02.12.2015
Action Points
- Menopausal hormone therapy (HT) conferred a “small but real” risk of ovarian cancer in women who used it for at least 5 years.
- Note that the association pertained to the two most common types of ovarian cancer — serous and endometrioid — but not mucinous or clear-cell tumors.
Menopausal hormone therapy (HT) conferred a “small but real” risk of ovarian cancer in women who used it for at least 5 years, a review of more than 50 studies showed.
The analysis showed an ovarian cancer risk on the order of one in 800 to one in 1,000 women treated for 5 years. The risk increased with duration of HT.
The association pertained to the two most common types of ovarian cancer — serous and endometrioid — but not mucinous or clear-cell tumors, British investigators reported online in The Lancet.
The study provides the statistical power to resolve a longstanding controversy that had been fueled by inconsistent findings from individual studies, said Richard Peto, FRCP, of the University of Oxford.
“What’s new is that just a few years of postmenopausal hormone therapy definitely produces some increase in risk,” Peto toldMedPage Today. “It had been claimed that 5 years, for example, would just be completely safe, and this isn’t correct. We’ve got the data more reliably than previously because it’s mainly from prospective studies.”
“If you restrict attention to just the prospective studies, you get very clear answers,” he added. “The two commonest types of ovarian cancer are moderately increased.”
Controversial History
Dozens of epidemiologic studies have examined the relationship between HRT and ovarian cancer. Half of the studies remain unpublished. Among published studies, retrospective evaluations are limited by the potential for participation and recall bias, Peto and co-authors noted in their introduction to the journal article.
In an effort to clarify the association, investigators searched for prospective and retrospective investigations of menopausal HT and ovarian cancer. The search included published data, written communications, and presentations and discussions at scientific meetings.
Eligible studies had complete information on HT use, parity, and oophorectomy and hysterectomy. Studies completed after 2006 had at least 200 cases of ovarian cancer.
The investigators excluded studies with incomplete information for any of the key clinical characteristics and outcomes. Data analysis included 52 studies (17 prospective, 35 retrospective), all but one of which had individual patient data available for analysis. As many as four randomly selected control participants were matched with each case.
Information about HT included ever use, current use, age at first and last use, total duration of HT, and the hormonal composition of therapy used. Tumors were categorized as fully or borderline malignant and epithelial or not. Epithelial tumors were further classified as serous, endometrioid, mucinous, or clear cell.
The search identified 21,488 postmenopausal women with ovarian cancer. The 17 prospective studies accounted for 12,110 of the cases, mean year of diagnosis of 2001, prevalence of HT of 55% (6,601 participants), and median duration of HT of 6 years. In the retrospective studies, 29% (2,702) of the women reported ever using HT, median duration of use was 4 years, and mean year of diagnosis was 1992 (years before use of menopausal hormones peaked).
Overall Risk
Overall, women who reported any use of menopausal HT had a 14% higher relative risk of ovarian cancer as compared with never users (RR 1.14, 95% CI 1.10-1.19, P<0.0001). Data from the prospective studies yielded a slightly higher risk (RR 1.20, 95% CI 1.15-1.26, P<0.0001).
The recency of HT influenced cancer risk. Defining recent use as within the past 5 years, investigators found significantly larger differences versus never users. In the prospective studies, women reporting current or recent HT had relative risk of 1.37 for ovarian cancer compared with never users.
The significant difference between current-recent users and never users disappeared in the analysis of retrospective studies (HR 1.04, 95% CI 0.93-1.16). The difference between the prospective and retrospective studies was significant (P<0.0001 for heterogeneity).
Analysis of results by tumor histology showed a relative risk of 1.40 for serous tumors and 1.28 for endometrioid tumors in the comparison of current-recent users versus never users. The results held up in separate analyses of prospective studies and type of hormonal therapy (unopposed estrogen or estrogen-progestin combinations).
The relative risk of mucinous and clear-cell ovarian cancer was slightly lower in current-recent HT users (RR 0.80). In the analysis of prospective studies, the risk reduction remained significant only for clear-cell tumor histology (RR 0.75, 95% CI 0.57-0.98).
Duration of HT significantly influenced the risk of ovarian cancer. Five years of therapy was associated with an excess ovarian cancer incidence of one case per 1,000 users, increasing to one case per 600 users when duration of HT increased to 10 years. The excess of ovarian cancer mortality was one per 1,700 users for 5 years of HT and one per 800 users for 10 years of treatment.
Perspective and Context
To put the risk into perspective, Peto compared the study findings to similar data for smoking and cancer risk.
“If a 50-year-old woman smokes and she continues to smoke, then there’s more than a 50% chance that she will be killed by tobacco,” he said. “If she stops, even at the age of 50, then she will avoid most of that risk. If a thousand smokers stopped smoking at age 50, then about 500 deaths from smoking would be avoided.
“If a thousand women age 50 were to take hormone therapy for menopause for 5 years, one ovarian cancer would be caused. So, in comparison with smoking cessation, there is about a 500-fold difference.”
The modest increase in ovarian cancer risk should be considered within the context that 5 million women in the U.S. are HT users, Peto continued. That translates into about 1,000 excess cases of ovarian cancer each year.
Though acknowledging the strength of the new data, authors of an accompanying commentary cautioned that the findings will not end the debate over HT and ovarian cancer risk.
“In the context of the observational data presented in this study, it is still not clear whether the current recommendation to use hormone therapy for the shortest duration possible is appropriate for women who are concerned about an increased risk of ovarian cancer,” said Nicolas Wentzensen, MD, PhD, and Britton Trabert, PhD, of the National Cancer Institute.
They based their assessment on the relatively uncommon occurrence of ovarian cancer in association with HT, as compared with breast cancer and cardiovascular disease, both of which have more established associations with menopausal hormone therapy. HT use has stabilized — but not increased — since a dramatic decline beginning in 2000, prompted by evidence of adverse effects from the Women’s Health Initiative. The current patterns of use will make it even more difficult to reach a definitive conclusion for HRT and ovarian cancer risk.
Otis Brawley, MD, chief medical officer of the American Cancer Society, called the study “a fine piece of work and appropriately points out that it establishes correlation but cannot distinguish causality. It is my own view that postmenopausal hormones were introduced in the post-World War II era without adequate study … . The Lancet study is another reason to discourage the use of postmenopausal hormones and support doing good science before we widely disseminate something that seems good.”
The study underscores the need for careful discussion between patients and clinicians regarding the use of postmenopausal hormones, said Cheryl Iglesia, MD, of MedStar Washington Hospital Center, adding that the results speak directly to the current dictum about using the lowest dose for the shortest period of time.
Despite the study’s statistical strengths, the results should be considered with the recognition of what they don’t address, as well as what they do address, she told MedPage Today. The analysis excluded women who had hysterectomies and/or oophorectomies before age 55, a group that deserves special consideration with regard to menopausal HT.
“We have done a disservice to that group of women,” said Iglesia, who chairs the committee on patient education for the American College of Obstetricians & Gynecologists (ACOG). “They have had hysterectomy or had their ovaries and their Fallopian tubes removed for reasons unrelated to cancer as early as age 35 or 40.
“These women really do need estrogen replacement for hot flashes and cardiovascular risk and other factors, and ACOG has a position paper on that.”
Women also have multiple options in terms of formulations and doses of HT, including topical preparations, that might not have the same risks as those associated with systemic preparations, Iglesia added. Those issues were not addressed in the study.
The study was supported by the Medical Research Council and Cancer Research U.K.
The authors disclosed no relevant relationships with industry.
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