Increased Risk Of Cancer Found In Women Who Have Discontinued Therapy With Estrogen Plus Progestin

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Main Category: Endocrinology
Also Included In: Breast Cancer;  Cancer / Oncology;  Women's Health / Gynecology
Article Date: 14 Mar 2008 - 0:00 PDT

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Women who discontinue a hormone therapy involving estrogen and progestin may have an increased risk of cancer, according to a study published in the March 5, 2008 issue of JAMA. The women had participated in a clinical study related to this therapy, and were compared to the women in the placebo group of the study. Risk of cardiovascular disease and of fracture were similar between the two groups, but the global risk index, which combines many endpoints including death, was higher in the women who participated in the therapy.

The hormone therapy was given as a part of the Women's Health Initiative (WHI) trial, in which estrogen and progestin were administered to healthy, post menopausal women between 1993 and 1998. Specifically, the study used conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA). An evaluation was performed of the therapy's effects on heart disease, hip fractures, and breast cancer risks. When it was found that there was an increased risk of breast cancer coupled with a lack of overall health benefit, the study was discontinued. Additional analysis showed that women in the group taking CEE plus MPA actually had a higher risk of cardiovascular disease, coronary heart disease, stroke, and venous thromboembolism, but lower risks of fracture and colorectal cancer.

Gerardo Heiss, M.D., of the University of North Carolina, Chapel Hill, N.C., and colleagues investigated the effects in a follow-up study between July 2002 and March 2005, after the women had stopped the hormone therapy. Of the 16,608 women in the original study, 15,730 were examined. For this time period, it was found that:

• Annualized event rates for all types of cancer was higher for the CEE plus MPA group (1.56% each year) than in the placebo group (1.26% each year.) This is a reflection of increased instances of invasive breast cancer and others.
• Risk of breast cancer was elevated in the CEE plus MPA group, but not at the levels experienced in the trial.
• Rates of endometrial cancer were lower in the CEE plus MPA group.
• Rates of colorectal cancer did not differ significantly between the two groups.
• Annualized event rates for cardiovascular events were comparable between the CDD plus MPA group (1.97%) and placebo (1.91%).
• Risk of hip, vertebral, and other osteoporotic fractures was similar between the two groups.
• Rates of death from all causes was 15% higher in thr CEE plus MPA group, but this was not statistically significant.

These results indicate that effects, risks and benefits alike, that were present during the trial period weakened after the drugs were discontinued.

The global index summarizes the risks and benefits, including outcomes for coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death from other causes. The investigators found that the global index was 12% higher in women in the CEE plus MPA group in comparison to the placebo. This did not change significantly once intervention was discontinued.

The authors conclude with a cautionary comment for patients who have experienced this therapy. "This analysis of delayed and sustained health benefits and risks following randomized allocation to CEE plus MPA vs. placebo adds new information to inform the optimal use of postmenopausal CEE plus MPA. Over the course of [an average of] 2.4 years from termination of intervention with CEE plus MPA, rapid changes in hormone therapy�"related risks and benefits were observed, as well as trends that suggest that continued follow-up of the study participants of this trial will be informative as regards possible delayed effects of CEE plus MPA." The continue: "Following termination of use of CEE plus MPA of 3.5 to 8.5 years, clinical vigilance seems warranted with respect to a sustained higher risk of malignancies."

Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin
Gerardo Heiss, MD; Robert Wallace, MD; Garnet L. Anderson, PhD; Aaron Aragaki, MS; Shirley A. A. Beresford, PhD; Robert Brzyski, MD; Rowan T. Chlebowski, MD; Margery Gass, MD; Andrea LaCroix, PhD; JoAnn E. Manson, MD; Ross L. Prentice, PhD; Jacques Rossouw, MD; Marcia L. Stefanick, PhD; for the WHI Investigators
JAMA. 2008;299(9):1036-1045.
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Written by Anna Sophia McKenney
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