Tamoxifen (Nolvadex), a nonsteroidal antiestrogen initially developed
as an antifertility agent, was approved for the treatment of metastatic
breast cancer in postmenopausal women in the 1970s. Since that time,
tamoxifen's therapeutic role has continued to expand to include the management
of early breast cancer in postmenopausal women, early and advanced breast
cancer in premenopausal women, and breast cancer in men. In addition, it
is currently studied for chemoprotection in healthy women at increased
risk for breast cancer (Table 1).[1-27]
In this review, the impact of menopausal, estrogen-receptor (ER), and
nodal status on the role of tamoxifen in the medical management of breast
cancer is discussed. In addition, current opinion regarding the optimum
duration of tamoxifen therapy, the efficacy of tamoxifen-chemotherapy combinations,
and tamoxifen's potential for toxicity are presented.
The results of a number of clinical studies support the efficacy and
safety of tamoxifen when used as first-line endocrine therapy in the management
of advanced breast cancer in both premenopausal and postmenopausal women[1,2,17-27]
and stress the importance of the presence of estrogen receptors in response.
Postmenopausal Women: Complete or partial responses to tamoxifen
therapy have been observed in 30% to 40% of postmenopausal women with metastatic
disease.[1,2,17-20] Response rates increase to 50% in women with ER-positive
tumors and to 60% to 70% in women with ER-positive and progesterone receptor
(PR)-positive tumors.[1,2,17-20] In women with ER-negative and PR-negative
tumors, response rates on the order of 10% have been reported with response
durations ranging from two months to more than 24 months.[1,2,17,19] However,
more recent data from studies with better statistical reliability indicate
that the percentage of receptor-negative pa-tients responding to tamoxifen
is lower, and that tamoxifen may not have a significant role in receptor-negative
The effects of tamoxifen in unselected postmenopausal women are similar
to those observed with other agents such as diethylstilbestrol (DES), ethinyl
medroxyprogesterone acetate (MPA), and megestrol acetate (MA); however,
tamoxifen has been demonstrated to have a more favorable toxicity profile
than other hormonal therapies.[1,2,21-25]
In postmenopausal women with advanced disease, tamoxifen administered
in combination or sequentially with chemotherapy has been demonstrated
to produce a higher overall response rate than tamoxifen alone, but survival
rates associated with this combination have been either not significantly
different from or lower than those observed in response to monotherapy
with either agent. For postmenopausal women with advanced breast cancer,
it may be appropriate to limit chemotherapy to patients who have failed
to respond to tamoxifen or those with fulminating disease.
Premenopausal Women: Tamoxifen has consistently been demonstrated
to be as efficacious as bilateral oophorectomy in premenopausal women with
advanced disease with respect to response rates, response duration, and
survival time, but with lower associated toxicity.[1,25] Response rates
following daily administration of 20 to 120 mg of tamoxifen have ranged
from 20% to 45%, with median response durations of 2.5 months to 36 months.
 Results of the Mayo Clinic trial indicated that tamoxifen may be more
effective than oophorectomy in patients with soft-tissue or osseous disease
and less effective in patients with visceral-dominant disease.[1,26,27]
Menstrual irregularities in premenopausal women with advanced breast cancer
treated with tamoxifen are common and between 16% and 39% of women experience
Males: Although male breast cancer is rare, studies have indicated
that tamoxifen does have a role in its treatment. Male breast cancer patients
are more likely to have tumors positive for estrogen receptors than are
female patients, indicating a role for adjuvant tamoxifen treatment.
Several small studies have confirmed its efficacy[28-30]; studies have
demonstrated an overall response rate of 50% in unselected patients and
71% in patients with tumors positive for estrogen receptors. In the
absence of data from large, randomized trials in males, the treatment selection
guidelines established for the use of adjuvant therapy in women have been
At the 1985 National Institutes of Health Consensus Conference on Breast
Cancer Chemotherapy, the goals of adjuvant therapy in the management of
breast cancer were defined as the prolongation of survival and the maintenance
of an acceptable quality of life. To that end, the Consensus Committee
recommended tamoxifen as the treatment of choice for postmenopausal women
with positive nodes and ER-positive tumors. This recommendation was the
first step in establishing the role of tamoxifen in the adjuvant setting.
Within eight years following this recommendation, the results of 14
randomized trials involving 2,559 pre-menopausal and 10,989 postmenopausal
women with early breast cancer demonstrated that adjuvant tamoxifen therapy
was consistently associated with improved disease-free survival.[1,10-14]
However, a statistically significant increase in overall survival was reported
for only four of these clinical trials (Table
In the Nolvadex Adjuvant Trial Organization (NATO) and Scottish studies,
improvement in overall survival was independent of menopausal, ER, or nodal
status.[1,10-14] In the trial conducted at Christie Hospital, a statistically
significant improvement in overall survival with tamoxifen therapy was
reported only when the entire population of patients was considered and
not for either premenopausal or postmenopausal subpopulations. However,
the duration of therapy in this study was only one year, compared with
two years in the NATO and at least five years in the Scottish trials.[1,10,13,14]
Women with receptor-positive, node-negative disease were found to have
an improved survival with five years of tamoxifen therapy in the National
Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial.[1,11,12]
In an attempt to more clearly define the comparative therapeutic benefits
of various therapies, as well as to illustrate the impact of menopausal,
nodal, and ER status on these benefits, the Early Breast Cancer Trialists'
Collaborative Group (EBCTCG) pooled the results from 133 randomized trials
involving 75,000 women with early breast cancer receiving tamoxifen, chemotherapy,
ovarian ablation, or immunotherapy.[15,16] Table
3 and Table 4 summarize the results
from this overview with respect to the approximately 32,000 women enrolled
in 45 clinical trials evaluating either adjuvant tamoxifen therapy versus
no adjuvant therapy, tamoxifen plus chemotherapy versus chemotherapy alone,
or varying durations of tamoxifen therapy.
The EBCTCG meta-analyses clearly demonstrated that tamoxifen therapy
reduced annual rates of recurrence and death for all patients.[1-3,15,16]
However, women aged 50 or older appear to derive a greater benefit from
tamoxifen therapy than younger women, although the age-related differences
in recurrence and mortality rates were small. A confounding variable may
be related to the potential need to administer tamoxifen for a longer duration
(more than two years) in premenopausal women than in postmenopausal women
to achieve similar results. Both node-positive and node-negative women
benefited from tamoxifen therapy with a similar proportional reduction
in mortality risk.[1,15,16] The absolute improvement in 10-year survival
and overall reduction in risk for recurrence were lower for patients with
node-negative compared with node-positive disease, due to an initially
lower risk for recurrence. [1,3,15,16] As expected, treatment of women
with ER-rich tumors resulted in a greater reduction in mortality and recurrence
than treatment of women with ER-poor tumors.
A previous diagnosis of breast cancer can result in a threefold increase
in risk for contralateral breast cancer. The EBCTCG analysis demonstrated
that adjuvant tamoxifen therapy reduced the risk for development of contralateral
breast cancer by 39% compared with no adjuvant therapy, despite the fact
that the longer recurrence-free survival associated with tamoxifen presented
a greater opportunity for the disease to develop. Therapy durations
longer than two years resulted in a 53% reduction in risk for contralateral
disease compared with a 26% reduction with less than two years of treatment.
Tamoxifen in Combination with Chemotherapy: A significant improvement
in disease-free survival for postmenopausal women has been observed with
tamoxifen in combination with chemotherapy (cyclophosphamide [Cytoxan,
Neosar], methotrexate, fluorouracil) and prednisone, compared with tamoxifen
in combination with prednisone alone.[1,33] Similarly, the EBCTCG analysis
demonstrated that, for women aged 50 to 69, chemotherapy plus tamoxifen
resulted in a greater reduction in mortality rate than chemotherapy alone
and a greater reduction in recurrence rate than either chemotherapy alone
or tamoxifen alone.[15,16] However, due to the limited amount of available
clinical data, the EBCTCG overview could not establish whether women under
age 50 derived benefit from a combination of tamoxifen and chemotherapy
compared with the use of either agent alone.
The consensus opinion of the 1995 International Conference on Adjuvant
Therapy of Primary Breast Cancer was that the combination of chemotherapy
and tamoxifen was an acceptable treatment option for premenopausal and
postmenopausal women with node-positive disease as well as premenopausal
and postmenopausal women with high-risk, node-negative disease. The
optimum sequence and chemotherapy regimen for administration of a combination
tamoxifen-chemotherapy regimen had not yet been determined. Certain clinical
data suggest a possible negative interaction between tamoxifen and certain
cytotoxic agents (eg, L-PAM, fluorouracil).
Optimum Dose and Duration of Adjuvant Tamoxifen Therapy: The EBCTCG
analysis demonstrated that tamoxifen doses higher than the standard 20
mg/d did not appear to provide greater therapeutic benefits.[1,15,16] In
the EBCTCG analysis, in which the most widely-tested regimen was 20 mg/d
for two years, the overall reduction in recurrence rate associated with
tamoxifen therapy maximized during the first four years, and remained essentially
unaltered between five and 10 years after initiation of therapy.[15,16]
Survival benefits, however, continue to increase, with a 5% reduction
in mortality at five years and an 8% reduction at 10 years.[3,15,16] Fifty-nine
percent of women administered tamoxifen were alive 10 years after initiation
of therapy, compared with 53% of women administered placebo.[1,15,16] This
steady divergence in survival between tamoxifen-treated and control patients
during years five through 10 following initiation of therapy had not been
anticipated by the EBCTCG collaborators and should be considered in the
interpretation of data pertaining to therapy duration.
The EBCTCG analysis demonstrated that, compared with less than two years
of tamoxifen therapy, longer durations of administration were associated
with larger reductions in annual risk for mortality (24% vs 11%) and risk
for recurrence (38% vs 16%). [3,15,16] The typical percentage reduction
in the annual odds of recurrence was greater for patients aged at least
50 years than for those aged less than 50 years for durations of tamoxifen
treatment of no more than one year (19% vs 5%) and two years (33% vs 10%).
However, tamoxifen administered for more than two years produced similar
reductions in both age groups (38% vs 43%). Similarly, for patients
aged 50 years or more the typical percentage reduction in the annual odds
of mortality from any cause was greater than for those aged less than 50
years for durations of tamoxifen treatment of less than or equal to one
year (13% vs 4%) and two years (23% vs 4%), but similar for therapy of
more than two years (23% vs 27%).
The EBCTCG analysis was unable to determine whether two years, five
years, 10 years, or indefinite tamoxifen administration was the optimum
duration of therapy. The recent Swedish study has established that five
years of tamoxifen is more beneficial than two years in postmenopausal
women with receptor-positive, early-stage invasive breast cancer.
The NSABP B-14 study results suggest that in node-negative patients,
no significant additional therapeutic benefit was observed after five years
of tamoxifen therapy. However, some members of the medical community
felt that the available data were insufficient for the formulation of definitive
duration guidelines, given that the relationship between age/menopausal
status and/or nodal status and optimum therapy duration has not been extensively
explored. In addition, the question of therapy duration must also address
the effect of tamoxifen on other estrogen target tissues as well as individual
patient risk factors for side effects.
Beneficial Bone and Cardiovascular Effects: Bone fractures due
to loss of mineral density cause substantial morbidity and mortality in
postmenopausal women. Tamoxifen therapy for more than one year appears
to be associated with increased bone mineral density and in some studies
decreased fracture rates. Tamoxifen may be as efficacious as estrogen replacement
therapy for bone loss prevention in postmenopausal women.[2,36-38]
In addition, long-term adjuvant tamoxifen treatment (two or five years)
is associated with a reduced risk for hospital admission due to cardiac
disease and fatal myocardial infarction.[2,39,40]
Tamoxifen Safety Profile: Tamoxifen is a well-tolerated agent,
and less than 5% of women with early breast cancer discontinue therapy
due to side effects.[1,2] Side effects are usually limited to those associated
with tamoxifen's antiestrogenic properties; for example, hot flashes are
the most frequently experienced side effect, particularly in premenopausal
women, and vaginal bleeding, fluid retention, irregular menses, irritability,
headache, and dizziness have also been observed.[1,2]
In 1% to 3% of patients, long-term tamoxifen therapy has been associated
with thromboembolic events.[1,2] Although rare at currently used doses,
very high doses of tamoxifen, particularly with previous or concurrent
cytotoxic therapy, have been associated with retinal changes, keratopathy,
and optic neuritis.
The results of laboratory studies in rats have indicated that high daily
doses of tamoxifen administered over a significant portion of the lifespan
are hepatocarcinogenic. However, clinical observations and epidemiologic
evidence do not support an increased risk for liver tumors in patients
treated with tamoxifen.[1-3,41]
Tamoxifen administration appears to produce a modest increase in risk
for endometrial cancer, with a rate of detection of 0.2% to 0.3% per year,
compared with 0.1% in breast cancer patients not receiving tamoxifen.[1-3,41]
However, the risk for high-grade endometrial cancers of poor prognosis
is not increased with tamoxifen therapy. Tamoxifen may have a causative
or stimulatory role. The general consensus of the medical community is
that the benefits of tamoxifen in patients with breast cancer clearly outweigh
the risk of endometrial carcinoma.[1-3,41] Whether the risk/benefit ratio
is sufficient for administration of tamoxifen as a chemoprotective agent
in healthy women at high risk for breast cancer remains to be determined.
Over the last 20 years, tamoxifen has become the most widely used endocrine
agent for the management of advanced breast cancer in both pre- menopausal
and postmenopausal women. In addition, tamoxifen is considered to be the
adjuvant agent of choice for postmenopausal women with node-positive disease
or good risk node-negative disease at high risk for recurrence. In addition,
tamoxifen-chemotherapy combinations are another viable option for premenopausal
or postmenopausal women with node-positive disease or high-risk, node-negative
disease. However, the chemotherapy agents must be chosen with care since
not all combinations provide beneficial results.
Controversy still exists in the medical community as to tamoxifen's
role in premenopausal women with node-positive disease or high-risk, node-negative
disease. However, the results of the EBCTCG analysis indicate that estrogen
receptor status may be a better indicator than either menopausal or nodal
status when determining the clinical role of tamoxifen.
While tamoxifen remains the agent of choice in the medical management
of breast cancer, many issues still need to be resolved regarding the optimum
duration of tamoxifen therapy and its potential use as a chemoprotective
agent in healthy women at high risk for breast cancer.
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