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Deputy Editor Sadhna R Vora, MD

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Systemic treatment of metastatic breast cancer in women: Chemotherapy

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Dec 2015. | This topic last updated: Aug 21, 2015.

INTRODUCTION — Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-

related death among females worldwide [1]. Despite the gains in early detection, up to five percent of women

diagnosed with breast cancer in the United States have metastatic disease at the time of first presentation. In

addition, up to 30 percent of women with early-stage, non-metastatic breast cancer at diagnosis will develop

distant metastatic disease [2]. Although metastatic breast cancer is not curable, meaningf ul improvements insurvival have been seen, coincident with the introduction of newer systemic therapies [ 3-5].

The role of chemotherapy for the treatment of metastatic breast cancer will be reviewed here. A general overview

of the approach to metastatic breast cancer, endocrine therapy for hormone receptor-positive metastatic breast

cancer, Human Epidermal Growth Factor Receptor 2 (HER2)-directed agents and other molecularly targeted

therapy, and breast cancer in men are reviewed separately. In addition, commonly used treatment regimens used

in the treatment of breast cancer are also compiled in a separate topic.

INDICATIONS — The goals of treatment of metastatic breast cancer are to prolong survival and improve quality

of life by reducing cancer-related symptoms. In order to achieve these goals, an individualized approach is needed

since no one strategy can be applied for all women. Cytotoxic chemotherapy may be used to achieve these goals

in the following situations:

Patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive disease should have a HER2-directed

agent included as part of their treatment. A discussion on the approach to treatment of HER2-positive breast

cancer is covered separately. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

®

®

(See "Systemic treatment for metastatic breast cancer: General principles".)

(See "Treatment approach to metastatic hormone receptor-positive breast cancer: Endocrine therapy".)

(See "Systemic treatment for HER2-positive metastatic breast cancer".)

(See "Breast cancer in men".)

(See "Treatment protocols for breast cancer".)

Hormone receptor-negative breast cancer – Unlike patients with hormone receptor-positive breast cancer,

these patients are not candidates for endocrine therapy.

Patients with symptomatic hormone receptor-positive breast cancer, in whom endocrine therapy is unlikely to

result in a prompt clinical response [6]. These include patients who present with:

Rapid disease progression following more than one endocrine therapy (ie, endocrine-resistant disease)•

A large tumor burden involving visceral organs•

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In general, we prefer not to administer chemotherapy with endocrine therapy for women with hormone receptor-

positive disease in order to minimize side effects, including an increased risk of thromboembolic events [ 7]. In

addition, a 1998 meta-analysis showed that combining these treatments was not more effective than the use of

chemotherapy alone [8]. The administration of endocrine therapy for patients with hormone receptor-positive

metastatic breast cancer is covered separately. (See "Systemic treatment for metastatic breast cancer: General

principles", section on 'Endocrine therapy versus chemotherapy' and "Treatment approach to metastatic hormone

receptor-positive breast cancer: Endocrine therapy".)

FACTORS INFLUENCING CHEMOTHERAPY CHOICE — For patients in whom chemotherapy is

recommended, the choice between a single agent or a combination regimen, and the selection of a specific

therapy, should take into account several factors in an effort to individualize therapy as much as possible.

Because of the availability of many agents to treat metastatic breast cancer, there is no ideal sequence of

treatments that can be applied to all patients. It is likely that patients with metastatic breast cancer will receive

many (if not all) of these treatments throughout the course of their disease. However, below we illustrate the

principles that can guide the choice of therapy in the first- or later-line setting. Given that currently available

systemic treatments for metastatic breast cancer are not curative, we encourage participation in well-designed

clinical trials.

Tumor burden — Tumor burden (the extent of disease detected on imaging or clinical exam and/or the presence

of tumor-related symptoms) can impact on whether single-agent chemotherapy or a combination regimen isadministered:

General health status — Treatment decisions should take into account the overall health status of the patient,

which can be gauged by the performance status (table 1) or, in the case of older women, a comprehensive

geriatric analysis (CGA). (See "Comprehensive geriatric assessment for patients with cancer" and "Treatment of

metastatic breast cancer in older women".)

For patients in whom a single agent is recommended, an understanding of the patient’s health status also may

influence the appropriate selection of agents. As examples (see 'Single-agent chemotherapy' below):

We prefer the sequential use of single-agent chemotherapy, especially for patients with a limited tumor

burden and/or limited or minimal cancer-related symptoms. Sequential single-agent treatment is often less

toxic and results in similar overall survival compared with combination chemotherapy [9]. (See 'Single-agent

chemotherapy' below.)

For select patients, we favor the use of a combination regimen rather than a single agent because

combination therapy results in a higher response rate, which may justify the risks of treatment [ 10].

Appropriate patients include those with symptomatic disease due to the location of specific metastatic

lesions (eg, right upper quadrant pain due to expanding liver metastases, or dyspnea related to diffuse lung

metastases), a large tumor burden, and those with rapidly progressive disease. (See 'Combination

chemotherapy' below.)

For patients with brain metastases, systemic treatment may not be required if there is no evidence of

systemic disease. In the presence of systemic disease, treatment of both the central nervous system and

systemic disease should be individualized. (See "Management of brain metastases in breast cancer".)

Patients with a history of cardiac disease or heart failure and those who are felt to be at a greater risk for

cardiac injury (eg, elderly patients) should not be treated with an anthracycline. There are multiple appropriate

alternatives (eg, paclitaxel or capecitabine).

Patients with symptomatic peritoneal metastases, those who have difficulty swallowing pills, or those who

are not able to follow instructions required to use a daily regimen may not be good candidates for oral

therapies (eg, capecitabine).

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For patients in whom a combination regimen is preferred, the patient’s health status also can help choose the

most appropriate regimen. As examples (see 'Combination chemotherapy' below):

Prior treatment and toxicities — For the patient who has been previously exposed to chemotherapy (eg, asadjuvant treatment or previous therapy for metastatic breast cancer), there is no optimal sequence of

administration of chemotherapy agents used to treat metastatic breast cancer. In general, treatment with

chemotherapy drugs of different classes (non-cross resistant agents) may result in a higher probability of

response, especially if disease progression occurred within six months following the previously administered

regimen [11]. However, the treatment history (ie, agents used and any previous toxicity experienced or persisting)

should be reviewed to help inform the choice of a subsequent regimen. As examples:

Patient preferences — Patient preferences help to individualize treatment plans for metastatic breast cancer. For

example, some patients may not accept the additional risks of toxicity associated with combination chemotherapy

if the goal of treatment is not cure (or remission). On the other hand, others may accept a higher chance of a

treatment response despite the additional toxicity risks and may opt for combination chemotherapy.

Additional examples include:

Patients at risk for hyperglycemia (eg, patients with diabetes) and those who cannot tolerate steroids for

whatever reason may derive more of a benefit from agents that do not require premedication (eg, nanoparticle

albumin bound [nAb]-paclitaxel, capecitabine, and gemcitabine).

Patients with a poor performance status or those with significant competing comorbidities may not benefit

from treatment at all, especially if they have a higher risk of dying from a cause other than breast cancer.

Therefore, the benefits and risks of single-agent therapy should be balanced against overall prognosis.

Ideal candidates for an anthracycline-containing regimen include women with chemotherapy naive, stage IV

breast cancer (ie, no prior cytotoxic therapy and those who received endocrine therapy initially) and those

who did not previously receive an anthracycline (eg, those who received docetaxel plus cyclophosphamide in

the adjuvant setting). These are among of the most active regimens for metastatic breast cancer. (See

'Anthracycline-containing regimens' below.)

Patients with a cardiac history (including prior anthracycline-induced cardiac injury) should not be treated with

an anthracycline. Our preference is to administer a taxane-based regimen (eg, gemcitabine plus paclitaxel or

docetaxel). (See 'Non-anthracycline, taxane-based regimens' below.)

Patients who received doxorubicin or epirubicin in the adjuvant setting, even years previously, may not be

good candidates for repeat anthracycline therapy due to increasing risk of cardiac toxicity at higher

cumulative doses. Of the available alternative agents, we typically administer a taxane in these patients.

(See 'Taxanes' below.)

Patients with a history of myelosuppression with prior therapy that resulted in dose modification or treatment

delay may not be good candidates for combination chemotherapy, particularly those using agents or

schedules with significant myelotoxicity risks (eg, ixabepilone, gemcitabine, and every three-week

docetaxel). In these situations, single-agent treatment using a weekly anthracycline, capecitabine, or a

weekly taxane may be more appropriate. (See 'Taxanes' below and 'Anthracyclines' below.)

Patients with baseline or a history of serious (grade 3/4) neuropathy may not be good candidates for

microtubulin-directed agents (eg, taxanes, ixabepilone, eribulin, or vinorelbine). These patients are appropriate

candidates for anthracyclines, especially in the first-line setting in a patient who was never treated with an

anthracycline. Alternatives to anthracyclines include capecitabine, etoposide, or gemcitabine. (See

'Anthracyclines' below and 'Other agents' below.)

Patients who prefer less frequent visits for intravenous treatments may opt for treatment administered every

three weeks, rather than weekly. Appropriate regimens that can be administered every three weeks include

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SINGLE-AGENT CHEMOTHERAPY — There are a number of agents with activity in metastatic breast cancer.

Because the taxanes and anthracyclines are most commonly administered, especially in the first-line treatment of

metastatic breast cancer, they are presented first. (See 'Indications' above.)

Taxanes — Taxanes are among the most active agents for metastatic breast cancer. Agents in this class include:

Comparing taxanes — For patients in whom a taxane is indicated, the choice between taxanes can be based

on their comparative safety profiles and patient preferences regarding scheduling of treatments. For example:

There are limited data comparing each of the taxanes against each other. However, they show that the activity

and toxicity differ by which schedule was used (ie, weekly or every three weeks) and by agent. As examples:

single-agent taxanes, anthracyclines, or ixabepilone, or combination therapy using cyclophosphamide,

methotrexate, and fluorouracil (CMF) or doxorubicin plus cyclophosphamide (AC). (See 'Taxanes' below and

'Anthracyclines' below and 'Other agents' below and 'Cyclophosphamide, methotrexate, and fluorouracil

(CMF)' below and 'Anthracycline-containing regimens' below.)

Patients who prefer a low risk of alopecia may want to avoid taxanes and anthracyclines (where the risk of

alopecia is close to 90 percent). Options in this circumstance include agents with a lower risk of alopecia,

such as gemcitabine (up to 15 percent) and capecitabine (less than 10 percent). (See 'Other agents' below.)

Patients who prefer less intrusion on their lifestyle may opt for an orally administered agent, such ascapecitabine, rather than treatments that require intravenous infusion. (See 'Capecitabine' below.)

Docetaxel – Docetaxel can be administered every three weeks (80 to 100 mg/m ) or weekly (30 to 40 mg/m

weekly for three weeks followed by one week off) [12]. Of these schedules, we prefer dosing every three

weeks based on the results of a randomized trial in the adjuvant setting that showed every three-week

dosing results in an improvement in disease-free survival (DFS) compared with weekly dosing [ 13].Docetaxel is associated with a significant risk of fluid retention, which is reduced by premedication with

dexamethasone [14].

2 2

Paclitaxel – Paclitaxel can be administered weekly (80 to 100 mg/m on days 1, 8, and 15 of a 28-day cycle)

or every three weeks (175 mg/m ) [12,13,15]. Whenever possible, we prefer weekly scheduling based on the

results of a 2010 meta-analysis, which showed that compared with every three-week treatment, weekly

administration of paclitaxel resulted in an improvement in overall survival (OS, hazard ratio [HR] 0.78, 95%

CI 0.67-0.89) [12].

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2

It should be noted that patients treated with paclitaxel are at risk for allergic reactions as a result of the

composition of paclitaxel, which is mixed with Cremophor. At most institutions, steroid premedication

(dexamethasone 20 mg the night before and morning of infusion) is administered, although it can usually be

discontinued if the first two or three doses are tolerated. However, the schedule and administration of

dexamethasone varies by institution.

Nab-paclitaxel – Nab-paclitaxel has activity in metastatic breast cancer similar to other taxanes [16-18]. It

may be of particular benefit to patients who are at risk for hyperglycemia and those who cannot tolerate

steroids. Nab-paclitaxel has a lower risk of allergic reactions compared with other taxanes, which negates

the requirement for steroid premedications and the risk of steroid-induced hyperglycemia.

The risks of neuropathy and myalgia are greater with paclitaxel than with docetaxel.

Paclitaxel can be administered in the setting of mild-moderate hepatic dysfunction. In contrast, docetaxel

should not be administered in this context.

Docetaxel given every three weeks is the more myelosuppressive taxane agent. Risks from docetaxel also

include febrile neutropenia, edema, and gastrointestinal toxicities.

Docetaxel was compared with paclitaxel (both on a 21-day cycle) in a trial of 449 patients with advanced

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Anthracyclines — The anthracyclines are important agents for the treatment of breast cancer. However, their use

in the adjuvant context often limits their application in women with metastatic disease. Despite this,

anthracyclines may be appropriate in select patients, particularly those who are chemotherapy naive and those

who were not treated with an anthracycline in the past. In addition, anthracyclines can be used in patients with

mild to moderate hepatic dysfunction with dose modification.

The anthracyclines used in the treatment of metastatic breast cancer are:

One potential downside of using anthracycline regimens is the risk for cumulative cardiac toxicity, which may limitthe duration of anthracycline-based therapy. However, for patients who are responding to treatment and otherwise

are tolerating therapy, the use of dexrazoxane may minimize the risk of treatment-related cardiac damage. For

patients treated with doxorubicin, dexrazoxane is indicated after a cumulative doxorubicin dose of 300 mg/m .

(See "Cardiotoxicity of anthracycline-like chemotherapy agents", section on 'Dexrazoxane'.)

Comparing anthracyclines — Our preferred anthracycline is doxorubicin or epirubicin because they are both

relatively easy to administer. A choice between them is based on geographic and institutional preferences. For

example, doxorubicin is more commonly used in the United States while epirubicin is more commonly used in

Europe. Although there are no prospective trials comparing it to standard dosing every three weeks, we prefer the

use of weekly anthracycline dosing in the metastatic setting because it is better tolerated.

breast cancer that had progressed after an anthracycline-containing chemotherapy regimen. Docetaxel

produced a significantly better median time to progression (TTP, 5.7 versus 3.6 months) and OS (15.4 versus

12.7 months) compared with paclitaxel [19]. However, both hematologic and nonhematologic toxicity were

worse with docetaxel.

Although this study found that every three-week dosing of docetaxel is superior to the same schedule using

paclitaxel, weekly paclitaxel (which is the preferred method of administration) has not been compared with

every three-week docetaxel in the metastatic setting.

Paclitaxel and nab-paclitaxel were evaluated as a first-line treatment (as single agents or with optional

administration with bevacizumab) in the Alliance trial, conducted by Cancer and Leukemia Group B (CALGB)

and the North Central Clinical Trials Group (NCCTG) (CALGB 40502/NCCTG N063H) [20]. The study

randomized 799 patients (44 percent who were previously treated with adjuvant paclitaxel) to bevacizumab

with either weekly treatment with paclitaxel (90 mg/m ) or nab-paclitaxel (150 mg/m ) on a three week on,

one week off schedule. A third arm including weekly ixabepilone (16 mg/m ) was closed for futility at the first

interim analysis. The results for paclitaxel versus nab-paclitaxel are discussed below. (See 'Ixabepilone'

below.)

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No significant difference in progression-free survival between paclitaxel and nab-paclitaxel (11 versus

9.3 months, respectively; HR 1.20; 95% CI 1.00-1.40).

•

No significant difference in overall survival between paclitaxel and nab-paclitaxel (26.5 versus 23.5

months, respectively, HR 1.17, 95% CI 0.92-1.47).

•

A higher rate of serious toxicity (grade 3 or higher) in the nab-paclitaxel versus paclitaxel arms,

including sensory neuropathy (27 versus 18 percent, respectively) and hematologic toxicity (55 versus

22 percent).

•

Doxorubicin (60 to 75 mg/m every three weeks, or 20 mg/m weekly for three weeks followed by one week

off) – ORR 30 to 47 percent [21,22]

2 2

Epirubicin (75 to 100 mg/m every three weeks, or 20 to 30 mg/m weekly for three weeks followed by one

week off) – ORR 42 to 50 percent [23-25]

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Pegylated liposomal doxorubicin (40 mg/m every four weeks) – ORR 10 to 33 percent [26,27] 2

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For patients who desire a less frequent administration schedule, pegylated liposomal doxorubicin administered

every four weeks appears to be equally active and less toxic compared with doxorubicin administered every three

weeks. This was shown in a trial of 509 patients with metastatic breast cancer (56 percent who had previously

received anthracyclines) who were randomly assigned treatment with pegylated liposomal doxorubicin 50 mg/m

given every four weeks or doxorubicin 60 mg/m given every three weeks [26]. Compared with pegylated

liposomal doxorubicin, doxorubicin resulted in:

Anthracycline versus taxane — There is no evidence of superiority of either anthracyclines or taxanes in the

metastatic setting, although the duration of treatment using anthracyclines is more likely to be limited due to thecumulative risk of cardiac toxicity. (See 'Anthracyclines' above.)

While a 2008 meta-analysis of individual patient data (n = 919 patients) found that administration of an

anthracycline resulted in an improvement in the ORR (38 versus 33 percent) and PFS (median, 7 versus 5

months) compared with taxanes [28], we do not feel that these small differences in ORR and PFS are clinically

significant in the current era in which multiple other therapies are available. In addition, the analysis was limited by

multiple factors including:

Capecitabine — In our practice, single-agent capecitabine (1000 to 1250 mg/m twice daily for 14 days followed

by seven days of rest) is a frequent choice as a first-line treatment for metastatic breast cancer, particularly in

patients with bone-predominant, estrogen receptor-positive metastatic disease who have progressed despite at

least two trials of endocrine therapy. In addition, capecitabine also appears to cross the blood brain barrier better

than some agents and may be a good consideration in patients with a history of central nervous system

metastases [29]. (See "Management of brain metastases in breast cancer".)

Capecitabine is a prodrug of the anti-metabolite fluorouracil. It is orally available, and unlike many agents used in

the treatment of breast cancer, it causes very little alopecia or neuropathy. Its primary toxicities are hand-foot

syndrome and diarrhea, and it can be used in settings of hepatic dysfunction. The benefit of capecitabine was

shown in two multicenter single-arm phase II trials [ 30,31]:

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Slightly higher ORR (38 versus 33 percent)

Similar PFS (median, 7.8 versus 6.9 months; HR 1.0, 95% CI 0.82-1.22) and OS (median, 22 versus 21months; HR, 0.94, 95% CI 0.74-1.19), though PFS measures were confounded by more frequent

assessments in the every three-week doxorubicin arm.

An increase in the risk cardiotoxicity (26 versus 7 percent, HR 3.16; 95% CI 1.58-6.31).

Higher rates of alopecia (66 versus 20 percent), nausea (53 versus 37 percent), vomiting (31 versus 19

percent), and neutropenia (10 versus 4). In contrast, pegylated liposomal doxorubicin was associated with a

higher rate of plantar-plantar erythrodysesthesia (48 versus 2 percent), stomatitis (22 versus 15 percent), and

mucositis (23 versus 13 percent).

Heterogeneity between the included trials

Differences in administration schedules for the taxane used (including the lack of inclusion of trials using

weekly administration of paclitaxel)

The inclusion of patients with or without prior exposure to endocrine therapy

Lack of inclusion of patients treated with adjuvant taxanes

2

In one study, 126 patients were treated with capecitabine (1250 mg/m dose). The median TTP was 5

months and the ORR was 28 percent. Median OS was 15 months [30].

2

In a second study, 95 women were randomly assigned to capecitabine or cyclophosphamide, methotrexate,

plus fluorouracil (CMF). Capecitabine resulted in a higher ORR compared with CMF (30 versus 16 percent,

respectively). The median TTP was similar (4 versus 3 months) but capecitabine resulted in a slightly longer

median OS (20 versus 17 months) [31].

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Other agents — For patients who are not candidates for the agents above, others are available and have

documented activity against breast cancer.

Eribulin — Eribulin mesylate (1.4 mg/m days 1 and 8 every 21 days) is derived from a marine sponge and

inhibits the polymerization of tubulin and microtubules. It results in less neuropathy than other microtubule-directed

agents and can be administered with dose adjustment for mild to moderate hepatic dysfunction. Therefore, it is a

good agent to administer in these situations.

The activity of eribulin was shown in a phase III trial of 762 heavily pretreated patients who were randomly

assigned to treatment with eribulin or other chemotherapy (based on physician’s and patient’s choice) [32].Treatment with eribulin significantly improved OS (median, 13.1 versus 10.6 months). The primary toxicity with

eribulin was neutropenia, with grade 3 and 4 neutropenia in 45 percent of patients, and grade 3 and 4 febrile

neutropenia in 5 percent. Peripheral neuropathy was the most common adverse event leading to discontinuation of

eribulin, occurring in 5 percent of patients. (See "Overview of neurologic complications of non-platinum cancer

chemotherapy", section on 'Eribulin'.)

Of note, a subsequent randomized trial was performed in women with metastatic breast cancer who had received

prior anthracycline and taxane therapy with an aim to formerly evaluate eribulin versus capecitabine as first,

second, or third-line therapy [33]. Unlike the trial above, there was no difference between eribulin and capecitabine

in terms of PFS (four months in each) or overall response rates (11 and 11.5 percent, respectively). In addition,

there was no clinically meaningful difference in OS (15.9 versus 14.5 months, respectively; HR 0.88, 95% CI 0.77-1.00).

Vinorelbine — Vinorelbine is an intravenously administered agent usually dosed at 30 mg/m on a weekly

schedule (days 1 and 8 every 21 days) [34]. Vinorelbine causes little nausea, vomiting, and hair loss, and is active

as a single agent (ORR 25 to 45 percent), even in heavily pretreated patients [ 35-37].

Gemcitabine — Although data suggest gemcitabine is active in combination with paclitaxel in first-line

metastatic breast cancer, gemcitabine (commonly 1000 mg/m days 1 and 8 of a 21-day cycle) is frequently used

as a single agent. (See 'Gemcitabine plus paclitaxel or docetaxel' below.)

Gemcitabine appears to cross the blood brain barrier and may be a good option in patients with a history of central

nervous system metastases [38]. Alopecia and gastrointestinal toxicity are mild, and it is not associated withsignificant neuropathy. Gemcitabine is well tolerated and active in metastatic breast cancer, though when

gemcitabine was directly compared with weekly epirubicin as first-line chemotherapy in women not previously

exposed to an anthracycline, it resulted in a significantly shorter time to progressive disease and a lower OS [ 39-

41]. Thrombocytopenia can be a dose-limiting toxicity, especially in heavily pretreated patients.

Ixabepilone — Ixabepilone is an epothilone, a class of non-taxane tubulin polymerizing agents that have

activity in taxane-resistant patients. As single agent treatment, ixabepilone (40 mg/m every 21 days) resulted in

an ORR of 19 percent with a median duration of response of 5.7 months in a clinical trial [42]. Median OS was 8.6

months. Grade 3 and 4 peripheral sensory neuropathy occurred in 14 percent of patients.

Some data suggest that ixabepilone may have less activity when compared with the taxanes, although it may be

better tolerated. In the CALGB 40502 trial discussed earlier, weekly ixabepilone resulted in a shorter median PFS

compared with taxanes (7.6 months versus 10 months with paclitaxel and nab-paclitaxel) and OS (21 versus 26

and 27 months, respectively) but resulted in a lower incidence of hematologic toxicity (12 versus 21 and 51

percent) [43]. Of note, the incidence of serious (grade 3/4) sensory neuropathy was equivalent between

ixabepilone and nab-paclitaxel (25 percent in both arms). Further results of CALGB 40502 are discussed above.

(See 'Comparing taxanes' above.)

In the presence of mild to moderate hepatic impairment, ixabepilone doses should be adjusted. Its usefulness in

later line therapy is often limited by its toxicities of neuropathy, anemia, and fatigue. However, epothilones may

cross the blood brain barrier [44], suggesting it may be an option for patients with central nervous system disease.

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(See "Management of brain metastases in breast cancer".)

Despite FDA approval, it is not available in Europe because the European Medicines Agency (EMA) Committee

for Medicinal Products for Human Use (CHMP) concluded that the benefit was marginal at best and the risk of

peripheral neuropathy to be significant [45]. Alternate dosing schedules are also under active investigation [46,47].

Etoposide — Oral etoposide (50 mg/m daily for 21 days every 28 days) is a reasonable choice, especially for

patients with slow-growing disease who desire an oral agent. Etoposide has shown an ORR of 30 percent in

pretreated patients, but may produce hematologic and gastrointestinal toxicity [48-50].

Platinum agents — Carboplatin and cisplatin are rarely used as single agents in metastatic breast cancer.

Available data suggest the response rate to cisplatin is higher among chemotherapy naive patients rather than in

women who were previously treated (ORR 42 to 54 percent versus less than 10 percent, respectively) [51].

However, there is renewed interest in using these agents as part of a combination regimen, particularly to treat

tumors where DNA damage repair pathways are impaired (such as in women harboring germline BRCA1

mutations and patients with triple-negative breast cancer). (See 'Combination regimens incorporating platinum

salts' below.)

COMBINATION CHEMOTHERAPY — 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:

Although a 2009 meta-analysis that included 43 trials (n = 9742 women, 55 percent of whom were treated in the

first-line setting) showed that combination therapy could improve OS [ 10], 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 significantrisks of combination therapy.

Available combination regimens are discussed below.

Anthracycline-containing regimens — Anthracycline-based chemotherapy regimens are associated with

response rates of up to 60 percent 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

2

A higher overall response rate (ORR) compared with doxorubicin or to paclitaxel (47 versus 36 and 34

percent)

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)

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anthracycline plus taxane combinations [28]. Compared with non-taxane containing therapy, taxane plus

anthracycline treatment resulted in a significantly higher ORR (57 versus 46 percent) 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 [28].

Examples of commonly used anthracycline-based combinations include (see "Treatment protocols for breast

cancer"):

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 themshould be based on individual considerations around each of their toxicity profiles.

Gemcitabine plus paclitaxel or docetaxel — Gemcitabine (1250 mg/m on days 1 and 8) plus paclitaxel (175

mg/m on day 1) resulted in an ORR of 41 percent when administered as a first-line therapy for metastatic breast

cancer [61]. In a separate trial, gemcitabine (1000 mg/m on days 1 and 8) plus docetaxel (75 mg/m on day 1)

resulted in an ORR of 43 percent in first-line therapy [ 62]. 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/m , twice daily for 14 of every 21 days) plus

docetaxel (75 mg/m every 21 days) (CD) resulted in an ORR of 42 percent [63]. 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 [62].

Other regimens — 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/m every three weeks) plus capecitabine (1000 mg/m

twice daily for 14 of every 21 days) resulted in an ORR of 35 percent [ 65].

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

percent) in one trial [66]. 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. (See "Epidemiology, risk factors and the clinical approach to ER/PR negative, HER2-negative (Triple-

negative) breast cancer", section on 'Treatment approach to triple-negative breast cancer' .)

Doxorubicin plus cyclophosphamide (AC) – ORR ranges from 47 to 54 percent [57,58]

Epirubicin with cyclophosphamide and fluorouracil (FEC) – ORR ranges from 45 to 55 percent [23,56]

Doxorubicin, docetaxel, plus cyclophosphamide (TAC) – ORR 77 percent [59]

Doxorubicin plus paclitaxel or docetaxel – ORR is approximately 40 percent for either combination [60]

2

2

2 2

2

2

2 2

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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 [67].

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 [68].

ADJUNCTIVE THERAPY — The role of adjunctive therapy, such as pain medications and osteoclast inhibitors,

in the treatment of patients with metastatic breast cancer is covered separately.

MONITORING THERAPY — The ongoing evaluation of patients during therapy (including timing of imaging andthe selection of imaging modality) should be individualized according to patient and provider preferences. Further

discussion on the monitoring of patients with metastatic breast cancer is covered separately. (See "Systemic

treatment for metastatic breast cancer: General principles", section on 'Monitoring therapy' .)

Careful assessment for response to treatment requires serial clinical examination, repeat lab evaluation (including

tumor markers), and radiographic imaging. Although there is no standard schedule for evaluation during treatment,

a reasonable approach would be as follows:

DURATION OF TREATMENT — Unlike in the adjuvant setting, there is no predetermined duration of treatment.

Therefore, the duration of chemotherapy should be individualized taking into account the patient’s goals of

treatment, presence of treatment toxicities, and alternative options that might be available. In general, patients

should continue chemotherapy to the best response, disease progression, or if toxicity requires discontinuation of

treatment.

For women who respond to chemotherapy, some data suggest that there are benefits to continuing treatment

beyond their best response (ie, maintenance therapy):

(See "Cancer pain management: Adjuvant analgesics (coanalgesics)" and "Cancer pain management: Use of

acetaminophen and nonsteroidal antiinflammatory drugs" and "Cancer pain management with opioids:

Optimizing analgesia" and "Cancer pain management: General principles and risk management for patients

receiving opioids" and "Cancer pain management: Interventional therapies".)

(See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)

History and physical exam prior to the start of each treatment cycle (ie, day one of a new 21- or 28-day

treatment cycle).

Repeat imaging studies (using the same imaging modality throughout) after completion of two cycles of therapy (ie, after cycle two, cycle four, etc).

Serial assay for serum tumor markers (eg, cancer antigen [CA] 15-3, CA 27.29, and/or carcinoembryonic

antigen [CEA]) if they were elevated at baseline. If performed, we typically reevaluate them at the beginning

of each treatment cycle.

A 2011 meta-analysis of first-line treatment randomized trials that included almost 2300 women compared

maintenance treatment with treatment over a prespecified duration (range, three to eight cycles) [69]. Longer

chemotherapy duration was associated with improvement in progression-free survival (PFS; hazard ratio

[HR] 0.64, 95% CI 0.55-0.76) and overall survival (OS; HR 0.91, 95% CI 0.84-0.99).

A randomized trial published in 2013 consisted of 324 patients with metastatic breast cancer, all of whom

were treated with paclitaxel and gemcitabine [70]. Patients who achieved disease control (complete or partial

response, or stable disease) to treatment (n = 231) were randomly assigned to observation or maintenance

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While these data support maintenance chemotherapy for women with metastatic breast cancer, it should not be

considered a universal approach to the treatment of these patients, especially when one considers the biologic

heterogeneity of breast cancer and the multiple ways that disease can be treated. However, for the young patient

who is responding to treatment, these data support the continuation of chemotherapy beyond best response,

particularly if she accepts the increased risks of toxicity associated with continued chemotherapy [71].

DEFINITION OF TREATMENT FAILURE — In our own practice, we monitor for treatment failure by taking into

account serial changes in tumor markers, evidence of disease progression based on serial imaging, and the

clinical status of the patient. Some criteria that we use to define treatment failure include any of the following:

RECIST criteria — The primary role of Response Evaluation Criteria in Solid Tumors (RECIST 1.1) is to

standardize the reporting of results on clinical trials (table 2) [72]. RECIST primarily applies to imaging of

metastatic disease, and it encompasses two of the three reasons for treatment failure.

According to RECIST, disease progression on imaging is defined as any of the following:

SUMMARY AND RECOMMENDATIONS

chemotherapy with the same agents until disease progression.

The administration of maintenance chemotherapy resulted in a higher PFS rate at six months compared with

observation (60 versus 36 percent, respectively; HR 0.73, 95% CI 0.55-0.97) and improved OS (median, 32

versus 24 months; HR 0.65, 95% CI 0.42-0.99). However, continuation of paclitaxel and gemcitabine

resulted in a higher incidence of serious (grade 3/4) neutropenia (61 versus 0.9 percent) and grade 2/3

neuropathy (0.9 verus 0 percent).

Despite these findings, several issues limit the universal application of these data in metastatic breastcancer:

Over 70 percent of patients in this study had hormone-positive breast cancer; of these patients, only

about 20 percent of these women had received prior endocrine therapy and, for those in the control arm,

endocrine therapy was not initiated after chemotherapy was discontinued.

•

The median age of participants was 48, suggesting that younger patients were preferentially enrolled.•

The benefit in PFS was seen predominantly in the subgroup of women who were age <50 years, had

hormone receptor-negative disease, had responded to chemotherapy, and had visceral disease.

•

Clinical deterioration during treatment (ie, increasing disease related symptoms, intolerable treatment

toxicities, declining performance status)

Evidence of new metastases

Increasing size of previously documented metastatic lesions

A 20 percent or more increase in the sum of measurable target lesions compared with the smallest sum

previously recorded

The appearance of any new lesions

Worsening of existing non-target lesions, for example, bone metastases

Despite the gains in early detection, up to five percent of women diagnosed with breast cancer have

metastatic disease at the time of first presentation. In addition, up to 30 percent of women with early-stage,

non-metastatic breast cancer at diagnosis will develop distant metastatic disease. Although metastatic

breast cancer is unlikely to be cured, meaningful improvements in survival have been seen, coincident with

the introduction of newer systemic therapies. (See 'Introduction' above.)

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Topic 83848 Version 8.0

The goals of treatment of metastatic breast cancer are to prolong survival and improve quality of life by

reducing cancer-related symptoms. In order to achieve these goals an individualized approach is needed

since no one strategy can be applied for all women. (See 'Indications' above.)

For patients with estrogen-receptor (ER), progesterone-receptor (PR), and Human Epidermal Growth Factor

Receptor 2 (HER2)-negative (triple-negative) breast cancer, chemotherapy is the only option for treatment of

metastatic breast cancer because they are not candidates for endocrine or HER2-directed therapy. (See

'Indications' above.)

For most patients with hormone receptor-positive disease, endocrine therapy is the preferred treatment for

metastatic breast cancer. However, we suggest chemotherapy if they are symptomatic from their disease

(Grade 2C). This includes patients who experience rapid disease progression and those with a large tumor

burden involving visceral organs. (See 'Indications' above.)

For patients in whom chemotherapy is recommended, the choice of regimen (ie, single-agent or a

combination) and selection of a specific therapy depends on multiple factors, including the tumor burden

(both in tumor volume and the presence of disease-related symptoms), general health status, prior treatments

and toxicities, and patient preferences. These factors can help in the formulation of an individualized

treatment plan in the first- or later-line setting. (See 'Factors influencing chemotherapy choice' above.)

For patients with a limited tumor burden and/or limited or minimal cancer-related symptoms, we suggest

single-agent chemotherapy administered sequentially rather than combination chemotherapy (Grade 2B).(See 'Single-agent chemotherapy' above.)

For select patients with symptomatic disease due to the location of specific metastatic lesions (eg, right

upper quadrant pain due to expanding liver metastases, or dyspnea related to diffuse lung metastases) and a

large tumor burden, we suggest a combination regimen rather than a single-agent (Grade 2B). Combination

therapy results in a greater likelihood of a response compared with single-agent therapy, which may be of a

sufficient benefit to justify the risks of treatment. (See 'Combination chemotherapy' above.)

Careful assessment for response to treatment requires serial clinical examination, repeat lab evaluation

(including tumor markers), and radiographic imaging. (See 'Monitoring therapy' above.)

Unlike in the adjuvant setting, there is no predetermined duration of treatment. For the young patient who isresponding to treatment, we suggest continuation of chemotherapy beyond best response (Grade 2B).

However, for patients who experience side effects to treatment or prefer not to continue treatment for

whatever reason, discontinuation of treatment is reasonable. (See 'Duration of treatment' above.)

Some criteria that we use to define treatment failure include any of the following: clinical deterioration during

treatment (ie, increasing disease-related symptoms, intolerable treatment toxicity, a decline in performance

status), appearance of new metastases, and increasing size of previously documented metastatic lesions.

(See 'Definition of treatment failure' above.)