New Strategies for Managing Metastatic Breast Cancer
New Strategies for Managing Metastatic Breast Cancer
Metastatic breast cancer is a devastating
problem, with only a small percentage of patients surviving 5 years
or longer. In 1999, about 45,000 women died of metastatic breast
cancera mortality statistic that has not changed appreciably in
decades. The median survival after the detection of distant
metastases is about 3 years for all patients and about 2 years for
patients whose disease is endocrine refractory. Thus, metastatic
breast cancer remains an essentially incurable disease.
Until recently, little progress had been made in treatment. However,
the development of newer endocrine, chemotherapeutic, and, most
recently, biological agents, may lead to modest but definite
improvements in these grim statistics. Except for clinical trials
that use high-dose therapies, palliation remains the major goal of therapy.
Nevertheless, several highly debated, controversial treatment-related
issues remain. These include: (1) whether initial treatment should
consist of endocrine therapy or chemotherapy; (2) whether combination
chemotherapy (polychemotherapy) is superior to
single-agent chemotherapy; (3) the optimal sequence of administration
of chemotherapeutic agents and regimens; (4) whether dose
intensification is superior to standard-dose treatment; and (5) what
constitutes the optimal duration of treatment.
The most important therapeutic issue is whether treatment is being
initiated with curative or palliative intent. Despite the aggressive
trimodality efforts of medical oncology, radiation oncology, and
surgical oncology, almost all patients with metastatic breast cancer
eventually succumb to the disease. Physicians and patients should
discuss and clarify the intent of treatment and decide how they wish
to navigate the delicate balance among relief of symptoms,
prolongation of survival, and toxicity.
An awareness of the natural history of untreated breast cancer is
also important. In a series of 250 patients with breast cancer who
opted for no treatment at diagnosis, median survival was 2.7 years,
and 10% of patients lived 10 years or longer. These data indicate
that, in a small percentage of patients, breast cancer may behave as
a chronic disease, even without treatment.
Prolonged remissions have been well documented in patients treated
with endocrine therapy. In one study of 156 patients treated with
tamoxifen (Nolvadex) for estrogen receptorpositive metastatic
breast cancer, 15% were alive and 7.6% were progression free after 5 years.
The potential for cure using state-of-the-art
polychemotherapy is well illustrated by a review of 1,581 patients
with metastatic breast cancer treated between 1973 and 1982 with a
doxorubicin-containing induction regimen followed by
cyclophosphamide, methotrexate, and fluorouracil (CMF) maintenance
therapy. Complete responses occurred in 16.6% of patients, but
only 3.1% remained in complete remission for more than 5 years. With
a median follow-up of 16 years, only 1.6% (26 of the 1,581 initial
patients) were still alive and disease free. Favorable
characteristics of these remarkable long-term survivors included
younger age, premenopausal status, good performance status, and a low
tumor burden at the time of treatment. These sobering statistics are
characteristic of the results of current chemotherapeutic regimens
used in the metastatic setting.
Is it better to initiate treatment with endocrine therapy or
chemotherapy? Two randomized trials have addressed this question. In
the first trial, 339 postmenopausal women with metastatic breast
cancer, 75% of whom had unknown hormone receptor status, were
randomized to receive tamoxifen alone, tamoxifen and concurrent
cyclophosphamide and Adriamycin (CA), or CA alone. Although the
response rates ranged from 51% in patients treated with tamoxifen
plus CA to 22% in those given tamoxifen alone, overall survival rates
were virtually identical among the three groups. Of the tamoxifen
treated patients, 35% responded to CA as a second-line therapy. In
no subgroup was initial chemotherapy associated with superior
survival when compared with endocrine therapy.
A similar trial compared initial therapy with CMF vs tamoxifen in
patients 65 years of age and older. Complete and partial response
rates were 45% for patients treated with tamoxifen and 38% for those
given CMF, with median response durations of 10.4 and 7.9 months,
respectively. Overall survival data favored tamoxifen as initial
therapy, even in estrogen receptornegative patients.
Currently, most patients with receptor-positive invasive breast
cancer receive systemic therapy with tamoxifen at the time of initial
diagnosis, and it is uncertain as to whether such patients may do as
well with initial endocrine therapy in the metastatic setting. In our
view, patients who relapse within 1 to 2 years after the initiation
of adjuvant tamoxifen or oophorectomy are more likely to benefit from
chemotherapy than from further endocrine therapy, but this decision
is unlikely to have any major effect on survival. In all other
patients, with the exception of patients with rapidly progressive
visceral metastatic disease, initial treatment in the metastatic
setting should consist of endocrine therapy.
In patients who are receptor positive and seriously ill, chemotherapy
combined with endocrine therapy is a reasonable option so as to
maximize the patients chance for a rapid response. Numerous
trials comparing concurrent chemotherapy and endocrine therapy with
chemotherapy alone have failed to show a survival benefit for
Endocrine therapies should be continued indefinitely in patients with
stable disease and until disease progression in responding patients.
Individuals who have displayed stable disease for 4 to 6 months or
longer should be observed for a withdrawal response at the time of
disease progression and prior to initiation of further therapies.
Agents that should be considered for hormonal therapy are described below.
Selective Estrogen Receptor Modulators
There is major interest in the development of new selective estrogen
receptor modulators (SERMs). Tamoxifen, the first SERM widely
available for the treatment of breast cancer, has demonstrated
efficacy in both the metastatic and adjuvant settings and has served
as the prototype for the development of newer SERMs.
The search for the ideal SERM continues. This agent should have
estrogen antagonistic effects on breast and endometrial tissues (less
breast and endometrial cancer), estrogen agonistic effects on the
hypothalamus (cessation or decrease in vasomotor symptoms), skeleton
(maintenance of bone density), and liver (lowering of cholesterol),
and no effect on the coagulation system. To date, no agent has met
all of these goals.
Toremifene (Fareston) is currently available for the treatment of
metastatic breast cancer and appears to have less estrogen agonistic
effects on the endometrium compared with tamoxifen. In the metastatic
setting, toremifene offers no advantages over tamoxifen.
Raloxifene (Evista) has been approved by the Food and Drug
Administration (FDA) for the treatment of osteoporosis in
postmenopausal women and may decrease the risk of breast cancer.
Although raloxifene has shown activity in patients with metastatic
breast cancer, no trials have directly compared it with tamoxifen or
other hormonal agents. As a result, raloxifene should not be used in
patients with metastatic breast cancer outside of a clinical trial.
Other SERMs, including droloxifene and idoxifene, are
unlikely to be associated with a better therapeutic index than
available agents. Newer SERMs with potentially superior therapeutic
indices are currently in clinical trials.