Update on menopause: An expert’s insight on pivotal studies
Confusion about what to do—on the part of both physicians and patients—may be the greatest consequence of recent studies.
In this randomized, double-blind, placebo-controlled trial, 16,608 women were assigned to either EPT (0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate) or placebo; none of the women had undergone a hysterectomy.
After an average follow-up of 5.6 years:
- There were 20 cases of invasive ovarian cancer in the EPT group (n = 8,506) and 12 cases in the placebo group (n = 8,102). Compared with placebo, the hazard ratio (HR) for invasive ovarian cancer among EPT recipients was a nonsignificant 1.58 (95% CI, 0.77-3.24 [adjusted 95% CI, 0.59-4.23]).
- For endometrial cancer, 27 and 31 cases occurred, respectively, which translated statistically to a nonsignificant hazard ratio for EPT recipients of 0.81 (95% CI, 0.48-1.36).
- For cervical cancers, 8 and 5 cases were reported, respectively, with a nonsignificant HR of 1.44 (95% CI, 0.47-4.42).
COMMENT
Bias against hormone therapy?
The authors concluded that EPT may increase the risk of ovarian cancer but has no significant effect on the risk of endometrial cancer. They commented, however, that, since the EPT arm of the trial was prematurely stopped, the precision of the results is limited and examination of longer-term exposure is precluded.
This paper once again raises the question of whether the writers of the WHI trial have a bias against hormone therapy. In this report, the EPT arm of the WHI trial had an observed annual incidence of 34 ovarian cancer cases per 100,000 person-years—somewhat less than the anticipated population-based rate of 45 per 100,000 person-years. In the authors’ words, the ovarian cancer rate in the EPT group “was elevated (HR 1.58; 95% CI 0.77-3.24 [adjusted 95% CI, 0.59-4.23]) but not statistically significant.” The Kaplan-Meier estimates of cumulative hazards also did not reach statistical significance. Yet in the conclusion of the abstract, the authors state that continuous combined EPT “may increase the risk of ovarian cancer while producing endometrial cancer rates similar to placebo.”
Regarding the conclusion on endometrial cancer risk, the observed incidence for EPT users was 62 per 100,000 person-years, which is also lower than the anticipated population-based rate of 83 per 100,000 person-years. The authors state that this was a “small, nonsignificant reduction” in endometrial cancer risk (HR 0.81; 95% CI, 0.48-1.36). Yet, in the conclusion, while claiming that the nonsignificant difference in ovarian cancer suggests an increased risk, the authors do not state that the nonsignificant reduction in endometrial cancer suggests a decreased risk.
What do the authors expect us to believe, their data or their conclusions? My interpretation of the data in this article is that ovarian and uterine cancers need not be of major concern when determining a woman’s risk-benefit ratio for hormone therapy.
A retraction. Of interest, when this issue was raised in subsequent JAMA correspondence, the WHI authors agreed—representing perhaps the first time that a WHI report publicly retracted a potentially biased conclusion.1,2
Fewer biopsies will be needed with lower dosage. It is not surprising that women taking hormonal therapy containing estrogen had more bleeding and, therefore, more endometrial biopsies than women taking placebo, because a known effect of estrogen is proliferation of the endometrial lining. With the lower-dose hormonal preparations currently available (which result in lower systemic estrogen levels and less endometrial stimulation), uterine bleeding episodes in menopausal hormone therapy users should diminish, along with the number of endometrial biopsies.
1. Utian WH. Hormone therapy and risk of gynecologic cancers [letter]. JAMA. 2004;291:42.-
2. Anderson GL, Judd HL, Kaunitz AM, et al. Hormone therapy and risk of gynecologic cancers—Reply. JAMA. 2004;291:43.-
MILLION WOMEN STUDYBreast cancer risks increased by estrogen plus progestogen
Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419–427.
- LEVEL II-2 EVIDENCE: COHORT OR CASE-CONTROLLED
A total of 1,084,110 women aged 50 to 64 were enrolled between May 1996 and March 2001 and followed to the study finish (end of 2002). Mean follow-up was 2.6 years for breast cancer incidence and 4.1 years for mortality. Nearly half of the women had used postmenopausal hormone therapy, either estrogen therapy alone (ET) or EPT. Primary endpoints were diagnosis of breast cancer and death from breast cancer.
Current ET or EPT use (compared with nonuse) was associated with a statistically significant increased risk of both breast cancer incidence (RR, 1.66; 95% CI, 1.58-1.75) and breast cancer mortality (RR, 1.22; 95% CI, 1.00-1.48). Past use did not increase the risk of incident (RR, 1.01; 95% CI, 0.94-1.09) or fatal disease (RR, 1.05; 95% CI, 0.82-1.34), and the risk decreased with time since last use.
