Tamoxifen's Impact on the Management of Breast Cancer: The Oncologist's Perspective

Introduction

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(Drug information on 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 describe—from the oncologists' perspective—the evolution of breast cancer therapy over the years, with a focus on tamoxifen.

Metastatic Breast Cancer

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(Drug information on 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(Drug information on 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 as common.

Adjuvant Therapy

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,[1] 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,[2] a pivotal conference was held at St. Gallen in 1988 during which slightly different guidelines and treatment criteria were developed (Table 2).[3] 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.

Unanswered Questions

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(Drug information on cyclophosphamide) and doxorubicin(Drug information on doxorubicin).[2]

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.