In North America, approximately 182,000 women are diagnosed with
breast cancer each year, and 46,000 women die of the disease .
As many as 10% of these women present with metastatic disease
at the time of diagnosis, and a substantial proportion of patients
initially diagnosed with localized disease will develop metastases.
The vast majority of women who develop metastatic disease will
ultimately die of it, with a median survival of 2 to 3 years [2,3].
The prognosis of patients with advanced breast cancer is highly
variable; some patients die within a few months of developing
metastatic disease and others survive for 10 years or longer.
More treatment options exist for patients with metastatic breast
cancer than for most patients with cancer. A wide range of both
hormonal therapies and cytotoxic treatments have been in use over
the past 10 to 20 years, and several new agents have recently
become available. Although systemic therapy probably prolongs
survival [4,5], definitive evidence that treatment prolongs life
is difficult to find. The primary goal of treatment is to improve
quality of life by palliating the symptoms related to cancer.
The heterogeneity among patients, the wide range of treatment
options, and the need to weigh the risks versus the benefits of
available therapies pose a challenge for medical oncologists caring
for women with advanced breast cancer.
For patients with estrogen and/or progesterone receptor-positive
tumors, hormonal therapy is often the first-line treatment of
metastatic disease because of its high degree of efficacy and
minimal toxicity. Chemotherapy is usually recommended for patients
with hormone receptor-negative tumors or for patients who have
become refractory to hormonal therapy.
When chemotherapy is indicated, combination therapy is often administered.
Some of the most common first-line regimens are listed in Table
1. Response rates for these regimens range from approximately
35% to 75%.6 Doxorubicin-containing regimens are usually associated
with higher response rates than regimens that do not contain this
agent. For this reason, many oncologists opt for doxorubicin-based
regimens as initial chemotherapy for patients with metastatic
breast cancer, particularly for patients with troublesome cancer
symptoms. Less toxic regimens (eg, cyclophosphamide [Cytoxan,
Neosar], methotrexate, and fluorouracil [CMF] or mitoxantrone
[Novantrone]-containing regimens) are often administered to older
patients, individuals with comorbidities, or patients who have
particular difficulty tolerating the side effects of chemotherapy.
Data from the M. D. Anderson Cancer Center, however, suggest that
age alone is not a reason to avoid an anthracycline-based regimen
For patients with metastatic disease who have received adjuvant
treatment with doxorubicin, a taxane-based regimen, usually single-agent
paclitaxel (Taxol), often is used as first-line treatment in the
metastatic setting [8,9]. Gianni et al  have reported a response
rate in excess of 90% with a combination of paclitaxel and doxorubicin
as first-line therapy for metastatic disease. Unfortunately, this
regimen was also associated with higher cardiotoxicity than would
have been expected given the total doxorubicin dose. Additional
clinical trials evaluating doxorubicin/paclitaxel regimens must
be completed before this option can be considered a standard first-line
The use of high-dose chemotherapy with autologous bone marrow
or peripheral stem cell support has gained great attention in
recent years, but this treatment is usually reserved for younger
patients who have chemotherapy-responsive disease . Of the
total population of patients with metastatic breast cancer in
North America, a relatively small percentage receive this intensive
treatment during the course of their illness.
Regardless of the choice of first-line chemotherapy, virtually
all patients will develop disease progression, often after an
initial response to treatment or a period of disease stabilization.
Most patients with metastatic breast cancer are potential candidates
for second-line chemotherapy. Although large population- based
studies of treatment of advanced breast cancer have not been performed,
the majority of patients with breast cancer in the United States
probably receive two or more chemotherapeutic regimens in the
metastatic setting. In the remainder of this article, the term
"refractory breast cancer" will be used to describe
patients with hormone-refractory metastatic breast cancer whohave
developed disease progression following an initial chemotherapeutic
A number of chemotherapeutic agents and regimens are available
for patients with refractory breast cancer. As with first-line
therapy, the primary goal of treatment is the palliation of cancer-related
symptoms. If there is any survival advantage as a result of treatment
of refractory disease, it is almost certainly of a very small
magnitude. In this setting, the potential for treatment-induced
toxicity must be considered carefully before any therapy is initiated.
Unfortunately, only a limited number of patients who receive treatment
of refractory breast cancer will have an objective (or even subjective)
response to treatment, but all patients (whether or not they derive
benefit from treatment) are at risk for developing minor side
effects and/or debilitating complications. For patients with few
cancer symptoms, the option to withhold further chemotherapy until
symptoms worsen is always worthy of consideration. Many physicians
have difficulty with this "watchful waiting" approach,
particularly for younger patients, for whom they may hope that
a response to treatment could offer some prolongation of life.
Many patients are also more comfortable receiving active treatment.
In these situations, especially when patients are entirely asymptomatic,
treatment regimens without serious toxicity should be strongly
considered. Although continuing active treatment may facilitate
a sense of hopefulness, it is difficult to know how much this
enhanced hopefulness is counterbalanced by the side effects, risks,
and inconvenience that result from chemotherapy.
As we consider new treatments for refractory breast cancer, it
is helpful to view these treatment programs from a historical
perspective. Between 1975 and 1991, 1,756 patients underwent treatment
of metastatic breast cancer at Guy's Hospital in London .
A total of 758 (43%) received first-line chemotherapy for metastases.
More than half of these patients received an anthracycline-containing
regimen as initial treatment, with most of the remaining patients
receiving CMF. The overall response rate in patients receiving
first-line therapy was 35%, and the median time to progression
in responding patients was 7.8 months. As expected, a longer disease-free
interval and the absence of metastases were both predictive of
a response to therapy.
Of patients who underwent first-line treatment, approximately
one-third received a second-line chemotherapeutic regimen. The
overall response rate to second-line therapy was only 16%; patients
who had responded to first-line treatment had a significantly
higher chance of responding to treatment in the refractory setting
than did patients who had not responded to first-line treatment.
Of interest, the response rate seen in 58 patients who received
third-line therapy was similar to that seen in the second-line
experience, including a small number of responses in patients
who had failed to respond to either of the first two regimens.
Investigators from Finland  have described the outcome of
treatments administered for refractory disease in a group of patients
who had participated in a study evaluating two different first-line
anthracycline-based chemotherapeutic schedules. Although response
to therapy could only be determined in approximately half of the
treatment courses, the results echoed those of the Guy's Hospital
experience. Where data were available, the response rates to second-
and third-line chemotherapy were 20% and 12%, respectively. It
is important to note that these results, like those from Guy's
Hospital, do not reflect the availability of some of the newer
cytotoxic agents, such as paclitaxel and docetaxel (Taxotere).
Nevertheless, such findings indicate the need to evaluate critically
the risks and benefits of treatment programs in this population.
Of interest, occasional responses were seen with third-line chemotherapy
in both the Guy's Hospital and Finnish series. This finding suggests
that the use of chemotherapy cannot be arbitrarily discontinued
after a patient has received two regimens.
A wide range of combination regimens have been evaluated over
the past 5 to 10 years; a partial list of these regimens appears
in Table 2 [14-23]. Response rates vary but rarely exceed the
30% to 40% range and are often much lower. The median duration
of response in responders is consistently in the range of 5 to
7 months. Because most regimens have been evaluated in the setting
of single-institution phase II trials, it is very difficult to
compare one regimen with another. It remains unclear whether there
is any advantage to combination therapy compared with single agents.
Clearly, there is no combination regimen that could be considered
the gold standard for patients with refractory disease.
Although some combination regimens are well tolerated, the toxicity
of most multiagent regimens tends to be higher than that of single
agents. Mitomycin (Mutamycin), which is often combined with one
of the vinca alkaloids or other agents, is active in refractory
disease. Unfortunately, it is highly myelosuppressive and can
limit options for subsequent treatment regimens because of its
profound effect on bone marrow reserve. With the availability
of new agents, the use of mitomycin has probably declined in recent
years. Cisplatin (Platinol), another agent often found in combination
therapy, is active in patients with no prior exposure to chemotherapy
in the metastatic setting . As a single agent, it has limited
efficacy in patients with refractory disease, and combinations
containing cisplatin tend to be quite toxic. For these reasons,
cisplatin has no established role in the treatment of refractory
breast cancer. Another platinum analog, carboplatin (Paraplatin),
has no definitive role in the treatment of refractory metastatic
All the agents used in the combinations previously discussed,
as well as several other cytotoxic agents, have been evaluated
as single agents for patients with refractory breast cancer. In
particular, fluorouracil (5-FU) is quite active in patients with
refractory disease, especially when it is administered as a continuous
infusion or in combination with leucovorin [25-27]. Toxicity with
continuous infusion 5-FU is usually quite modest; when administered
as a low-dose infusion over a number of weeks, it causes minimal
myelosuppression and few serious toxicities. Although 5-FU has
been deleted from some adjuvant regimens in recent years, it remains
an effective agent in patients with refractory disease.
Table 3 includes trials with single-agent paclitaxel, docetaxel,
and vinorelbine (Navelbine) [9,28-33]. Each agent is active in
patients with refractory breast cancer. In many centers, paclitaxel
has become the standard second-line regimen, based on promising
results from initial phase II trials [9,28] and subsequent approval
by the Food and Drug Administration (FDA). A number of questions
concerning the optimal use of paclitaxel in the treatment of breast
cancer remain. Ongoing studies are addressing several of these
questions, including the importance of dose intensity and the
role of different infusion durations.
Docetaxel (Taxotere) has been found to have remarkable activity
in patients with anthracycline-resistant refractory breast cancer
[30,31]. Unfortunately, significant fluid retention with cumulative
doses of docetaxel has slowed the development of this agent, but
premedication with steroids has decreased the severity of this
problem. It will be important to see whether the promising early
results are sustained with additional clinical trials. [Docetaxel
was recently appproved by the FDA for treatment of patients with
locally advanced or metastatic breast cancer that has progressed
during anthracycline-based therapy or has relapsed during anthracycline-based
Finally, vinorelbine has also been demonstrated to be active in
patients with refractory disease [32,33], including patients with
anthracycline-refractory and both anthracycline- and taxane-refractory
breast cancer . Although response rates with single-agent
vinorelbine have been somewhat lower than those seen in some of
the taxane trials, the toxicity of vinorelbine is quite mild.
Vinorelbine has yet to gain FDA approval for use in patients with
breast cancer, but this agent ultimately may play an important
role in the treatment of patients who cannot tolerate side effects
from therapy or patients who have had severe toxic effects with
prior treatment regimens.
Other promising agents in early clinical development include gemcitabine
(Gemzar), trimetrexate, and losoxantrone.
Is there an ideal single agent for patients with refractory breast
cancer? The single agents previously discussed have yet to be
compared with one another or with combination regimens in randomized
clinical trials, although some studies are underway. Until further
information is available, the decision to treat patients with
either a single agent or a combination regimen must be based on
individual symptoms, comorbid illnesses, response to prior chemotherapy,
ability to tolerate different types of toxicities, and eagerness
to proceed with treatment. Whenever possible, patients should
be encouraged to participate in clinical trials that address unresolved
questions about the use of current therapies or that seek to identify
new treatments for refractory breast cancer.
Little research has addressed physicians' attitudes about the
treatment of patients with refractory breast cancer. In a study
conducted several years ago, Benner and colleagues  surveyed
oncologists in Maryland to characterize their knowledge and attitudes
about the use of chemotherapy for hormone-unresponsive metastatic
breast cancer. A total of 71% of oncologists cited palliation
as the primary goal of treatment. Although they were enthusiastic
about recommending first-line chemotherapy to their patients,
they were less likely to encourage patients to consider second-line
treatments. Of interest, however, is the fact that 47% of physicians
indicated that they would not reduce the dose of second-line therapy,
even if a patient had experienced febrile neutropenia. Whether
physicians' attitudes vary in different geographic regions is
unknown. It is also unclear as to what extent the availability
of new agents such as the taxanes has affected practice patterns.
Further research in this area will provide a fuller understanding
of physicians' attitudes and expectations with regard to the treatment
of refractory breast cancer.
Although palliation is the primary goal of treatment for patients
with refractory breast cancer, obtaining a clear assessment of
palliation is often quite difficult. Quality-of-life issues are
often discussed, but incorporating meaningful quality-of-life
measurements into clinical trials (and into clinical practice)
is an arduous task. A number of validated quality-of-life instruments
have been developed and are available as a means to assess outcomes
in patients with refractory breast cancer. To date, few studies
have successfully incorporated quality-of-life end points. Coates
and colleagues  documented improvements in quality of life
as a result of chemotherapy despite the side effects of treatment.
Their study, however, was limited to first-line chemotherapy.
In the future, studies of patients with refractory breast cancer
should include quality-of-life assessments that can complement
the more traditional end points of response and survival. Quality-of-life
assessments can capture the subjective improvements often seen
in patients who respond to treatment. As the number of treatment
options increases for patients with breast cancer, well-designed
quality-of-life assessments can help physicians and their patients
choose from among the various alternatives.
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