When to Initiate Systemic Chemotherapy and Choosing a Chemotherapy Drug
Breast cancer is a relatively chemosensitive disease. As discussed above, endocrine manipulation should be considered for all patients with hormone-receptor–positive disease and small volume, bone-only or asymptomatic visceral disease. Cytotoxic chemotherapy is appropriate for those with hormone-refractory disease, rapidly progressive visceral disease, or early relapse after adjuvant therapy. It is the only therapeutic option for patients with HER2-negative, hormone-resistant metastatic breast cancer.
Commonly Used Chemotherapy Regimens for Metastatic Breast CancerGiven the wide choice of available agents, it is paramount to individualize therapy as much as possible. Pertinent physician and patient factors in treatment choice include performance status, personal preference or experience, compliance, drug administration route, comorbidities, drug toxicities, efficacy, and prior exposure to the same drug class (Table 2). Circulating tumor cells can be detected in a small percentage of patients with metastatic disease and are an early predictor of progression.[14,15] However, their clinical utility in directing a change in therapy and their impact on clinical outcome has not yet been determined and is the subject of a prospective randomized trial.
Sequential Single Agents vs Combination Chemotherapy
A Cochrane review in 2005 found that, compared with single chemotherapeutic agents, combination regimens showed a statistically significant advantage for tumor response and time to progression in women with metastatic breast cancer, a modest improvement in overall survival, and significantly worse toxicities.[16] Administering agents sequentially has the advantage of giving each drug at its maximum tolerated dose without overlapping toxic effects. The emergence of newer targeted agents that do not or only modestly exacerbate the adverse effects of most conventional cytotoxic agents allow for safe combinations and, in some cases, improved survival (eg, trastuzumab(Drug information on trastuzumab) [Herceptin]). At present, combination chemotherapy in the metastatic setting is best reserved for select, fit patients with rapidly progressing disease. Improved prognostic and predictive tools will hopefully help with drug selection in the future.
Anthracyclines
Since the 1970s, doxorubicin(Drug information on doxorubicin) has shown increased response rates over non–anthracycline-containing regimens.[17,18] No significant difference in efficacy was noted between epirubicin(Drug information on epirubicin) (Ellence) and doxorubicin in the metastatic setting in a trial comparing CAF (cyclophosphamide, doxorubicin, fluorouracil(Drug information on fluorouracil) [5-FU]) with CEF (cyclophosphamide, epirubicin, 5-FU).[19] Pegylated liposomal doxorubicin (Doxil) has shown comparable antitumor activity and less cardiotoxicity than conventional doxorubicin.[20] Doxorubicin-containing regimens are available in multiple dosing and scheduling formats.
Following the results demonstrated by the Early Breast Cancer Trialists’ Collaborative Group that anthracycline-based adjuvant polychemotherapy reduces the annual breast cancer death rate by about 38% for women younger than 50 years and by about 20% for those aged 50 to 69 years,[21] many women with recurrent disease will already have received anthracycline-based chemotherapy regimens and often taxanes. The same is true for many endocrine manipulations, and it is unclear whether rechallenge with anthracycline-containing regimens is effective as a first-line therapy.
One small retrospective study was designed to address this issue.[22] This randomized phase III trial compared the efficacy of epirubicin plus docetaxel(Drug information on docetaxel) (Taxotere) with that of docetaxel alone as first-line chemotherapy of metastatic breast cancer patients pretreated with epirubicin in the adjuvant or neoadjuvant setting. Antitumor efficacy was similar in the two arms, while epirubicin/docetaxel produced significantly worse leukopenia, nausea, and stomatitis. These data suggest that rechallenge with an anthracycline-containing regimen as first-line therapy in anthracycline-pretreated metastatic breast cancer patients may not be worthwhile.
Taxanes
Given many patients’ prior exposure to anthracyclines and their associated cardiotoxicity, taxanes are an appealing first-line metastatic chemotherapy choice. Both docetaxel and paclitaxel(Drug information on paclitaxel) have been compared with doxorubicin in the first-line treatment of metastatic breast cancer. Docetaxel produced a higher overall response rate than doxorubicin (47.8% vs 33.3%; P = .008) but no difference in time to progression or overall survival.[23]
A more recent study compared every-3-week single-agent docetaxel to paclitaxel and found superior overall survival and time to progression in the docetaxel arm given at a dose of 100 mg/m2; however, this treatment was associated with an increase in hematologic and nonhematologic toxicities.[24] Weekly paclitaxel is superior to the same drug given every 21 days.[25] Weekly paclitaxel and 3-weekly docetaxel have yet to be directly compared, but they appear to be equally efficacious in the adjuvant setting.[26] Anecdotal reports suggest that weekly paclitaxel after its adjuvant use in a 3-weekly or dose-dense schedule may be effective.
Albumin-bound paclitaxel (nab-paclitaxel [Abraxane]) every 3 weeks produces a higher response rate (33% vs 19%; P = .001) and time to progression (23 vs 16.9 weeks; P = .006) in metastatic breast cancer patients, compared to 3-weekly paclitaxel, with potentially less associated toxicity.[27] Weekly nab-paclitaxel has not been compared to weekly paclitaxel. A randomized phase II study found greater progression-free survival with nab-paclitaxel (at all of three different doses) compared to docetaxel.[28] Avoidance of steroid premedication is a key feature of nab-paclitaxel, but cost compared to generic paclitaxel should be considered in the absence of efficacy data.
Taxanes have been combined with various other chemotherapies. A meta-analysis of 12 of these studies found increased response rates and progression-free survival for the taxane/anthracycline combinations over single-agent taxanes, but this did not translate to an overall survival advantage.[29]
Other Chemotherapy Agents
Capecitabine (Xeloda) has a high single-agent efficacy in metastatic breast cancer,[30] although it is potentially less active in patients with hormone receptor–negative disease.[31] For women transitioning from oral endocrine treatments or those who wish to avoid infusion therapy and alopecia, the drug is an attractive option. However, it requires a compliant patient and can cause neutropenia, nausea, fatigue, diarrhea, and hand-foot syndrome. Use of capecitabine(Drug information on capecitabine) upfront as palliative therapy may also limit the subsequent use of bevacizumab(Drug information on bevacizumab) (Avastin), an additional consideration in light of the 2008 US Food and Drug Administration (FDA) approval of this antibody for use with paclitaxel in the first-line setting. Capecitabine has been combined with docetaxel with increased response rates and increased toxicity.[32] See below for discussion of capecitabine combined with trastuzumab.
Gemcitabine (Gemzar) can be used in combination with paclitaxel for women who have previously received anthracyclines[33] and has considerable antitumor activity as a single agent[34] or in combination with paclitaxel.[35] Intravenous vinorelbine has shown responses in metastatic breast cancer after anthracycline and taxane failure.[36,37] Other available and useful treatments for multiply treated and relapsed patients include the platinum compounds and 5-FU.
Ixabepilone (Ixempra) is a member of a new class of antitubulin agents that lacks cross-resistance with the taxanes. As a single agent in the metastatic setting, it showed promise in phase II trials[38,39] and has recently been combined with capecitabine, showing increased objective response rates over capecitabine alone (35% vs 14%) in anthracycline- and taxane-resistant metastatic or locally advanced breast cancer.[40] Grade 3/4 treatment-related sensory neuropathy (21% vs 0%), fatigue (9% vs 3%), and neutropenia (68% vs 11%) occurred more frequently with combination therapy, as did death as a result of toxicity (3% vs 1%, with patients who had liver dysfunction [≥ grade 2 liver function tests] at greater risk). Therefore, this drug should be used with caution especially, when combined with other agents.
Bevacizumab
Bevacizumab is a recombinant, humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF). In a recent trial, patients with untreated metastatic breast cancer and HER2-negative disease were randomly assigned to receive either paclitaxel and bevacizumab or paclitaxel alone. The combination significantly prolonged progression-free survival compared with paclitaxel alone (median, 11.8 vs 5.9 months; hazard ratio for progression = 0.60; P < .001) and increased the objective response rate (36.9% vs 21.2%, P < .001). The overall survival rate, however, was the same in the two groups (median = 26.7 vs 25.2 months). Hypertension, proteinuria, headache, and cerebrovascular ischemia and infection were more frequent in patients receiving paclitaxel plus bevacizumab.[41]
A study of first-line bevacizumab in combination with capecitabine in HER2-negative breast cancer demonstrated an overall response rate of 38.5%[31] but a disappointingly low rate of response in patients with estrogen receptor–negative disease. Other groups are looking at combinations of bevacizumab with nab-paclitaxel and docetaxel, but to date these studies are small and prospective data are lacking. Currently, there are no data to support the continuation of bevacizumab with another chemotherapy agent upon disease progression. A randomized adjuvant trial is ongoing in North America.
Therapy for HER2-Positive Disease
If a tumor overexpresses HER2 (either by immunohistochemistry or by fluorescence in situ hybridization), targeted treatment is possible with the monoclonal antibody trastuzumab or the newer tyrosine kinase inhibitor (TKI) lapatinib (Tykerb). As a single agent given weekly, trastuzumab was established as safe and effective in patients whose tumors had already progressed through prior chemotherapies[42] or as a first-line therapy.[43,44] It was subsequently shown to have substantial activity when combined with an anthracycline/cyclophosphamide regimen or single-agent paclitaxel,[45] but excessive cardiac toxicity limits the ability to combine trastuzumab with anthracyclines.
Docetaxel or vinorelbine in combination with trastuzumab have shown comparable efficacy and tolerability to trastuzumab and paclitaxel.[46,47] Recent data show response rates of up to 48% in patients previously treated with trastuzumab who were treated with a combination of capecitabine and trastuzumab.[48] Data on continuation of trastuzumab with a new chemotherapy drug upon progression are lacking.
Certainly the importance of trastuzumab in the treatment of HER2-overexpressing metastatic breast cancer is great. However, the optimal sequence in which to give the agent has yet to be tested—ie, trastuzumab followed by the addition of chemotherapy or the combination upfront.
The Trastuzumab in Dual HER2 ER-positive Metastatic breast cancer (TAnDEM) trial showed for the first time a doubling of progression-free survival and a statistically significant (though clinically less meaningful) improvement in time to progression and overall response rate when trastuzumab was added to anastrozole(Drug information on anastrozole).[49] However, the time to progression in both arms was disappointingly low, suggesting that patients with HER2-positive disease are less likely to benefit from endocrine therapy in general.
Lapatinib is a small-molecule dual tyrosine kinase (epidermal growth factor receptor [EGFR] and HER2) inhibitor recently approved for use in combination with capecitabine for the treatment of patients who have progressive disease on trastuzumab. In a heavily pretreated population, it produced a longer median time to progression than those treated with capecitabine alone.[50] Unlike the monoclonal antibody trastuzumab, the small molecule lapatinib crosses the blood-brain barrier, and a lower incidence of central nervous system progression was observed in an updated report of the lapatinib/capecitabine arm of this trial.[51] This regimen also has central nervous system activity after progression on lapatinib.[52] Moreover, lapatinib is associated with a superior time to tumor progression when combined with paclitaxel vs paclitaxel alone, but offered no benefit in patients with HER2-negative disease.[53]
Pertuzumab and trastuzumab bind to distinct epitopes of the HER2 extracellular domain, and pertuzumab appears to perturb the ability of HER2 to homo- or heterodimerize. The addition of pertuzumab to trastuzumab after disease progression on trastuzumab alone appears active and well tolerated.[54] Trials with pertuzumab monotherapy are ongoing. The immunoconjugate combination of trastuzumab with a highly potent antimicrotubule drug derived from maytansine (T-DM1) is also active in this setting.[55]
