Barton, Loprinzi, and Gostout provide a comprehensive, accurate, and multidisciplinary review of the management of menopausal symptoms in patients with a previous diagnosis of cancer. The article is clearly enhanced by the authorship of individuals from different backgrounds, each of whom bring a valuable perspective to the subject. Additional attention to several issues would, however, make interpretation of the data on this subject, and hence, the management of patients with these problems, more clear.
Barton, Loprinzi, and Gostout provide a comprehensive,accurate, and multidisciplinary review of the management of menopausal symptomsin patients with a previous diagnosis of cancer. The article is clearly enhancedby the authorship of individuals from different backgrounds, each of whom bringa valuable perspective to the subject. Additional attention to several issueswould, however, make interpretation of the data on this subject, and hence, themanagement of patients with these problems, more clear.
Observational vs Randomized Trial Data
First, it is important to distinguish between data obtained fromobservational trials and data obtained from randomized intervention trials. Theauthors discuss the results of both types of trials with little differentiation.They are not, of course, the first or the only to mix these levels of evidencewith insufficient distinction. They do point out, however, that the fewrandomized trials of estrogen replacement therapy (ERT) for coronary arterydisease produced results that were quite different from those obtained from along series of observational studies.
Observational data have repeatedly shown an association between the use ofestrogen replacement therapy (ERT) or estrogen and progesterone replacementtherapy (hormone replacement therapy, or HRT) and a reduced incidence ofmyocardial infarction and/or death from cardiac disease. This phenomenon wasbelieved to be explicable by documented changes in levels of low-densitylipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol in womenreceiving estrogen therapy, and perhaps by other beneficial effects on vessels,platelets, and myocardium.
At least one trial of secondary prevention following one cardiac event,however, has shown that women randomized to receive ERT actually experience anincreased number of cardiac events in the first year following randomization(although they may experience fewer subsequent events, such that these effectsmay balance out over 3 to 4 years). In addition, an overview analysis of cardiacend points in randomized trials of HRT with other primary end points has shownno significant reduction in cardiac events. Patients in such studies arebeing followed further to ascertain their ultimate outcome. Similar results havebeen seen with the use of estrogen as primary prevention in the Women’s HealthInitiative. In that trial, women randomized to receive ERT or HRT experiencedan increased number of cardiac events in the first 18 months to 2 years but thenexperienced fewer subsequent events.
Treatment Standards Overturned
The contradictory data in this field are a frightening demonstration of theway in which the dogma of many years, based on observational studies, can beoverturned by trials of stronger methodologic design. It has previously beenwell appreciated that women who use ERT/HRT assume much different health-seekingbehaviors than women who do not. Women who use ERT/HRT are known to seephysicians more frequently, have more gynecologic exams and Pap smears, be morelikely to exercise, weigh less, and pursue different diets. Thus, theassociation between ERT/HRT and reduced cardiac events may not be acause-and-effect issue.
Similarly, the literature on ERT and cognition is based almost completely onobservational studies. Clearly women who have better cognition may also be morelikely to seek out or adhere to prescribed medication including ERT/HRT.Furthermore, many other health-seeking behaviors could be the cause of, orcaused by, improved cognition. Thus, at this point, it would be useful toseparate observational data from randomized interventional data, giving a higherweight to data obtained in the randomized setting.
Using this model, it is interesting to examine the evidence presented by theauthors in terms of how much is obtained from randomized trials. Clearly theauthors’ own data on alternatives to ERT/HRT for control of hot flashes areexemplary in this regard. Dr. Loprinzi has, in a series of short but efficientrandomized trials, delineated the role of a variety of alternatives to ERT inthe control of vasomotor symptoms. Similarly, many of the findings on raloxifene(Evista), ERT/HRT, and bisphosphonates for the prevention and treatment ofosteoporosis are obtained from randomized controlled intervention trials.
Data on the role of ERT/HRT in the management of skin health, vaginaldryness, and urinary incontinence, however, are largely based on less rigorousmethodology and should, therefore, be viewed with more skepticism. Similarly,data on exercise and its effects on health, while seeming logical enough, arebased almost completely on noninterventional studies.
Medroxyprogesterone in Women With Breast Cancer
A second issue worthy of comment is the role of medroxyprogesterone astreatment for hot flashes in women with a previous diagnosis of breast cancer.As with estrogen, there is much literature based on in vitro and animal modelssuggesting that progesterone is important in the development and maintenance ofbreast cancer. Although in vitro and animal models are not as consistentlydependent on progesterone as on estrogen, many such models do showprogestational agents to be pivotal in the development and progression of breastcancer. In some models, however, progesterone is associated with breast celldifferentiation and may, therefore, reduce breast cancer development and growth.
There is also much observational literature showing that continuous menstrualcycling, which involves both estrogen and progesterone peaks, is clearlyassociated with an increased incidence of breast cancer. For example, earlymenarche, late menopause, and no pregnancies are clearly linked to increasedbreast cancer risk. Just what it is about this continuous cycling that raisesthe risk of breast cancer is not clearly understood. It is also increasinglyclear, however, at least from observational literature, that the addition ofprogesterone to ERT is associated with a greater increase in the risk ofdeveloping breast cancer.[4-7]
Thus, in my view, the same caution should be used in prescribing progesteroneto women following a diagnosis of breast cancer as is felt to be appropriatewith estrogen. I disagree with the belief that because medroxyprogesterone hasbeen used as a treatment for breast cancer, it is, therefore, safe for womenwith a previous diagnosis of breast cancer. At least one of the authors of thisreview is, like myself, old enough to remember when estrogen, in the form ofdiethylstilbestrol, was also used to treat postmenopausal breast cancer. Doesthis mean that estrogen is not associated with the development and perhapsrecurrence of breast cancer? I do not think so.
It is not well understood why estrogen can be both a treatment and acausative factor for breast cancer, but its usefulness as therapy may relate tothe observation that, in high doses, it acts as a pharmacologic antiestrogen.Similarly, high doses of medroxyprogesterone for the treatment of breast cancerhave been shown to cause reduced serum estrogen levels, which may explain themechanism of action of this agent as therapy for breast cancer. However, thisassociation may not be the same with the lower doses of medroxyprogesterone usedto prevent hot flashes. Clearly, this matter needs to be investigated further,preferably in randomized controlled clinical trials, before we can accept thatprogestational agents in any dose are safe in women with a previous diagnosis ofbreast cancer.
Nonetheless, this article provides an evidence-based, practical summary ofthe options available to treat menopausal symptoms in women with a previousdiagnosis of cancer. The authors are to be congratulated both on their excellentcontributions to the literature, based on interventional randomized trials inthe area of hot flashes, and on producing this useful summary of the subject.
1. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plusprogestin for secondary prevention of coronary heart disease in postmenopausalwomen. For the Heart and Estrogen/progestin Replacement Study (HERS) ResearchGroup. JAMA 280:605-613, 1998.
2. Hemminiki E, McPherson K: Impact of postmenopausal hormone therapy oncardiovascular events and cancer: Pooled data from clinical trials. Br Med J315:149-153, 1997.
3. The Women’s Health Initiative Study Group: Design of the Women’sHealth Initiative clinical trial and observational study. Control Clin Trials19:61-109, 1998.
4. Schairer C, Lubin J, Troisi R, et al: Menopausal estrogen and estrogen-progestinreplacement therapy and breast cancer risk. JAMA 283:485-491, 2000.
5. Colditz GA, Rosner B, Nurses Health Study Research Group: Use of estrogenplus progestin is associated with greater increase in breast cancer risk thanestrogen alone. Am J Epidemiol 147:645, 1998.
6. Persson I, Weiderpass E, Bergkvist L, et al: Risks of breast andendometrial cancer after estrogen and progestin replacement. Cancer CausesControl 10:253-260, 1999.
7. Ross RK, Paganini-Hill A, Wan PC, et al: Effect of hormone replacementtherapy on breast cancer risk: Estrogen vs estrogen plus progestin. J NatlCancer Inst 92:328-332, 2000.