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It’s a familiar scenario: News stories give a quick sound bite linking estrogen use with increased risk for ovarian cancer, and calls pour into clinicians’ offices from worried women who are using some form of hormone replacement therapy (HRT) for menopausal symptoms. What do you tell your patients?
"Neither the Rodriguez study1 nor our work brings with it the need to change the current standard of care," states James Lacey Jr., MPH, PhD, an epidemiologist in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute in Rockville, MD, who is researching
the possible link between ovarian cancer and HRT. "Women should be encouraged to discuss all of the potential risks and benefits of HRT with their health care providers before making an individual decision about whether to use HRT."
Initial concerns were raised with the recent release of research from the Cancer Prevention Study II. The study, coordinated by the American Cancer Society (ACS) in Atlanta, recruited 1.2 million people in 1982 and followed them through 1996. Researchers periodically obtained information from death certificates and tabulated cancer deaths among the participants.
The paper has just been published in the Journal of the American Medical Association by Carmen Rodriguez, MD, MPH, senior epidemiologist in the Epidemiology and Surveillance Research division of the ACS, and colleagues at the society. The report looked at 211,581 postmenopausal women who completed a baseline questionnaire in 1982 and had no history of cancer, hysterectomy, or ovarian surgery at enrollment. The main outcome measure was ovarian cancer mortality, compared among never-users, users at baseline, and former users as well as by total years of use of estrogen replacement therapy (ERT).
A total of 944 ovarian cancer deaths were recorded in 14 years of follow-up. Among the 46,260 women who in 1982 reported having taken estrogen at some point, 255 women had died of ovarian cancer by 1996, compared with 689 of 165,321 nonestrogen-takers also in the study.
Duration of use was associated with increased risk in baseline and former users, according to the researchers’ analysis. Baseline users with 10 or more years of use had a relative risk of 2.20 (95% confidence interval, 1.53-3.17), while former users with 10 or more years of use had a relative risk of 1.59 (95% confidence interval, 1.13-2.25). Scientists concluded that among this study population, postmenopausal estrogen use for 10 or more years was associated with increased risk of ovarian cancer mortality that persisted up to 29 years after cessation of use.
Research eyes HRT link
Look for further evidence to come from the Rockville, MD-based National Cancer Institute, which also is reviewing data on the use of combined hormonal therapy and the risk of ovarian cancer.
"Our findings are generally consistent with the Rodriguez, et al. paper [that] reported that long-term use of estrogen replacement therapy was significantly associated with an increased risk of death due to ovarian cancer," states Lacey, who presented preliminary findings at the recent American Association for Cancer Research conference in New Orleans.2 "Our data suggested that long-term use of estrogen replacement therapy was significantly associated with an increased risk of incident ovarian cancer; however, our data also suggest that use of the combined estrogen-progestin replacement therapy [an issue that was not addressed in the Rodriguez et al. paper] was not associated with ovarian cancer incidence, although we cannot rule out a slight increase in risk associated with the combined estrogen-progestin therapy."
More research is needed on the complex relationships between menopausal estrogens, menopausal progestins, and ovarian cancer, states Lacey.
It is important to understand the differences in current medical practice and those observed during the time of the ACS study’s data collection, says Rodriguez. Today, women who have uterus and ovaries intact use combined HRT with estrogen and progestin. In the 1970s and 1980s, HRT consisted of administration of conjugated estrogens
in high dosages and without added progestins.
The ACS study also did not examine the dose of hormones used, says David Archer, MD, professor of obstetrics and gynecology and director of the Clinical Research Center at the Eastern Virginia Medical School in Norfolk. Current therapy generally employs a lower dose of estrogen.
According to the ACS, about 23,100 new cases of ovarian cancer were estimated to occur in the United States in 2000, which makes it the sixth most common cancer in women.
"The risk of ovarian cancer, the baseline risk, is very low," remarks Rodriguez. "So even if it doubles, we don’t get into a very high likelihood of having the disease."
Susan Wysocki, RNC, NP, president and CEO of the Washington, DC-based National Association of Nurse Practitioners in Women’s Health, agrees that the risk is low. Along with that point, keep the following three in mind, she suggests:
• Even when the risk is increased, the risk remains low.
• The ACS study looked at regimens of HRT that are no longer used today.
• No change in prescribing has been recommended as a result of the research.
Some patients may express concern about use of combined oral contraceptives (OCs) because they also contain estrogen, states Robert Hatcher, MD, MPH, professor of gynecology and obstetrics at Emory University School of Medicine in Atlanta. Remind them that OCs make women less likely to develop ovarian cancer.
"In no way does this study suggest that our current advice to women initiating use of combined oral contraceptives is incorrect, when we say that combined pills have a dramatic protective effect against ovarian cancer," states Hatcher.
Be aware of symptoms
Even though the risk for ovarian cancer is low, it is still important for women and clinicians to be aware of its signs and symptoms, clinicians warn.
Early cancers of the ovary often have no symptoms. Since tumors on the ovary cannot usually be found through a Pap test, only one-fourth of ovarian cancers is found at an early stage, state ACS statistics.
"For ovarian cancer, there’s not a screening [modality] right now," observes Rodriguez. "People have to be very aware of the symptoms, and it can be a very silent kind of disease."
Teach patients about the possible symptoms. (See symptoms, p. 62.) While they often may be caused by other disorders than cancer, it is wise to have them checked out by a health care provider.
Imaging studies, such as computed tomography, magnetic resonance imaging scans, and ultrasound can show whether there is a mass in the pelvis. However, a biopsy must be performed to confirm if the mass contains cancerous cells.
The ACS researchers now are looking at a smaller group of the Cancer Prevention Study II women, those who used a combination of estrogen and progestin for HRT. The data will be examined to see if combination HRT increases the risk for ovarian cancer, as well as if the risk increased for those women who switched from estrogen-only to a combination HRT regimen, says Rodriguez.
Effect on breast cancer?
The scientists also are reviewing the impact of estrogen and combination therapy, as well as the effect of body mass, on the risk for breast cancer, states Rodriguez. The group already released results on the effect of body mass on the association between ERT and mortality among postmenopausal women, in which an analysis examined the association between postmenopausal estrogen use and different causes of death.3 After 12 years of follow-up, analysis results reveal that all-cause death rates were lower among baseline estrogen users than never-users.
1. Rodriguez C, Patel AV, Calle EE, et al. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of U.S. women. JAMA 2001; 285:1,460-1,465.
2. Lacey JV. Ovarian cancer and hormone replacement therapy in a prospective cohort study. Presented at the American Association for Cancer Research. New Orleans; March 25, 2001.
3. Rodriguez C, Calle EE, Patel AV, et al. Effect of body mass on the association between estrogen replacement therapy and mortality among elderly U.S. women. Am J Epidemiol 2001; 153:145-152.
For more information on hormone replacement therapy and ovarian cancer risk, contact:
• Carmen Rodriguez, MD, MPH, American Cancer Society, Epidemiology and Surveillance Research Division, 1599 Clifton Road N.E., Atlanta, GA 30329.
• David Archer, MD, Clinical Research Center, Eastern Virginia Medical School, Norfolk, VA. E-mail: firstname.lastname@example.org.
• Susan Wysocki, RNC, NP, National Association of Nurse Practitioners in Women’s Health, 503 Capitol Court N.E., Suite 300, Washington, DC 20002. E-mail: NPWHDC@aol.com.