With an ORR between 30% and 50%, the anthracyclines are one of the most active drug classes in breast cancer. However, their use in the metastatic setting is often limited secondary to concerns that exceeding cumulative dose levels from prior adjuvant chemotherapy will raise the risk of cardiotoxicity and, thus, is typically reserved for anthracycline-naive patients. Chemotherapy agents included within this class are doxorubicin and epirubicin, both of which are generally administered every three weeks,39–41 and pegylated liposomal doxorubicin, which is typically given every four weeks.40,41 All three anthracyclines can be given to patients with mild-to-moderate hepatic dysfunction. In the absence of comparative randomized trials, due to the perception of their improved tolerability, doxorubicin and epirubicin are typically given on weekly schedules. A trial of 509 patients with mBC (~50% had tumors that were ER negative), 56% of whom had previously received anthracyclines, patients were randomized to receive pegylated liposomal doxorubicin every four weeks or doxorubicin every three weeks. Compared with pegylated liposomal doxorubicin, doxorubicin resulted in a higher ORR (38% vs 33%) but similar PFS (7.8 vs 6.9 months) and OS (22 vs 21 months).41 Patients treated with doxorubicin compared with liposomal doxorubicin had higher rates of cardiotoxicity (26% vs 7%), alopecia (66% vs 20%), nausea (53% vs 37%), vomiting (31% vs 19%), and neutropenia (10% vs 4%) but had lower rates of palmar-plantar erythrodysesthesia (2% vs 48%), stomatitis (15% vs 22%), and mucositis (13% vs 23%). As a result of this trial, pegylated liposomal doxorubicin was established as a noninferior alternative to the other anthracyclines, especially in patients desiring less frequent drug administrations, significant accumulated anthracycline dosages, or a slightly different side effect profile. With regard to the management of cardiac toxicity in clinical practice, metastatic patients who are responding to and tolerating therapy but are approaching the upward limit of the cumulative anthracycline dose (ranging from 450 mg/m2 for doxorubicin to >900 mg/m2 for epirubicin) can be considered for the iron chelator dexrazoxane. By reducing the number of metal ions that complex with anthracyclines and subsequently decreasing the formation of superoxide radicals, this agent can be used to reduce the risk of anthracycline-induced cardiac damage.
Although there has only been a small amount of data suggesting a difference in treatment-related outcomes in the metastatic setting between single-agent anthracyclines and taxanes, a recent meta-analysis comparing the two classes of chemotherapies showed a modest superiority among anthracyclines, with a slightly improved ORR (38% vs 33%) and PFS (seven vs five months).41 However, the strength and clinical applicability of these results were limited due to trial heterogeneity, which included differences in taxane administration schedules and varying patient inclusion/exclusion criteria (ie, patients treated with taxanes in the adjuvant setting were excluded).
Capecitabine, a 5-fluorouracil (5-FU) prodrug and pyrimidine antimetabolite that inhibits thymidylate synthetase, is an oral chemotherapy agent administered on a two-week-on/one-week-off schedule.42–44Due to the ease of administration and comparable efficacy and tolerability compared to other agents, it is commonly used in the first-line metastatic setting. Compared to many other agents used in the treatment of mBC, capecitabine has a greater degree of CNS penetration and can be used in the setting of liver dysfunction. Capecitabine is also associated with a unique side effect profile, including minimal alopecia and neuropathy, but sometimes with dose-limiting adverse effects, including palmar-plantar erythrodysesthesia and diarrhea.44 Two multicenter Phase II trials, one of which used cyclophosphamide, methotrexate, and 5-FU (CMF) as a comparison arm, looked at capecitabine in the first-line mBC (prior adjuvant treatment with anthracycline and taxane) and not only demonstrated its comparative superiority but also reported an ORR between 28% and 30%, a TTP between four and five months, and a median OS between 15 and 20 months.43,44
Although less commonly used, single-agent gemcitabine also has activity in mBC45–47 but appears to be associated with an inferior TTP and OS when compared to weekly epirubicin. A pyrimidine antimetabolite that inhibits DNA synthesis, gemcitabine, is associated with limited side effects, including mild alopecia and gastrointestinal toxicity, such as constipation. Thrombocytopenia is common in pretreated patients and can be a severe dose-limiting adverse effect. Another less commonly used single agent in the treatment of mBC is the topoisomerase II inhibitor etoposide, which is administered orally daily for days 1–21 of a 28-day cycle. Although it produces an ORR of ~30% in heavily pretreated patients, it can also be associated with significant hematologic and gastrointestinal toxicities.48,49
Combination chemotherapy is uncommonly used in the treatment of mBC, but select combinations have been shown to be effective in producing swifter and more significant responses compared with single-agent chemotherapy. Notably, at the expense of tolerability and to our knowledge, there are no data demonstrating an improvement in patient survival using combination rather than single-agent therapy prescribed in a sequential fashion. However, several combinations of systemic chemotherapy have been associated with improved survival outcomes in the metastatic setting compared with nonsequential single-agent therapy alone. These combinations include capecitabine and docetaxel (vs docetaxel alone; OS: 14.5 vs 11.5 months), gemcitabine and paclitaxel (vs paclitaxel alone; OS: 18.6 vs 15.8 months), and capecitabine and ixabepilone (vs capecitabine alone; PFS: 5.8 vs 4.2 months).
In a large randomized trial, 700 patients with mBC were randomized to receive doxorubicin plus paclitaxel, doxorubicin, or paclitaxel with crossover allowed upon progression. The combination of doxorubicin plus paclitaxel resulted in a greater ORR (47% vs 36% vs 34%) and a longer TTP (eight vs six vs six months) but produced no difference in OS (22 vs 19 vs 22 months).50 A recent meta-analysis analyzed 43 trials (9,742 women) that primarily included anthracycline- and/or taxane-based combination chemotherapy trials and with ~55% treatment naive in the metastatic setting. The analysis showed an improvement in OS with combination compared with single-agent therapy (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.83–0.93, P < 0.00001) but a 32% greater risk of developing febrile neutropenia.13 These results are often disregarded, as a more recent meta-analysis failed to show the same improvement in OS (only PFS) and combination therapy was not directly compared with the sequential administration of agents (as opposed to a one time single-agent usage), a strategy that is commonly used in clinical practice.10
Although more toxic than sequential single-agent treatment or nonanthracycline-containing combinations, anthracycline-based chemotherapy regimens are associated with an ORR of ~60% in previously untreated patients with mBC. In a meta-analysis of eight trials and 3,000 patients looking at taxane plus anthracycline regimens compared with nontaxane anthracycline-containing combinations, an anthracycline plus taxane combination resulted in a higher ORR (57% vs 46%) but no difference in OS.31 Other anthracycline-based regimens include doxorubicin plus cyclophosphamide (ORR: 47%–54%, OS: 21.5 months),51 epirubicin with cyclophosphamide and fluorouracil (ORR: 45%–55%, OS: 18.9 months),52doxorubicin with docetaxel plus cyclophosphamide (ORR: 77%, OS: 20.5 months),53 and doxorubicin plus paclitaxel or docetaxel (ORR: 40%, OS: 20.6 months).54