Clinical Efficacy of Tamoxifen

ABSTRACT: In 1977, tamoxifen, a nonsteroidal antiestrogen,was approved in the United States for the management of advanced breastcancer in postmenopausal women. Since that time, tamoxifen's therapeuticrole has grown to include management of advanced breast cancer in premenopausalwomen, systemic adjuvant therapy for early breast cancer in premenopausaland postmenopausal women, and treatment of breast cancer in men; the drugis now being studied in chemoprevention trials for women at high risk forbreast cancer. Tamoxifen therapy prolongs disease-free survival and reducesmortality in premenopausal, postmenopausal, node-positive, and node-negativepatients. Positive objective responses are more frequent in patients withestrogen receptor-positive tumors. The role of tamoxifen in combinationwith chemotherapy needs to be further clarified with respect to the optimalregimen, sequential vs concomitant therapy, and appropriate patient selection.While the optimum duration of tamoxifen therapy has not yet been established,tamoxifen remains a major therapeutic agent in the medical management ofbreast cancer. [ONCOLOGY 11(Suppl 1):15-20, 1997]

Introduction

Tamoxifen (Nolvadex), a nonsteroidal antiestrogen initially developedas an antifertility agent, was approved for the treatment of metastaticbreast cancer in postmenopausal women in the 1970s.[1] Since that time,tamoxifen's therapeutic role has continued to expand to include the managementof early breast cancer in postmenopausal women, early and advanced breastcancer in premenopausal women, and breast cancer in men. In addition, itis currently studied for chemoprotection in healthy women at increasedrisk for breast cancer (Table 1).[1-27]

In this review, the impact of menopausal, estrogen-receptor (ER), andnodal status on the role of tamoxifen in the medical management of breastcancer is discussed. In addition, current opinion regarding the optimumduration of tamoxifen therapy, the efficacy of tamoxifen-chemotherapy combinations,and tamoxifen's potential for toxicity are presented.

Tamoxifen and AdvancedBreast Cancer

The results of a number of clinical studies support the efficacy andsafety of tamoxifen when used as first-line endocrine therapy in the managementof 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 tamoxifentherapy have been observed in 30% to 40% of postmenopausal women with metastaticdisease.[1,2,17-20] Response rates increase to 50% in women with ER-positivetumors 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-negativetumors, response rates on the order of 10% have been reported with responsedurations ranging from two months to more than 24 months.[1,2,17,19] However,more recent data from studies with better statistical reliability indicatethat the percentage of receptor-negative pa-tients responding to tamoxifenis lower, and that tamoxifen may not have a significant role in receptor-negativepatients.

The effects of tamoxifen in unselected postmenopausal women are similarto those observed with other agents such as diethylstilbestrol (DES), ethinylestradiol,medroxyprogesterone acetate (MPA), and megestrol acetate (MA); however,tamoxifen has been demonstrated to have a more favorable toxicity profilethan other hormonal therapies.[1,2,21-25]

In postmenopausal women with advanced disease, tamoxifen administeredin combination or sequentially with chemotherapy has been demonstratedto produce a higher overall response rate than tamoxifen alone, but survivalrates associated with this combination have been either not significantlydifferent from or lower than those observed in response to monotherapywith either agent.[1] For postmenopausal women with advanced breast cancer,it may be appropriate to limit chemotherapy to patients who have failedto respond to tamoxifen or those with fulminating disease.[1]

Premenopausal Women: Tamoxifen has consistently been demonstratedto be as efficacious as bilateral oophorectomy in premenopausal women withadvanced disease with respect to response rates, response duration, andsurvival time, but with lower associated toxicity.[1,25] Response ratesfollowing daily administration of 20 to 120 mg of tamoxifen have rangedfrom 20% to 45%, with median response durations of 2.5 months to 36 months.[1] Results of the Mayo Clinic trial indicated that tamoxifen may be moreeffective than oophorectomy in patients with soft-tissue or osseous diseaseand less effective in patients with visceral-dominant disease.[1,26,27]Menstrual irregularities in premenopausal women with advanced breast cancertreated with tamoxifen are common and between 16% and 39% of women experienceamenorrhea.[1]

Males: Although male breast cancer is rare, studies have indicatedthat tamoxifen does have a role in its treatment. Male breast cancer patientsare more likely to have tumors positive for estrogen receptors than arefemale patients, indicating a role for adjuvant tamoxifen treatment.

Several small studies have confirmed its efficacy[28-30]; studies havedemonstrated an overall response rate of 50% in unselected patients and71% in patients with tumors positive for estrogen receptors.[31] In theabsence of data from large, randomized trials in males, the treatment selectionguidelines established for the use of adjuvant therapy in women have beenrecommended.[32]

AdjuvantTamoxifen Therapy for Early Breast Cancer

At the 1985 National Institutes of Health Consensus Conference on BreastCancer Chemotherapy, the goals of adjuvant therapy in the management ofbreast cancer were defined as the prolongation of survival and the maintenanceof an acceptable quality of life.[7] To that end, the Consensus Committeerecommended tamoxifen as the treatment of choice for postmenopausal womenwith positive nodes and ER-positive tumors. This recommendation was thefirst step in establishing the role of tamoxifen in the adjuvant setting.

Within eight years following this recommendation, the results of 14randomized trials involving 2,559 pre-menopausal and 10,989 postmenopausalwomen with early breast cancer demonstrated that adjuvant tamoxifen therapywas consistently associated with improved disease-free survival.[1,10-14]However, a statistically significant increase in overall survival was reportedfor only four of these clinical trials (Table2).[1,10-14]

In the Nolvadex Adjuvant Trial Organization (NATO) and Scottish studies,improvement in overall survival was independent of menopausal, ER, or nodalstatus.[1,10-14] In the trial conducted at Christie Hospital, a statisticallysignificant improvement in overall survival with tamoxifen therapy wasreported only when the entire population of patients was considered andnot for either premenopausal or postmenopausal subpopulations. However,the duration of therapy in this study was only one year, compared withtwo 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 havean improved survival with five years of tamoxifen therapy in the NationalSurgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial.[1,11,12]

In an attempt to more clearly define the comparative therapeutic benefitsof 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 trialsinvolving 75,000 women with early breast cancer receiving tamoxifen, chemotherapy,ovarian ablation, or immunotherapy.[15,16] Table3 and Table 4 summarize the resultsfrom this overview with respect to the approximately 32,000 women enrolledin 45 clinical trials evaluating either adjuvant tamoxifen therapy versusno adjuvant therapy, tamoxifen plus chemotherapy versus chemotherapy alone,or varying durations of tamoxifen therapy.

The EBCTCG meta-analyses clearly demonstrated that tamoxifen therapyreduced 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 fromtamoxifen therapy than younger women, although the age-related differencesin recurrence and mortality rates were small. A confounding variable maybe related to the potential need to administer tamoxifen for a longer duration(more than two years) in premenopausal women than in postmenopausal womento achieve similar results. Both node-positive and node-negative womenbenefited from tamoxifen therapy with a similar proportional reductionin mortality risk.[1,15,16] The absolute improvement in 10-year survivaland overall reduction in risk for recurrence were lower for patients withnode-negative compared with node-positive disease, due to an initiallylower risk for recurrence. [1,3,15,16] As expected, treatment of womenwith ER-rich tumors resulted in a greater reduction in mortality and recurrencethan treatment of women with ER-poor tumors.

A previous diagnosis of breast cancer can result in a threefold increasein risk for contralateral breast cancer.[3] The EBCTCG analysis demonstratedthat adjuvant tamoxifen therapy reduced the risk for development of contralateralbreast cancer by 39% compared with no adjuvant therapy, despite the factthat the longer recurrence-free survival associated with tamoxifen presenteda greater opportunity for the disease to develop.[15] Therapy durationslonger than two years resulted in a 53% reduction in risk for contralateraldisease compared with a 26% reduction with less than two years of treatment.[15]

Tamoxifen in Combination with Chemotherapy: A significant improvementin disease-free survival for postmenopausal women has been observed withtamoxifen in combination with chemotherapy (cyclophosphamide [Cytoxan,Neosar], methotrexate, fluorouracil) and prednisone, compared with tamoxifenin combination with prednisone alone.[1,33] Similarly, the EBCTCG analysisdemonstrated that, for women aged 50 to 69, chemotherapy plus tamoxifenresulted in a greater reduction in mortality rate than chemotherapy aloneand a greater reduction in recurrence rate than either chemotherapy aloneor tamoxifen alone.[15,16] However, due to the limited amount of availableclinical data, the EBCTCG overview could not establish whether women underage 50 derived benefit from a combination of tamoxifen and chemotherapycompared with the use of either agent alone.

The consensus opinion of the 1995 International Conference on AdjuvantTherapy of Primary Breast Cancer was that the combination of chemotherapyand tamoxifen was an acceptable treatment option for premenopausal andpostmenopausal women with node-positive disease as well as premenopausaland postmenopausal women with high-risk, node-negative disease.[9] Theoptimum sequence and chemotherapy regimen for administration of a combinationtamoxifen-chemotherapy regimen had not yet been determined. Certain clinicaldata suggest a possible negative interaction between tamoxifen and certaincytotoxic agents (eg, L-PAM, fluorouracil).[9]

Optimum Dose and Duration of Adjuvant Tamoxifen Therapy: The EBCTCGanalysis demonstrated that tamoxifen doses higher than the standard 20mg/d did not appear to provide greater therapeutic benefits.[1,15,16] Inthe EBCTCG analysis, in which the most widely-tested regimen was 20 mg/dfor two years, the overall reduction in recurrence rate associated withtamoxifen therapy maximized during the first four years, and remained essentiallyunaltered between five and 10 years after initiation of therapy.[15,16]

Survival benefits, however, continue to increase, with a 5% reductionin mortality at five years and an 8% reduction at 10 years.[3,15,16] Fifty-ninepercent of women administered tamoxifen were alive 10 years after initiationof therapy, compared with 53% of women administered placebo.[1,15,16] Thissteady divergence in survival between tamoxifen-treated and control patientsduring years five through 10 following initiation of therapy had not beenanticipated by the EBCTCG collaborators and should be considered in theinterpretation of data pertaining to therapy duration.[16]

The EBCTCG analysis demonstrated that, compared with less than two yearsof tamoxifen therapy, longer durations of administration were associatedwith larger reductions in annual risk for mortality (24% vs 11%) and riskfor recurrence (38% vs 16%). [3,15,16] The typical percentage reductionin the annual odds of recurrence was greater for patients aged at least50 years than for those aged less than 50 years for durations of tamoxifentreatment of no more than one year (19% vs 5%) and two years (33% vs 10%).

However, tamoxifen administered for more than two years produced similarreductions in both age groups (38% vs 43%).[15] Similarly, for patientsaged 50 years or more the typical percentage reduction in the annual oddsof mortality from any cause was greater than for those aged less than 50years for durations of tamoxifen treatment of less than or equal to oneyear (13% vs 4%) and two years (23% vs 4%), but similar for therapy ofmore than two years (23% vs 27%).

The EBCTCG analysis was unable to determine whether two years, fiveyears, 10 years, or indefinite tamoxifen administration was the optimumduration of therapy. The recent Swedish study has established that fiveyears of tamoxifen is more beneficial than two years in postmenopausalwomen with receptor-positive, early-stage invasive breast cancer.[34]

The NSABP B-14 study results suggest that in node-negative patients,no significant additional therapeutic benefit was observed after five yearsof tamoxifen therapy.[35] However, some members of the medical communityfelt that the available data were insufficient for the formulation of definitiveduration guidelines, given that the relationship between age/menopausalstatus and/or nodal status and optimum therapy duration has not been extensivelyexplored.[3] In addition, the question of therapy duration must also addressthe effect of tamoxifen on other estrogen target tissues as well as individualpatient risk factors for side effects.[3]

Beneficial Bone and Cardiovascular Effects: Bone fractures dueto loss of mineral density cause substantial morbidity and mortality inpostmenopausal women.[2] Tamoxifen therapy for more than one year appearsto be associated with increased bone mineral density and in some studiesdecreased fracture rates. Tamoxifen may be as efficacious as estrogen replacementtherapy 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 cardiacdisease 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 therapydue to side effects.[1,2] Side effects are usually limited to those associatedwith tamoxifen's antiestrogenic properties; for example, hot flashes arethe most frequently experienced side effect, particularly in premenopausalwomen, 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 associatedwith thromboembolic events.[1,2] Although rare at currently used doses,very high doses of tamoxifen, particularly with previous or concurrentcytotoxic therapy, have been associated with retinal changes, keratopathy,and optic neuritis.[2]

The results of laboratory studies in rats have indicated that high dailydoses of tamoxifen administered over a significant portion of the lifespanare hepatocarcinogenic. However, clinical observations and epidemiologicevidence do not support an increased risk for liver tumors in patientstreated with tamoxifen.[1-3,41]

Tamoxifen administration appears to produce a modest increase in riskfor 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 prognosisis not increased with tamoxifen therapy. Tamoxifen may have a causativeor stimulatory role. The general consensus of the medical community isthat the benefits of tamoxifen in patients with breast cancer clearly outweighthe risk of endometrial carcinoma.[1-3,41] Whether the risk/benefit ratiois sufficient for administration of tamoxifen as a chemoprotective agentin healthy women at high risk for breast cancer remains to be determined.

Conclusions

Over the last 20 years, tamoxifen has become the most widely used endocrineagent for the management of advanced breast cancer in both pre- menopausaland postmenopausal women. In addition, tamoxifen is considered to be theadjuvant agent of choice for postmenopausal women with node-positive diseaseor good risk node-negative disease at high risk for recurrence. In addition,tamoxifen-chemotherapy combinations are another viable option for premenopausalor postmenopausal women with node-positive disease or high-risk, node-negativedisease. However, the chemotherapy agents must be chosen with care sincenot all combinations provide beneficial results.

Controversy still exists in the medical community as to tamoxifen'srole in premenopausal women with node-positive disease or high-risk, node-negativedisease. However, the results of the EBCTCG analysis indicate that estrogenreceptor status may be a better indicator than either menopausal or nodalstatus when determining the clinical role of tamoxifen.

While tamoxifen remains the agent of choice in the medical managementof breast cancer, many issues still need to be resolved regarding the optimumduration of tamoxifen therapy and its potential use as a chemoprotectiveagent in healthy women at high risk for breast cancer.

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