therapy) is most appropriate when the higher chance of response is assessed to be more important than the potential for higher treatment toxicity, due to concerns about impending organ dysfunction from existing or rapidly progressing disease burden. However, both clinicians and patients should know there are no prospective data that show combination chemotherapy improves overall survival compared with single-agent sequential cytotoxic chemotherapy.
This was shown in the Eastern Cooperative Group (ECOG) 1193 trial in which over 700 women were randomly assigned to doxorubicin plus paclitaxel (AP), doxorubicin, or paclitaxel. For those randomized to single-agent treatment, the protocol mandated cross over to the alternative agent at the time of disease progression. Treatment with AP resulted in:
- A higher overall response rate (ORR) compared with doxorubicin or to paclitaxel (47 versus 36 and 34%)
- A longer median time to progression (TTP; 8 versus 6 and 6 months)
- However, there was no difference in overall survival (OS; 22 versus 19 and 22 months)
Although a 2009 meta-analysis that included 43 trials (n = 9742 women, 55% of whom were treated in the first-line setting) showed that combination therapy could improve OS , these data are limited because they did not evaluate the benefits of combination chemotherapy compared with the sequential administration of agents (eg, drug A plus B versus drug A then B).
There are few data to inform the benefits of combination chemotherapy in the second- or later-line setting. However, the use of a combination in a heavily pretreated patient may be warranted, particularly if a patient has a significant tumor burden, desires the best chance of a response, and is willing to accept the potentially significant risks of combination therapy.
Available combination regimens are discussed below.
Anthracycline-based chemotherapy regimens are associated with response rates of up to 60% in previously untreated patients with metastatic breast cancer [52-55], although they are more toxic than sequential single-agent treatment or non-anthracycline-containing combinations [23,56].
Among the available regimens, an anthracycline plus taxane combination results in a higher response rate compared with non-taxane containing regimens. This was demonstrated in a meta-analysis of pooled individual patient data from eight trials (n = 3000) that compared anthracycline-containing regimens (without a taxane) with anthracycline plus taxane combinations . Compared with non-taxane containing therapy, taxane plus anthracycline treatment resulted in a significantly higher ORR (57 versus 46%) and an improvement in the risk of disease progression (hazard ratio [HR] 0.92, 95% CI 0.85-0.99). Despite these results, there was no difference in median overall survival between anthracycline plus taxane versus anthracycline combinations that do not contain a taxane .
Examples of commonly used anthracycline-based combinations include:
- Doxorubicin plus cyclophosphamide (AC) – ORR ranges from 47 to 54% [57,58]
- Epirubicin with cyclophosphamide and fluorouracil (FEC) – ORR ranges from 45 to 55% [23,56]
- Doxorubicin, docetaxel, plus cyclophosphamide (TAC) – ORR 77% 
- Doxorubicin plus paclitaxel or docetaxel – ORR is approximately 40% for either combination 
Non-anthracycline, taxane-based regimens
For patients who are not suitable candidates for anthracyclines, taxane-based regimens can be administered. The choice among the taxanes is usually determined by the prior treatment history. Given the lack of complete cross-resistance between paclitaxel and docetaxel, we often will administer the alternative agent to the one used in the adjuvant setting (eg, if paclitaxel was used adjuvantly, docetaxel is used in the metastatic setting). For patients who are chemotherapy naive, the choice between them should be based on individual considerations around each of their toxicity profiles.
Gemcitabine plus paclitaxel or docetaxel
Gemcitabine (1250 mg/m2 on days 1 and 8) plus paclitaxel (175 mg/m2 on day 1) resulted in an ORR of 41% when administered as a first-line therapy for metastatic breast cancer . In a separate trial, gemcitabine (1000 mg/m2 on days 1 and 8) plus docetaxel (75 mg/m2 on day 1) resulted in an ORR of 43% in first-line therapy . These two regimens have not been compared directly, but presumably gemcitabine plus docetaxel would have higher toxicity, given that both are myelotoxic as single agents.
Capecitabine plus docetaxel
Capecitabine (1250 mg/m2, twice daily for 14 of every 21 days) plus docetaxel (75 mg/m2 every 21 days) (CD) resulted in an ORR of 42% . Several studies also suggest it improves survival over single-agent docetaxel even when capecitabine was mandated on disease progression [63,64]. However, limited data suggest that CD is equivalent to gemcitabine plus docetaxel (GD) but is the more toxic combination .
For patients who are not candidates for anthracyclines or taxanes and those who have progressed despite prior treatment, there are several available alternate options. These are discussed below.
Ixabepilone plus capecitabine
Ixabepilone (40 mg/m2 every three weeks) plus capecitabine (1000 mg/m2 twice daily for 14 of every 21 days) resulted in an ORR of 35% .
Cyclophosphamide, methotrexate, and fluorouracil (CMF)
CMF is rarely administered for metastatic breast cancer because it appears to produce the same response rate when compared with oral capecitabine (20%) in one trial . However, CMF resulted in a shorter OS (median, 22 versus 18 months; HR 0.72, 95% CI 0.55-0.94). CMF may be indicated in patients who cannot tolerate capecitabine or for patients in whom an oral regimen is not feasible for whatever reason.
Combination regimens incorporating platinum salts
Regimens combining platinum salts with chemotherapies such as taxanes, vinorelbine, or gemcitabine have been postulated to be specifically efficacious in tumors where DNA repair pathways are faulty, such as in specific subsets of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer.
However, no prospective trials have been completed that demonstrate a survival advantage to such regimens compared with non-platinum regimens. We typically reserve platinum-containing combination regimens for those women with good performance status, but high disease burden, whose disease has progressed on other available chemotherapy agents .
High-dose chemotherapy protocols
High-dose chemotherapy with autologous stem cell transplantation is not an option for the standard treatment of metastatic breast cancer. A 2011 systematic review that included six randomized trials concluded that high-dose chemotherapy did not significantly improve overall survival and that any benefit from this treatment was minimal. Therefore, we advise against these treatments for metastatic breast cancer .