Official reprint from UpToDate

www.uptodate.com 2014 UpToDate

Author
Anne F Schott, MD
Section Editor
Daniel F Hayes, MD
Deputy Editor
Don S Dizon, MD, FACP
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: Jul 2014. | This topic last updated: Jan 16, 2014.
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, meaningful improvements in
survival 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".)
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:

(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

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 is administered:
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 patients health status also may
influence the appropriate selection of agents. As examples (see 'Single agent chemotherapy' below):
For patients in whom a combination regimen is preferred, the patients health status also can help choose the
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 to 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).

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.

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

Prior treatment and toxicities For the patient who has been previously exposed to chemotherapy (eg, as
adjuvant 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:
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 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 as
capecitabine, rather than treatments that require intravenous infusion. (See 'Capecitabine' below.)

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:
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 to weekly dosing [13].
Docetaxel is associated with a significant risk of fluid retention, which is reduced by premedication with
dexamethasone [14].

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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 to every three-week
treatment, weekly administration of paclitaxel resulted in [12]:

2
2
Improvement in the overall response rate (ORR, relative ratio [RR] for response 1.20, 95% CI 1.08-
1.32)

Improvement in overall survival (OS, hazard ratio [HR] for mortality 0.78, 95% CI 0.67-0.89)
Paclitaxel is mixed with Cremophor, which can result in allergic reactions. 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 for premedication 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 to 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 to paclitaxel (both on a 21-day cycle) in a trial of 449 patients with advanced
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 to 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 to 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
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
limit the 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.
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 to 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 to pegylated
liposomal doxorubicin, doxorubicin resulted in:
administration with bevacizumab) in a trial conducted by Cancer and Leukemia Group B (CALGB) and the
North Central Clinical Trials Group (NCCTG) (CALGB 40502/NCCTG N063H) [20]. At the 2012 American
Society of Clinical Oncology meeting, preliminary results were presented after enrollment of 799 patients
(44 percent who were previously treated with adjuvant paclitaxel) who were randomly assigned to weekly
treatment with paclitaxel (90 mg/m ), or nab-paclitaxel (150 mg/m ) on a three week on, one week off
schedule. An additional arm in this study utilized weekly ixabepilone (16 mg/m ) and these results are
discussed below. (See 'Ixabepilone' below.)
Compared to paclitaxel, nAb-paclitaxel resulted in:
2 2
2
No difference in progression-free survival (PFS, median, 10 months in both arms, HR 0.94, 95% CI
0.73-1.22)

No difference in overall survival (OS, 27 versus 26 months, respectively, HR 1.02, 95% CI 0.75-
1.38).

A higher rate of serious toxicity (grade 3 or higher), including sensory neuropathy (25 versus 16
percent, respectively) and hematologic toxicity (51 versus 21 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]

2 2
Pegylated liposomal doxorubicin (40 mg/m every four weeks) ORR 10 to 33 percent [26,27]
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2
2 2
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 21
months; 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.

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 the cumulative 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 to 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]:
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 physicians and patients 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'.)
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 to 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].

2
2
Vinorelbine Vinorelbine is an intravenously administered agent usually dosed at 30 mg/m on a weekly
schedule (days 1 and 8 every 21 days) [33]. 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 [34-36].
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 [37]. Alopecia and gastrointestinal toxicity are mild, and it is not
associated with significant neuropathy. Gemcitabine is well tolerated and active in metastatic breast cancer,
though when gemcitabine was directly compared to 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 [38-40]. 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 [41]. 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 to the taxanes, although it may be
better tolerated. In the CALGB 40502 trial discussed earlier, weekly ixabepilone resulted in a shorter median
PFS compared to 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) [20]. 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 [42], suggesting it may be an option for patients with central nervous system
disease. (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 [43]. Alternate dosing schedules are also under active investigation
[44,45].
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 [46-48].
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) [49].
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 to single agent sequential cytotoxic
chemotherapy.
This was shown in the Eastern Cooperative Group (ECOG) 1193 trial in which over 700 women were randomly
2
2
2
2
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 to 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-containing regimens Anthracycline-based chemotherapy regimens are associated with
response rates of up to 60 percent in previously untreated patients with metastatic breast cancer [50-53],
although they are more toxic than sequential single agent treatment or non-anthracycline-containing
combinations [23,54].
Among the available regimens, an anthracycline plus taxane combination results in a higher response rate
compared to 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) to
anthracycline plus taxane combinations [28]. Compared to 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 them should 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 [59]. 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 [60]. 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.
A higher overall response rate (ORR) compared to 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)
Doxorubicin plus cyclophosphamide (AC) ORR ranges from 47 to 54 percent [55,56]
Epirubicin with cyclophosphamide and fluorouracil (FEC) ORR ranges from 45 to 55 percent [23,54]
Doxorubicin, docetaxel, plus cyclophosphamide (TAC) ORR 77 percent [57]
Doxorubicin plus paclitaxel or docetaxel ORR is approximately 40 percent for either combination [58]
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2 2
2
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 [61]. Several studies also suggest
it improves survival over single agent docetaxel even when capecitabine was mandated on disease progression
[61,62]. However, limited data suggest that CD is equivalent to gemcitabine plus docetaxel (GD) but is the
more toxic combination [60].
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 [63].
Cyclophosphamide, methotrexate, and fluorouracil (CMF) CMF is rarely administered for metastatic
breast cancer because it appears to produce the same response rate when compared to oral capecitabine (20
percent) in one trial [64]. 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'.)
However, no prospective trials have been completed that demonstrate a survival advantage to such regimens
compared to 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 [65].
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 [66].
ADJUNCTIVE THERAPY The role of adjunctive therapy, such as pain medications and bone modifying
agents, 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 and
the 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:
2
2
2
2
(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 in the management of bone metastases from breast cancer" and "Overview of
the use of osteoclast inhibitors in early breast cancer".)

(See "Palliative care: Benefits, services, and models of care".)

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

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 patients 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):
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
[69].
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:
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 to treatment over a prespecified duration (range, three to eight cycles) [67]. 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 [68]. Patients who achieved disease control (complete or
partial response, or stable disease) to treatment (n = 231) were randomly assigned to observation or
maintenance chemotherapy with the same agents until disease progression.
The administration of maintenance chemotherapy resulted in a higher PFS rate at six months compared
to 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 breast
cancer:

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)

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) [70]. 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
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 to 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.)

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 to 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
is responding 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

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Topic 83848 Version 4.0
GRAPHICS
Comparison of Karnofsky and Eastern Cooperative Oncology Group
(ECOG) performance status measures
Karnofsky
Score Definition
100 Normal, no complaints, no evidence
of disease
90 Able to carry on normal activity,
minor signs or symptoms of disease
80 Normal activity with effort, some
signs or symptoms of disease
70 Cares for self, unable to carry on
normal activity or to do active work
60 Requires occasional assistance, but is
able to care for most needs
50 Requires considerable assistance and
frequent medical care
40 Disabled, requires special care and
assistance
30 Severely disabled, hospitalization is
indicated although death is not
imminent
20 Hospitalization is necessary, very
sick, active supportive treatment
necessary
10 Moribund, fatal processes progressing
rapidly
0 Dead
ECOG
Score Definition
0 Fully active; no performance
restrictions
1 Strenuous physical activity
restricted; fully ambulatory and
able to carry out light work
2 Capable of all selfcare but unable to
carry out any work activities. Up
and about >50 percent of waking
hours.
3 Capable of only limited selfcare;
confined to bed or chair >50
percent of waking hours
4 Completely disabled; cannot carry
out any selfcare; totally confined to
bed or chair
5 Dead
Graphic 57945 Version 3.0
Revised Response Evaluation Criteria in Solid Tumors (RECIST) for
assessing clinical tumor response
Response
assessment
RECIST guideline, version 1.1
Target lesions
CR Disappearance of all target lesions and reduction in the short axis
measurement of all pathologic lymph nodes to 10 mm
PR 30 percent decrease in the sum of the longest diameter of the target
lesions compared with baseline
PD 20 percent increase of at least 5 mm in the sum of the longest diameters of
the target lesions compared with the smallest sum of the longest diameter
recorded
OR
The appearance of new lesions including those detected by FDG-PET
SD Neither PR nor PD
Non-target lesions
CR Disappearance of all non-target lesions and normalization of tumor marker
levels
IR, SD Persistence of one or more non-target lesions and/or the maintenance of
tumor marker levels above normal limits
PD The appearance of one of more new lesions or unequivocal progression.
If patient has measurable disease, an increase in the overall level, or
substantial worsening in non-target lesions, such that tumor burden has
increased, even if there is a SD or PR in target lesions.
If no measurable disease, an increase in the overall tumor burden comparable
in magnitude to the increase that would be required to declare PD in
measurable disease (eg, an increase in pleural effusions from trace to large,
or an increase in lymphangitic disease from localized to widespread).
CR: complete response; IR: incomplete response; PD: progressive disease; SD: stable disease.
Reference:
1. Eisenhauer E, et al. Eur J Cancer 2009; 45:228.
Graphic 57181 Version 2.0
[1]
Disclosures: Anne F Schott, MD Grant/Research/Clinical Trial Support: Dompe; GSK; Merck [Breast cancer (Reparixin, WT-1
vaccine, MK-0752)]. Daniel F Hayes, MD Clinical Research Support: Janssen [Circulating Tumor Cell (Circulating Tumor Cell Kit)],
Breast cancer (abiraterone)]. Patent Holder: Circulating tumor cells (Circulating Tumor Cell Kit). Equity Ownership/Stock Options:
Inbiomotion; OncImmune. Don S Dizon, MD, FACP Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting
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