Tamoxifen (Nolvadex) is an effective, well-tolerated drug that can benefit
breast cancer patients by increasing survival, both overall and disease-free,
and reducing the risk of contralateral breast cancer. Tamoxifen has some
important secondary benefits such as decreasing lipid levels, reducing
cardiovascular risk, and preventing a decrease in bone mineral density,
all of which may be important factors in selection of treatment. As with
most drugs, tamoxifen is associated with side effects; however, tamoxifen
is a well-tolerated drug--less than 1% of patients discontinue its use
due to side effects.
It is important that balanced information on the risks and benefits
of tamoxifen be communicated to patients, preferably with information on
absolute risks and benefits. For the breast cancer patient, the benefits
of tamoxifen clearly outweigh the risks.
Over many years as clinicians, we have seen the impact of tamoxifen
in three different settings: metastatic breast cancer, adjuvant therapy,
and preventive therapy. The purpose of this article is to describefrom
the oncologists' perspectivethe evolution of breast cancer therapy over
the years, with a focus on tamoxifen.
In the 1970s, tamoxifen became widely accepted by oncologists for the
management of metastatic breast cancer, not only because of its efficacy,
but also because its toxicity was less than that of diethylstilbestrol
(DES), the hormonal treatment previously preferred. In addition to its
favorable toxicity profile, tamoxifen produced a high percentage of objective
remissions. It seems that tamoxifen became the preferred treatment for
the palliative management of metastatic breast cancer almost overnight,
and DES has not been used in a long, long time.
During that time period, we learned the importance of stable disease
with improved performance status. Patients with stable disease frequently
felt better and were continued on tamoxifen. In addition, some patients
who initially did not show an objective response to tamoxifen were continued
on tamoxifen therapy and eventually did demonstrate an objective complete
or partial response. This finding was significant for the role of hormonal
therapy in the 1970s and beyond.
During the 1970s, it was thought that chemotherapy might provide a cure
for metastatic breast cancer. After the subsequent disillusionment with
chemotherapy as a curative modality set in, hormonal therapy returned to
prominence for the palliation of hormone-responsive metastatic disease--essen-
tially a chronic but still incurable condition. Tamoxifen has emerged as
the standard of care for first-line treatment of metastatic disease in
pre- and postmenopausal women with estrogen receptor (ER)-positive and/or
progesterone receptor (PR)-positive breast cancer.
With the rise in the adjuvant use of tamoxifen, many patients are already
taking or have recently discontinued tamoxifen at the time of first metastasis.
Thus, the use of tamoxifen monotherapy for metastatic disease is no longer
In considering adjuvant therapy for breast cancer, the major goal of
treatment is to prolong survival while maintaining an acceptable quality
of life. In addition to overall survival--the major end point--we must
recognize that prolonged periods of disease-free survival are not only
a harbinger of overall survival to come, but a worthy goal in its own right.
When a breast cancer patient is free of metastatic disease, her psychological
as well as physical quality of life is much better than after diagnosis
of metastatic disease.
In the 1970s, some physicians refused to recognize the benefit of prolonged
disease-free survival and thus refused to treat these patients with adjuvant
therapy. We cannot minimize the effect on an individual patient of developing
metastatic disease when she has been disease free for a long period of
time. And such effects may not be seen in meta-analyses and overall survival
data. When a patient who has been free of breast cancer for 10 years develops
metastases, she becomes a candidate for palliative treatment. This has
an enormous effect on quality of life because the disease becomes part
of her everyday life. Thus, we believe that prolonged periods of disease
free survival are advantageous in their own right.
Our thinking on the adjuvant use of tamoxifen has evolved over the years
as a result of increasing experience and data from ongoing trials. In the
1985 National Cancer Institute (NCI) Consensus Development Conference on
Adjuvant Chemotherapy for Breast Cancer, the question of how to treat
patients outside clinical trials arose. Most participants thought that
every patient should be enrolled in a trial; however, the actual percentage
of eligible American patients entered into adjuvant trials at that time
was less than 3%. The turning point in the conference came when a physician
from rural Georgia stated that the lack of guidelines was not helpful to
either patients or doctors in the community. The Consensus Conference developed
the 1985 guidelines to aid physicians in selecting the most appropriate
therapy for patients not entered into a trial (Table
1). These were merely guidelines and were not rigid because physicians
cannot treat cancer patients simply by following general recommendations;
there are always nuances in the care of an individual patient.
As a result of this consensus conference, tamoxifen was established
as the standard of care for postmenopausal patients with positive axillary
lymph nodes and positive hormone receptors. This was a major step forward
in opening the door for additional studies on adjuvant use of tamoxifen.
At that time, the recommendation for adjuvant chemotherapy in premenopausal,
node- negative, high-risk patients was controversial.
Following the publication of the Early Breast Cancer Trialists' Collaborative
Group (EBCTCG) analysis of adjuvant trials, a pivotal conference was
held at St. Gallen in 1988 during which slightly different guidelines and
treatment criteria were developed (Table 2).
Chemotherapy was recommended for node-positive, premeno- pausal patients
with either positive or negative receptors. Tamoxifen remained the standard
of care for the node-positive postmenopausal, receptor-positive patient,
but chemotherapy was considered as an investigational option. For the first
time, chemotherapy for the receptor-negative postmenopausal patient gained
some credibility, particularly among the Europeans.
This was a significant change at that particular time. Chemotherapy
for the high-risk, node-negative patient was considered more as a proactive
recommendation, and tamoxifen for the low-risk patient was certainly promulgated.
At the time of that conference in 1988, the arbitrary definitions of low
vs high risk were very similar to what they are today, except that the
primary tumor size as a risk factor is now greater than two cm, while other
prognostic parameters remain very similar.
It is interesting to consider what questions were unanswered in 1988
(Table 3) and if they remain unanswered
today, eight years later.
The appropriate duration of tamoxifen, especially in the node-positive
patient, is still an open question despite the availability of additional
data in node-negative patients.
The appropriate timing of tamoxifen combined with chemotherapy, using
it concurrently or sequentially, has not been determined. In the United
States, most oncologists give tamoxifen after the completion of combination
chemotherapy. However, there are data from the National Surgical Adjuvant
Breast Project (NSABP) on the benefit of the concurrent use of tamoxifen
with cyclophosphamide and doxorubicin.
The role of ovarian ablation and/or tamoxifen in premenopausal, node-positive
patients when compared with chemotherapy alone has not been defined. EBCTCG
data from 1995 suggest that there is no additional advantage to ovarian
ablation in the presence of chemotherapy. Additional trials, including
a large intergroup trial, will hopefully provide a definitive answer.
The role of tamoxifen combined with chemotherapy compared with tamoxifen
alone in postmenopausal, ER-positive, node-positive patients is an open
question. In the United States, the practice is most often to give chemotherapy
followed by tamoxifen, while the practice in Europe has generally been
to give tamoxifen alone. Indirect evidence from the overview suggests chemotherapy
plus tamoxifen may be more beneficial. A recent large intergroup trial
in the United States should provide more data.
The role of tamoxifen plus chemotherapy compared with chemotherapy alone
in postmenopausal, ER-negative, node-positive patients is still uncertain.
In 1988, there was some feeling that these patients should also receive
tamoxifen, but there is less support for this since the recent discussion
of the 1995 overview results.
The role of tamoxifen in ER-negative, node-negative patients compared
to chemotherapy alone is not yet defined.
1. 1985 NIH Consensus Development Conference Report: Adjuvant chemotherapy
for breast cancer. JAMA 254:3461-3463, 1985.
2. 1990 NIH Consensus Development Conference Statement: Treatment of
early stage breast cancer. JAMA 265:391-395, 1991.
3. Early Breast Cancer Trialists' Collaborative Group: Systemic treatment
of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized
trials involving 31,000 recurrences and 24,000 deaths among 75,000 women.
Lancet 339:1-5, 71-85, 1992.
4. Fisher B, Dignam J, Bryant J, et al: Five versus more than five years
of tamoxifen therapy for breast cancer patients with negative lymph nodes
and estrogen receptor-positive tumors. J Natl Cancer Instit 88:1529-1542,
5. Goldhirsch A, Wood WC, Senn HJ et al: International consensus panel
on the treatment of primary breast cancer. J Natl Cancer Instit 87:1441-1445,