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

ABSTRACT: Breast cancer treatment has evolved greatlywithin the last 25 years. Tamoxifen was first introduced for the treatmentof metastatic breast cancer in the 1970s and later became accepted as standardadjuvant therapy. The emergence of tamoxifen as first-line hormonal therapyfor metastatic disease and in the adjuvant setting occurred due to itsefficacy in achieving prolonged overall survival as well as improved disease-freesurvival, the latter of which improves the psychological and physical qualityof life of the patient. Tamoxifen is currently being studied for the preventionof breast cancer. Completion of this important trial is eagerly awaited.[ONCOLOGY 11(Suppl 1):49-54, 1997]

Introduction

Tamoxifen (Nolvadex) is an effective, well-tolerated drug that can benefitbreast cancer patients by increasing survival, both overall and disease-free,and reducing the risk of contralateral breast cancer. Tamoxifen has someimportant secondary benefits such as decreasing lipid levels, reducingcardiovascular risk, and preventing a decrease in bone mineral density,all of which may be important factors in selection of treatment. As withmost drugs, tamoxifen is associated with side effects; however, tamoxifenis a well-tolerated drug--less than 1% of patients discontinue its usedue to side effects.

It is important that balanced information on the risks and benefitsof tamoxifen be communicated to patients, preferably with information onabsolute risks and benefits. For the breast cancer patient, the benefitsof tamoxifen clearly outweigh the risks.

Over many years as clinicians, we have seen the impact of tamoxifenin three different settings: metastatic breast cancer, adjuvant therapy,and preventive therapy. The purpose of this article is to describe—fromthe oncologists' perspective—the evolution of breast cancer therapy overthe years, with a focus on tamoxifen.

Metastatic Breast Cancer

In the 1970s, tamoxifen became widely accepted by oncologists for themanagement 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 itsfavorable toxicity profile, tamoxifen produced a high percentage of objectiveremissions. It seems that tamoxifen became the preferred treatment forthe 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 diseasewith improved performance status. Patients with stable disease frequentlyfelt better and were continued on tamoxifen. In addition, some patientswho initially did not show an objective response to tamoxifen were continuedon tamoxifen therapy and eventually did demonstrate an objective completeor partial response. This finding was significant for the role of hormonaltherapy in the 1970s and beyond.

During the 1970s, it was thought that chemotherapy might provide a curefor metastatic breast cancer. After the subsequent disillusionment withchemotherapy as a curative modality set in, hormonal therapy returned toprominence for the palliation of hormone-responsive metastatic disease--essen-tially a chronic but still incurable condition. Tamoxifen has emerged asthe standard of care for first-line treatment of metastatic disease inpre- and postmenopausal women with estrogen receptor (ER)-positive and/orprogesterone receptor (PR)-positive breast cancer.

With the rise in the adjuvant use of tamoxifen, many patients are alreadytaking or have recently discontinued tamoxifen at the time of first metastasis.Thus, the use of tamoxifen monotherapy for metastatic disease is no longeras common.

Adjuvant Therapy

In considering adjuvant therapy for breast cancer, the major goal oftreatment is to prolong survival while maintaining an acceptable qualityof life. In addition to overall survival--the major end point--we mustrecognize that prolonged periods of disease-free survival are not onlya 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 psychologicalas well as physical quality of life is much better than after diagnosisof metastatic disease.

In the 1970s, some physicians refused to recognize the benefit of prolongeddisease-free survival and thus refused to treat these patients with adjuvanttherapy. We cannot minimize the effect on an individual patient of developingmetastatic disease when she has been disease free for a long period oftime. And such effects may not be seen in meta-analyses and overall survivaldata. When a patient who has been free of breast cancer for 10 years developsmetastases, she becomes a candidate for palliative treatment. This hasan enormous effect on quality of life because the disease becomes partof her everyday life. Thus, we believe that prolonged periods of diseasefree survival are advantageous in their own right.

Our thinking on the adjuvant use of tamoxifen has evolved over the yearsas a result of increasing experience and data from ongoing trials. In the1985 National Cancer Institute (NCI) Consensus Development Conference onAdjuvant Chemotherapy for Breast Cancer,[1] the question of how to treatpatients outside clinical trials arose. Most participants thought thatevery patient should be enrolled in a trial; however, the actual percentageof eligible American patients entered into adjuvant trials at that timewas less than 3%. The turning point in the conference came when a physicianfrom rural Georgia stated that the lack of guidelines was not helpful toeither patients or doctors in the community. The Consensus Conference developedthe 1985 guidelines to aid physicians in selecting the most appropriatetherapy for patients not entered into a trial (Table1). These were merely guidelines and were not rigid because physicianscannot 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 establishedas the standard of care for postmenopausal patients with positive axillarylymph nodes and positive hormone receptors. This was a major step forwardin 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' CollaborativeGroup (EBCTCG) analysis of adjuvant trials,[2] a pivotal conference washeld at St. Gallen in 1988 during which slightly different guidelines andtreatment criteria were developed (Table 2).[3]Chemotherapy was recommended for node-positive, premeno- pausal patientswith either positive or negative receptors. Tamoxifen remained the standardof care for the node-positive postmenopausal, receptor-positive patient,but chemotherapy was considered as an investigational option. For the firsttime, chemotherapy for the receptor-negative postmenopausal patient gainedsome credibility, particularly among the Europeans.

This was a significant change at that particular time. Chemotherapyfor the high-risk, node-negative patient was considered more as a proactiverecommendation, and tamoxifen for the low-risk patient was certainly promulgated.At the time of that conference in 1988, the arbitrary definitions of lowvs high risk were very similar to what they are today, except that theprimary tumor size as a risk factor is now greater than two cm, while otherprognostic parameters remain very similar.

Unanswered Questions

It is interesting to consider what questions were unanswered in 1988(Table 3) and if they remain unansweredtoday, eight years later.

The appropriate duration of tamoxifen, especially in the node-positivepatient, is still an open question despite the availability of additionaldata in node-negative patients.

The appropriate timing of tamoxifen combined with chemotherapy, usingit concurrently or sequentially, has not been determined. In the UnitedStates, most oncologists give tamoxifen after the completion of combinationchemotherapy. However, there are data from the National Surgical AdjuvantBreast Project (NSABP) on the benefit of the concurrent use of tamoxifenwith cyclophosphamide and doxorubicin.[2]

The role of ovarian ablation and/or tamoxifen in premenopausal, node-positivepatients when compared with chemotherapy alone has not been defined. EBCTCGdata from 1995 suggest that there is no additional advantage to ovarianablation in the presence of chemotherapy. Additional trials, includinga large intergroup trial, will hopefully provide a definitive answer.

The role of tamoxifen combined with chemotherapy compared with tamoxifenalone in postmenopausal, ER-positive, node-positive patients is an openquestion. In the United States, the practice is most often to give chemotherapyfollowed by tamoxifen, while the practice in Europe has generally beento give tamoxifen alone. Indirect evidence from the overview suggests chemotherapyplus tamoxifen may be more beneficial. A recent large intergroup trialin the United States should provide more data.

The role of tamoxifen plus chemotherapy compared with chemotherapy alonein postmenopausal, ER-negative, node-positive patients is still uncertain.In 1988, there was some feeling that these patients should also receivetamoxifen, but there is less support for this since the recent discussionof the 1995 overview results.

The role of tamoxifen in ER-negative, node-negative patients comparedto chemotherapy alone is not yet defined.

Second Consensus Conference

A second NCI Consensus Conference was held in 1990 (Table4).[2] One of the questions discussed was the role of adjuvant therapyfor node-negative breast cancer. Although it was acknowledged that bothtamoxifen and combination chemotherapy reduced the rate of recurrence,no treatment recommendations were given regarding the role of these twotherapies. The only definitive statement from the 1990 conference is thatpatients with tumors one cm or less should not receive adjuvant therapy.

When the updated data from the Early Breast Cancer Trialists' CollaborativeGroup were published in 1992 (Table 5),[3]American oncologists were able to talk to the patients about the absolutebenefits of treatment. This has led to more extensive discussions withpatients about risks and benefits of treatment.

In 1992, another conference was held at St. Gallen. The guidelines generatedat that time are shown in Table 6, Table7, and Table 8. It was recommendedthat the minimal or low-risk, node-negative patient should receive eitherno additional systemic treatment or tamoxifen, and the good-risk patientshould receive tamoxifen. The node-negative, high-risk, receptor-positivepremenopausal patient should receive chemotherapy ± tamoxifen, apractice that has become more and more common in the United States. Thenode-negative, high-risk, receptor-negative premenopausal patient shouldreceive chemotherapy alone. Of postmenopausal, node-negative, high-riskpatients, those who are receptor positive should receive tamoxifen ±chemotherapy, whereas those who are receptor negative should receive chemotherapy± tamoxifen. For the node-positive patient, the only real changewas the recommendation for tamoxifen ± chemotherapy for the postmenopausal,receptor-positive patient.

The node-negative risk categories that most of us now accept were againrefined at the 1995 St. Gallen Conference (Table9). However, many oncologists in the United States also use flow cytometryresults to aid in the selection of therapy for an individual patient. Atthe 1995 conference,[5] there were no changes in the recommendations forthe minimal or low-risk node-negative patient (Table10).

Although tamoxifen is considered investigational for the low-risk patient,some physicians are prescribing the drug because of its other benefits.Tamoxifen is the treatment of choice for the good-risk, node-negative,ER-positive patient of any age, with the use of ovarian ablation and chemotherapybeing investigational. Chemotherapy ± tamoxifen is clearly the treatmentof choice for the premenopausal, node-negative, high-risk patient. Moreand more women with ER-positive breast disease will be treated with tamoxifenand chemotherapy.

Tamoxifen is the treatment of choice for the postmenopausal, node-negative,ER-positive patient; however, more of these women will probably be receivingtamoxifen following chemotherapy, depending on the data from recently completedclinical trials.

Duration of Tamoxifen

The question of when to discontinue tamoxifen adjuvant therapy remainscontroversial. If one views patients with node-positive breast cancer,especially those with four or more positive nodes, as having a form ofmetastatic disease, it is a reasonable argument to continue tamoxifen beyondfive years because the relapse rate over time is still great.

In our practice, we find that many node-positive patients want to continuetamoxifen because they feel that by taking it they are doing somethingproactive, and there is a life buoy effect. One concern these patientshave relates to recurrence after stopping tamoxifen. In this case, willthey blame themselves and their doctor? We still do not have definitiveclinical trial data on the optimal duration of tamoxifen for node-positivepatients.

In patients with node-negative breast cancer, there appears to be nobenefit to prolonging tamoxifen treatment beyond five years.[4]

The 1995 NCI Clinical Alert regarding tamoxifen duration has to be putinto clinical context because results for node-positive and node-negativepatients were not discussed separately. The document implies that tamoxifenshould be stopped at five years for all patients. At the time the NCI ClinicalAlert was issued, there were small numbers of node-negative patients atrisk in the study. Although we understand why the Clinical Alert was issued,we do not take it to mean that the drug has to be stopped for node-positivepatients. However, for node-negative patients, five years of tamoxifenis now the standard therapy.

We have heard some discussion that five years of tamoxifen is appropriatefor node-negative patients, but we do not have good data on node-positivepatients. Large clinical trials in estrogen receptor-positive, node-positivepatients are required to further define the optimal duration of tamoxifenin this subset. At present we do not have the necessary data; we are extrapolatingfrom the node-negative data.

Patient Communication

In the treatment of breast cancer, it is important to establish a relationshipwith the patient and ensure that the patient fairly and realistically understandsthe risks and benefits of any adjuvant treatment. Consensus conferencestatements and overview analyses are useful in the general sense, but thedata have to be applied to the individual patient's needs. It is also importantto ensure that the patient understands treatment benefits in terms of bothrelative and absolute benefits. Tamoxifen may decrease the risk of contralateralbreast cancer from 2.0% to 1.3% at 10 years in absolute terms--a one-thirdreduction in relative terms. For some patients, a small absolute benefitmay be an important factor in deciding treatment. The physician also hasto mention other potential benefits of tamoxifen related to the cardiovascularsystem, bone mineral density, and lipids, especially if the patient hasa history or risk in these areas. In addition, the physician also has todiscuss the risks and put them into perspective for the individual patient.

Side Effect Profileof Tamoxifen

Tamoxifen is the most benign of all anticancer therapies we prescribein terms of serious side effects. In our own practice, fewer than 1% ofpatients withdraw from adjuvant tamoxifen due to side effects. Weight gainand hot flashes are the most distressing symptoms to our patients. Theweight gain is typically 3-15 lbs and occurs in about 30% to 40% of womenon tamoxifen. The weight gain--not merely fluid retention--frequently cannotbe avoided by diet and exercise and tends to remain after discontinuationof the drug. Weight gain can be particularly distressing to breast cancerpatients because it affects body image, which is already adversely affectedby breast cancer surgery, even if conservative surgical procedures areused.

Hot flashes clearly occur on tamoxifen and may be incapacitating insome cases. This symptom is sometimes alleviated by vitamin E, Bellergalspansules, clonidine, and other medications. Although vaginal dryness anda clear vaginal discharge are reported, they do not present a major problemfor most women if vaginal lubricants are used. A small subset of womenon the drug have reported emotional lability and memory loss, the latterof which reversed upon discontinuation of tamoxifen. We have not notedsignificant problems with nausea, skin rash, diarrhea, thrombocytopenia,leukopenia, thromboembolism, or liver function abnormalities.

Neither have we personally seen any cases of endometrial cancer amongthe several thousand patients treated. We warn patients about the slightincreased risk of endometrial cancer. We stress the importance of routinegynecologic examinations and the importance of quickly calling to our attentionvaginal bleeding so it can be investigated immediately. Very few patientswill stop the drug because of fear of endometrial carcinoma. Patients understandthat there is a risk of endometrial cancer, but do not appear to worryabout it; they worry about their breast cancer.

Concern has been raised in the media about an association between tamoxifenand liver cancer based upon data in laboratory animals. We have not seena single case of liver cancer in either our own practice or in any publishedUS study; several patients with alleged liver cancer clearly had metastaticbreast cancer to the liver. Application of animal results to patients canbe a problem, especially if there are extensive human data that contradictthe animal data, as is the case with tamoxifen. Indeed, liver cancer isnot included in our list of potential side effects.

Tamoxifenfor the Prevention of Breast Cancer

There is no more important study that still needs to be completed thanthe National Surgical Adjuvant Breast Project (NSABP) Prevention Study.Due to some adverse publicity, crucial momentum was lost from this trial.There is a critical need for effective chemopreventive agents in lightof genetic testing for cancer susceptibility genes. Today, the woman whocarries the BRCA-1 and/or 2 genes has as her only options either increasedsurveillance, prophylactic mastectomy (leaving some breast tissue behind),or prophylactic oophorectomy. The risk/benefit profile for tamoxifen inthis setting remains to be determined.

Conclusion

From a physician's point of view, tamoxifen is a remarkably effectivedrug. In the more than 20 years since tamoxifen was introduced in the UnitedStates, it has become the hormonal treatment of choice for breast cancer.For the breast cancer patient, the benefits of tamoxifen clearly outweighthe potential risks.

References:

1. 1985 NIH Consensus Development Conference Report: Adjuvant chemotherapyfor breast cancer. JAMA 254:3461-3463, 1985.

2. 1990 NIH Consensus Development Conference Statement: Treatment ofearly stage breast cancer. JAMA 265:391-395, 1991.

3. Early Breast Cancer Trialists' Collaborative Group: Systemic treatmentof early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomizedtrials 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 yearsof tamoxifen therapy for breast cancer patients with negative lymph nodesand estrogen receptor-positive tumors. J Natl Cancer Instit 88:1529-1542,1996.

5. Goldhirsch A, Wood WC, Senn HJ et al: International consensus panelon the treatment of primary breast cancer. J Natl Cancer Instit 87:1441-1445,1995.