Results of some individual trials show promise.Among the phytoestrogen trials, the authors note theirfindings (4 studies showing benefit) are similar to resultsof a systematic review published in 2004 (N � 2348).This information at least provides a point of reference forcertified nurse-midwives/certified midwives (CNMs/CMs) advising women on what may be worthwhile totry.

The tables in this article can be used as working toolsto educate CNMs/CMs and our clients about specificareas of CAM with respect to treatment of menopausalsymptoms. CNMs/CMs can continue to discuss withwomen what therapies are being used, with what expec-tations and at what costs. As it becomes available,CNMs/CMs need to share information about CAM ther-apies and safety risks, including possible drug interac-tions. The Clinical Trials portion of the NCCAM Website (http://nccam.nih.gov/clinicaltrials/) is a valuableresource that clinicians and savvy clients can use toupdate their working knowledge of study findings, theresults of completed trials, and the recruitment of volun-teer subjects.

ADDITIONAL REFERENCES

1. Committee on the Use of Complementary and AlternativeMedicine by the American Public. Complementary and AlternativeMedicine in the United States. Washington, DC: National Acad-emies Press, 2005.

2. Greene JG. Constructing a standard climacteric scale. Matu-ritas 1998;29:25–31.

3. Heinemann LA, Potthoff P, Schneider HP. International ver-sions of the Menopause Rating Scale (MRS). Health Qual LifeOutcomes 2003;1:28.

RALOXIFENE WORKS AS WELL AS TAMOXIFEN TO REDUCETHE RISK OF BREAST CANCER

Vogel VG, Costantino JP, Wickerham DL, Cronin W, Cecchini RS,Atkins J, et al. Effects of tamoxifen vs raloxifene on the risk ofdeveloping invasive breast cancer and other disease outcomes.JAMA 2006;295:2727– 41.

Reviewd by: Sharon Bond, CNM, APRN-BC

BACKGROUND

The American Cancer Society estimates that in 2006,there will be 212,920 diagnoses of invasive breast cancerleading to approximately 41,000 deaths among women inthe United States.1 This study, carried out by the NationalSurgical Adjuvant Breast and Bowel Project (NSABP),presents results from a large clinical trial designed tocompare safety and efficacy of raloxifene (Evista; EliLilly and Company, Indianapolis, IN) with tamoxifen(Nolvadex; AstraZeneca Pharmaceuticals LP, Wilming-ton, DE). The outcomes contrasted risks of developinginvasive and non-invasive breast cancer, uterine cancer,

other malignancies, fracture, heart disease and thrombo-embolic events for almost 20,000 postmenopausalwomen at high-risk for breast cancer in 200 clinicalcenters across the United States between 1999 and 2005.

Earlier placebo comparison studies by NSABP sup-ported the use of tamoxifen in reducing breast cancer by50%.2 Potential health risks of tamoxifen, such as thesomewhat greater likelihood of endometrial cancer,thromboembolic disease, and stroke, were believed to besmall relative to its benefits. Its use was approved by theUnited States Food and Drug Administration (FDA) inOctober 1998. Despite its approval, the drug has not beenas widely prescribed as was expected, perhaps because ofconcerns over adverse effects and other barriers.2 Duringthis time, scientists noted that in other clinical trials,raloxifene, typically prescribed for treatment of osteopo-rosis, revealed a coincidental effect in reduction ofinvasive breast cancer. Hence the NSABP’s Study ofTamoxifen and Raloxifene (STAR) trial to compare thedrugs head-to-head. Tamoxifen and raloxifene belong toa class of drugs known as selective estrogen receptormodulators (SERMs).

METHODS

STAR was a randomized, double-blinded trial (neitherclinicians nor participants knew which drug was beingused) among postmenopausal women having a 1.66%predicted risk of breast cancer within 5 years accordingto the Gail Model. Other medical and surgical criteriawere designated for inclusion in the study. At the time ofenrollment, the average age of women in the study was58 years, with 9% younger than 50 and more than 41%over the age of 60. The majority of subjects were white(93%). Fifty percent reported having had a hysterectomybefore participation in the study. Once informed consentwas obtained, women were randomized to receive eithertamoxifen or raloxifene for a 5-year period.

Subjects were followed every 6 months for 5 years.Visits consisted of clinical breast exams with mammog-raphy, gynecologic exams, and blood work every 6months or at least annually. Interim information wasconfirmed by medical records documenting conditionsvia surgical or pathology reports, hospital dischargesummaries, etc. At study visits, subjects reported anysymptoms and were assessed for quality of life concerns.The study used the Medical Outcomes Study Short-Form36, the Center for Epidemiologic Studies-DepressionScale, and the Medical Outcomes Study Sexual Func-tioning Scale as measurement instruments. Continuationrates in the study were higher than researchers hadestimated (between 68–72%). Subjects who were lost tofollow-up (605 from tamoxifen group and 532 fromraloxifene group) contributed about 2 years of informa-tion before becoming lost to follow-up.

The critical outcome for the study was invasive breast

Journal of Midwifery & Women’s Health • www.jmwh.org 175

cancer. Other disease outcomes included non-invasivebreast cancer, endometrial cancer, heart disease and othervascular events, fracture, quality of life issues, andcataracts. Subjects were monitored by an independentcommittee of expert clinicians, ethicists, epidemiologists,biostatisticians, and a consumer representative lookingfor differences between the tamoxifen and raloxifenegroups. A predetermined number of events, occurring ineach outcome area, served as a signal to the researchersthat the two drugs would be essentially equivalent at a95% level of probability.

RESULTS

The most important findings show that, with respect tothe incidence of invasive breast cancer, there were nodifferences between tamoxifen and raloxifene groups byeither subject or tumor characteristics. There were fewernon-invasive breast cancers in the tamoxifen group, butthis finding was not statistically significant. With respectto uterine cancers, there were no differences betweengroups, yet there were indications that the raloxifenegroup had less endometrial hyperplasia and fewer hys-terectomies. There were no statistically significant differ-ences between the two groups with respect to any othertype of cancer or in the incidences of ischemic heartdisease or stroke. The raloxifene group experiencedsignificantly fewer episodes of pulmonary embolism anddeep vein thrombosis. There was no difference betweengroups with respect to fractures of the hip, spine, andwrist. Women in the raloxifene group experienced sig-nificantly fewer cataracts than those in the tamoxifengroup. No differences were demonstrated betweengroups concerning self-reported quality of life issues.The number and causes of death between both groupswere similar during the course of the study.

STRENGTHS AND LIMITATIONS

The sheer size and design (prospective, randomized, anddouble-blinded) of this study allow the researchers tomake an authoritative statement about the equivalency oftamoxifen and raloxifene in the prevention of invasivebreast cancer among high-risk women. They have dem-onstrated negligible differences between the two drugs inincidence of other cancers and vascular events. Conse-quently, another choice has emerged as an alternative to

tamoxifen that can be considered in a discussion withone’s primary care provider.

The authors were clearly disappointed by efforts torecruit women of color in numbers sufficient to reflect theeven higher risks of breast cancer in African Americanwomen, for example, because race and ethnicity arefactors in estimating breast cancer risk. Only 2.5% ofparticipants were African American, another 2.0% His-panic, and the remaining 2.5% were comprised of otherethnic groups. The recruitment of women of color intoresearch studies has been problematic. Hopefully thisrecognition will cause researchers entrusted with expend-ing resources to investigate important health problems tocarefully consider specific methods to enroll and main-tain participation among populations of color. Limita-tions such as this can impede generalizability and hinderstudies about the effects of tamoxifen and raloxifene inbreast cancer prevention in other populations. Presently,there is not enough information to state how long therapyshould continue in order to fully benefit from the drug’sprotective effects, but studies are continuing.

SIGNIFICANCE FOR MIDWIFERY PRACTICE

One possible barrier to the widespread use of tamoxifen,in spite of its proven benefit, may be its reputation as acancer drug, resulting in less familiarity among preven-tion-focused primary care providers. Alternatively,raloxifene has been widely prescribed by primary careproviders for prevention and treatment of osteoporosisand consequently is more familiar to a larger group ofprescribers. If prevention of invasive breast cancer be-comes another FDA-approved indication for raloxifene,it may result in better breast cancer prevention simplybecause of its wider use. Many certified nurse-midwives/certified midwives (CNMs/CMs) routinely care for peri-and postmenopausal women. Raloxifene, familiar tomany, now has a possible role in the chemoprevention ofbreast cancer. CNMs/CMs can share this knowledgeabout the potential benefits of raloxifene and its efficacyin reducing the impact of breast cancer. In many cases,CNMs/CMs will be the prescribers.

REFERENCES1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al.

Cancer statistics, 2006. CA Cancer J Clin 2006;56:106–30.

2. Gradishar W, Cella D. Selective estrogen receptor modulatorsand prevention of invasive breast cancer. JAMA 2006;295:2784–6.

176 Volume 52, No. 2, March/April 2007