WHI Follow-Up Report
WHI Follow-Up Report
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: A 3-year follow-up report of the cancelled estrogen-progestin arm of the WHI finds no increase in cardiovascular events, a nonsignificant increase in breast cancer, and an increase in lung cancers during the follow-up period.
The Women's Health Initiative investigators reported health outcomes at 3 years after the estrogen-progestin arm of the clinical trial was canceled.1 This report includes 15,730 participants who were followed from July 2002 to April 2005 (95% of randomized women). Follow-up information was missing for 389 women. No increase in cardiovascular events, including venous thrombosis, in the women treated with estrogen-progestin was observed in the follow-up period. There were 79 cases of invasive breast cancer in the treated group in the follow-up period compared with 60 in the placebo group, a difference that gave a hazard ratio of 1.27, but it was not statistically significant (CI = 0.91-1.78). There was no difference in cases of colorectal cancer or fractures and a nonsignificant decrease in endometrial cancer in the treated group. There was a greater rate of mortality in the treatment group in the follow-up period, but this difference was small and not statistically significant (the number was influenced by a larger number of lung cancers in the treated group).
Commentary
This is the first of many anticipated follow-up reports from the canceled hormone therapy trials in the Women's Health Initiative (WHI). The WHI investigators, in the manner in which their report is written, convey the impression generated by the initial WHI reports that overall an adverse effect is observed with estrogen-progestin treatment. In my view, this far-reaching statement is not totally accurate in the two areas of controversy, cardiovascular disease and breast cancer.
By now the limitations of the WHI are familiar to most clinicians, specifically that the results apply to an older population of women (average age: 63, average number of years from menopause: 15). The latest report on coronary heart disease in the WHI confirms what could be seen in the initial reports, mainly that an increase in coronary events occurred only in the oldest women in the study.2 This follow-up report continues the mode of writing in the early WHI reports, generalizing findings limited to a specific elderly population to all postmenopausal women. The WHI investigators don't use these exact words, but the implication is clear, it seems to me, when they state that their assessment after the period of follow-up continues to be "weighted toward risk." An accurate appraisal would have spelled out in plain language that the stroke risks were increased only in women over age 60 or women with existing risks for stroke and that coronary events were increased only in women who were 70 years of age and older when they started treatment.
Let's give them the benefit of the doubt, and assume that the overall negative assessment hinged on the breast cancer results. Indeed, the investigators state that the results in the follow-up period are consistent with the results found during the treatment period. However, in the most recent previous WHI report on the subject, the investigators were compelled to perform multiple adjustments because of breast cancer risk factor differences between the treated and placebo groups.3 After these adjustments, the hazard ratio of 1.20 was no longer statistically significant. In their discussion, the WHI investigators expressed their "puzzlement" regarding these differences; why did not a randomized trial of this magnitude produce a balance in breast cancer risk factors in the two groups? A closer look at the treated group compared with the placebo group reveals an expected age-related increase in breast cancer in the treated group and no age-related increase in the placebo group. One would expect these differences to be on-going, and thus explain a lower rate of breast cancers in the placebo group in the follow-up report.
I continue to believe that a strong case can be made that the epidemiologic data on breast cancer reflect an impact of hormone therapy on preexisting tumors. This WHI follow-up report concludes that the trend of increasing breast cancer during the trial period did not extend into the follow-up period. This is the pattern one would expect if hormone therapy is causing earlier detection of pre-existing tumors only in current users.
This report has an overall negative impact, but this adverse interpretation is based on a small and nonsignificant increase in mortality in the treated group, because of deaths from various cancers, but most prominently lung cancers. In the discussion, the WHI investigators raise another warning flag about hormone therapy by referring to a retrospective chart review study in which postmenopausal hormone therapy was associated with decreased survival in women with lung cancer.4 They should have cited a case-control study from Detroit concluding that hormone therapy is associated with a reduced risk of non-small-cell lung cancer,5 case-control studies from the M.D. Anderson Cancer Center and from Taiwan that found a reduction in lung cancer risk in hormone users,6,7 and two studies that found a protective effect in hormone users against lung cancer especially in smokers.8,9 The lung cancer story is not consistent, with the literature indicating hormone sensitivity in lung cancers, with both harmful and beneficial effects of hormone therapy being reported (perhaps dictated by tumor and patient characteristics).
It is important to note that the protective effect of hormone therapy on osteoporotic fractures was diminished after treatment was discontinued. This reinforces many studies documenting that long-term duration of treatment is necessary to maintain protection against fractures.
The WHI investigators appropriately caution readers regarding interpretation of follow-up data. They recognize that the health care of the subjects in the two groups may have differed considerably after the trial was canceled. They further point out that there was a relatively small number of events in the follow-up period limiting the precision of their analysis.
Overall, this follow-up report continues the public approach taken by the WHI investigators to emphasize in an unbalanced fashion adverse findings, to fail to put negative findings in perspective, and to promote a negative reaction to hormone therapy. It is time for the WHI investigators to overcome their vested interests and to present a balanced point of view that it seems everyone else in the world has been able to acquire.
References
- Heiss G, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299:1036-1045.
- Rossouw JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465-1477.
- Anderson GL, et al. Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin. Maturitas. 2006;55:103-115.
- Ganti AK, et al. Hormone replacement therapy is associated with decreased survival in women with lung cancer. J Clin Oncol. 2006;24:59-63.
- Schwartz AG, et al. Reproductive factors, hormone use, and estrogen receptor expression and risk of non small-cell lung cancer in women. J Clin Oncol. 2007;25:5785-5792.
- Schabath MB, et al. Hormone replacement therapy and lung cancer risk: a case-control analysis. Clin Cancer Res. 2004;10:113-123.
- Chen KY, et al. Hormone replacement therapy and lung cancer risk in Chinese. Cancer. 2007;110:1768-1775.
- Kreuzer M, et al. Hormonal factors and risk of lung cancer among women? Int J Epidemiol. 2003;32:263-271.
- Olsson H, et al. Are smoking-associated cancers prevented or postponed in women using hormone replacement therapy? Obstet Gynecol. 2003;102:565-570.
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