ERT in Patients with a History of Endometrial Cancer
By David M. Gershenson, MD
Endometrial cancer is the most common type of gynecologic malignancy in the United States. According to the American Cancer Society, approximately 42,000 American women will have developed the disease in 1996. The use of estrogen replacement therapy (ERT) for women who have been treated for endometrial cancer remains one of the most controversial topics, both within the medical community, particularly among oncologists, and among women with the disease. Historically, ERT has not been offered to women with a history of endometrial cancer since this condition has been an absolute contraindication to its use. Theoretically, the argument goes, dormant or quiescent clones of cells in metastatic sites may be stimulated to proliferate and spread under the effects of ERT, and they otherwise would be controlled or even undergo spontaneous regression related to host defense mechanisms. Over the past decade or so, however, physicians and patients have increasingly questioned the validity and wisdom of this theory and practice.
There is a large body of literature that links estrogen use with endometrial cancer and that makes a strong theoretical argument against its administration once endometrial cancer has been diagnosed. In the 1970s and 1980s, several well-designed epidemiologic studies all demonstrated that estrogen use was associated with an increased risk of endometrial cancer. The degree of risk varied from twofold to almost nine times higher than nonusers, depending on the duration of estrogen use. In addition, we know that in about 10% of women with granulosa cell tumors of the ovarytumors that are capable of producing estrogenendometrial cancercoexists. In addition, we have appreciated for several years that about 30% of metastatic endometrial cancers may temporarily respond to progestational agents.
On the other hand, during the same period that the adverse effects of ERT in endometrial cancer patients were being questioned, we were continuing to learn more about the beneficial effects of ERT. There is increasing evidence that, in addition to its positive influence on osteoporosis, ERT protects women against the onset of cardiovascular disease, prevents genital atrophy and its effects on the urinary system, and may even decrease a woman’s risk of developing Alzheimer’s disease. Although there are some alternative medications for amelioration of the aging process, none offers the therapeutic index of ERT. It is true that the issue about the effect of ERT on the risk of breast cancer remains a concern. Evidence on this subject to date, however, suggests that, if there is any increased risk at all, it appears to be rather small.
Against this background, gynecologists and gynecologic oncologists have been selectively prescribing ERT to women who have been treated for endometrial cancer for the past several years. Over the past decade, a handful of retrospective reviews have focused on this issue. In 1986, Creasman et al at Duke University Medical Center reported that 47 of 221 patients with stage I endometrial cancer treated between 1975 and 1980 received ERT. (Obstet Gynecol 1986;67:326-330.) These patients were compared with the 174 patients who did not receive ERT. In the ERT group, the median follow-up time was 60 months and the median duration of ERT use was 26 months. Risk factors for recurrence were similar for the two groups. There were 26 recurrences (14.9%) among the 174 women who did not receive ERT and only one recurrence (2.1%) in the ERT group. The ERT group experienced a statistically significant longer disease-free survival. The authors conclude that a history of endometrial cancer does not appear to be a contraindication to ERT in patients with stage I disease.
In 1990, Lee et al reported on 144 patients with clinical stage I endometrial cancer treated over an 11-year period. (Gynecol Oncol 1990;36:189-191.) Following surgery, 44 selected patients received ERT for a median duration of 64 months. In the ERT group, there were no recurrences and no intercurrent deaths. Of the 99 nonusers, there were eight (8%) recurrences and eight intercurrent deaths. These authors also conclude that postoperative ERT appears to be safe in selected low-risk endometrial cancer patients.
And very recently, Chapman et al retrospectively reviewed 123 women with surgical stage I and II endometrial cancer treated between 1984 and 1994. (Am J Obstet Gynecol 1996;175:1195-1200.) Sixty-two of these women received ERT after cancer therapy. Compared with the nonusers, the ERT group had earlier-stage disease and less severe depth of invasion. The disease-free survival was not significantly different for the two groups. The authors conclude that there was no evidence to suggest that ERT decreased the disease-free interval or increased the risk for recurrence in early-stage disease.
All three studies reach the same conclusion: there is no evidence that ERT adversely influences the disease-free survival of women treated for endometrial cancer. Of course, we understand that these reports are retrospective and have the potential flaws associated with this type of analysis, such as selection bias. Obviously, what we really need is prospective randomized studies comparing ERT with no ERT in patients with endometrial cancer who are appropriately stratified for prognostic variables. The Gynecologic Oncology Group has been considering such a study for several months and, hopefully, will begin patient accrual in the near future. Nevertheless, the best case scenario is that it will be several years until we are able to unravel this mystery. Unresolved issues surrounding this controversy include the potential benefit/risk ratio of the addition of a progestagen to ERT in such a population and the significance, if any, of the steroid receptor status of the tumor in relation to ERT. In the meantime, for women treated for endometrial cancer, the decision about ERT is a very personal one that should be made by the patient herself once she is counseled about the benefits and risks by her physician. My own personal bias, based on available information, is to encourage the use of ERT as long as it is within a woman’s comfort zone.
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