Special Feature
Endometrial Cancer: Surprising Reports
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, is Editor for OB/GYN Clinical Alert
Epidemiologists at the National Cancer Institute organized and conducted a retrospective cohort study, recruiting patients treated between 1965 and 1988 from endocrine and infertility practices in 5 academic centers. Data on patient characteristics were collected by questionnaires returned by 5,597 patients from a total of 8,431 originally identified. Clinical information on uterine cancers was obtained from medical records and cancer registries in addition to the questionnaires. Thirty-nine percent of the subjects (a total of 3,280) had been treated with clomiphene. Uterine cancers (a total of 39 cases) were tested by statistical analysis for an association with clomiphene treatment. Of the 39 women, the histologic diagnosis could be identified only in 23 (19 adenocarcinoma, 1 clear cell, 1 papillary, 1 papillary serous, 1 unknown). The authors concluded that clomiphene may increase the risk of uterine cancer, with a higher risk associated with higher doses.1
The UK Million Women Study reported follow-up data on 716,738 postmenopausal women who used daily, combined estrogen-progestin (22%), sequential estrogen-progestin (45%), estrogen only (4%), and tibolone (9%).2 The reported results represent an average of 3.4 years of follow-up. The Study data were recorded from questionnaires returned prior to the mammography and the women were followed with another questionnaire 2-3 years after recruitment to determine cancer incidence and death. During the follow-up period, there were 1,320 cases of invasive endometrial cancer. Not surprising, the risk of endometrial cancer was reduced with the use of continuous, combined estrogen-progestin, but surprisingly, increased with the use of tibolone. The use of sequential estrogen-progestin neither increased nor decreased risk, and estrogen-only had an increased risk of 1.45 (1.02-2.06) The adverse effects of tibolone and estrogen-only were greatest in thin women and the beneficial effect of combined estrogen-progestin was greatest in obese women. In fact, in women who were not overweight, daily estrogen-progestin use did not change the risk compared with never users. The results were adjusted for multiple factors, including age, parity, oral contraceptive use, alcohol consumption, and BMI.
| Treatment |
Cases
|
Relative Risk
|
Confidence Interval
|
| Continuous Estrogen-Progestin |
73
|
0.71
|
(0.56-0.90)
|
| Tibolone |
86
|
1.79
|
(1.43-2.25)
|
The Clomiphene Study
Even though respected colleagues of mine are co-authors of this report and Louise Brinton, the senior author, has a long track record in epidemiology, the publication of this paper in a respected journal of epidemiology boggles my mind. I suppose the motivation for the authors’ interest can be traced to the similar chemical structure and biologic actions of tamoxifen and clomiphene. But exposure to clomiphene for 5 days monthly for less than one year is very different than daily treatment for several years with tamoxifen at a dose double what is used in Japan to induce ovulation.
The actual number of uterine cancers in clomiphene users that was recorded was 19. This was compared to 8.9 cases, the number expected in the general population in the United States, giving a risk ratio of 2.14 with a confidence interval of 1.3-3.3. Six cases with clomiphene at a total dose less than 900 mg gave a risk ratio of 1.91 that was not statistically significant, and 13 cases with a dose greater than 900 mg provided a ratio of 2.26 with a confidence interval of 1.2-3.9. Overall, infertile patients had an increased risk of uterine cancer: ratio of 1.56 (1.1-2.1). The authors obviously base their overall conclusion on the comparison between the clomiphene users and the general population. We learned from the studies on the risk of ovarian cancer associated with ovulation-inducing drugs, that this is an inappropriate comparison.3 Infertile women are not the same as women in the general population; these are two different populations, with different characteristics. Even comparing users and nonusers of clomiphene in infertile patients does not achieve the goal of matching the two groups. Users of clomiphene will be mostly anovulatory women (many with insulin resistance) with the remainder being women with unexplained infertility. Nonusers will represent all other diagnoses of infertility, a varied group that would fail to match the personal and hormonal characteristics of the user group. An accurate assessment requires a randomized, placebo-controlled trial in a uniform population of anovulatory women, a study that is unlikely ever to be performed.
When the authors compared clomiphene users to never users, not a single analysis indicated a statistically significant increase in risk, including the assessment of dose and number of cycles of exposure. This didn’t prevent the authors from concluding that their study demonstrated a dose-response effect.
When the authors analyzed various risk factors for uterine cancer, they found the expected association with the use of estrogen-only postmenopausal hormone therapy and with obesity, but no reduction was associated with the use of oral contraceptives, a well-documented benefit of oral contraceptive use that lasts for at least 20 years after discontinuation. The failure to find this benefit of oral contraceptives seriously questions the veracity of the study.
The authors adjusted their analyses for anovulation, obesity, and nulligravidy, and concluded that these factors had little effect on the risk estimate, suggesting an independent effect of clomiphene. This is not surprising since the effect of clomiphene analyzed in their infertile population never achieved a statistically significant increase anyway.
In the discussion, the authors emphasize that clomiphene treatment was associated with the highest risk in women who first used clomiphene 20 or more years ago. They argue that this significant latency effect suggests that clomiphene initiates carcinogenesis and that this is consistent with the fact that uterine cancer is a slow growing tumor. But in fact, the latent period for endometrial cancer is closer to 5 years; exposure for only one year to postmenopausal unopposed estrogen increases the risk of cancer; and when atypia is present, 20-25% of cases progress to carcinoma within a year.4,5 It makes more sense to me that factors in the 20 years since treatment with clomiphene are more important in these results than the treatment.
This report demonstrates the harm that can be produced by overanalysizing data based on a small number of cases. The authors conclude in their discussion that it is likely that "clomiphene increases uterine cancer risk simply by indirectly increasing estrogen levels during the first half of the menstrual cycle." However, in the majority of cases, clomiphene treatment is followed by ovulation with its progesterone-induced inhibition of endometrial growth. Clinicians should not be impressed with this study of a small number of cases that was hampered by a large percentage of subjects that could not be traced, refused participation, or did not complete a questionnaire.
The Million Women Study
To refresh your memory, the Million Women Study recruited women between 1996 and 2001 from those invited by the UK National Health Service Breast Screening Programme to have screening mammography every 3 years, and about 45% had used postmenopausal hormone therapy. The many flaws in the Million Women Study were listed in various articles and letters to the editor after the publication of the breast cancer results.6 For example, the Million Women Study collaborators like to point out that ". . .self-reported information at recruitment showed 97% agreement with prescription records for the type of HRT currently used, and 95% agreement with self-reported information."2 These are impressive percentages, but I have reviewed their report, and I discovered that only 527 of the nearly million women had their records evaluated.7
The accompanying editorial is written by a team from the National Cancer Institute, headed by Louis Brinton, the senior author of the clomiphene results reviewed above, and offers no criticisms of the Million Women Study. The editorial refers to another report that suggested an increased risk of endometrial cancer associated with long-term use of continuous, combined estrogen-progestin treatment. This was a case-control study that found a doubling of risk associated with a regimen that used 2.5 mg medroxyprogesterone acetate daily, a finding that was based on 18 cases.8 At the same time, we know that randomized clinical trials have found no hyperplasia associated with lower doses for as long as 2 and 3 years.9
A major reason the tibolone results with endometrial cancer are surprising is the biologic implausibility. The predominant, if not exclusive, tibolone metabolite produced within the endometrium is the D-4 isomer, which binds to the progesterone receptor and protects the endometrium from the agonist effects of the two estrogenic metabolites.10-14 The authors speculate that it is possible that some women are deficient in this important local enzyme activity. It should be emphasized that there is no evidence to support such variability among women. Furthermore, a protective effect on the endometrium has been documented in monkey experiments and in long-term (up to 8 years) human studies.12,13,15-20 In the major US clinical trial, 3 cases of endometrial cancer were observed, but in each case, pre-existing carcinoma was later detected when the initial biopsy samples were more extensively examined.21 In the Organon database of 4,269 women who participated in phase III and phase IV clinical trials, there were 2 cases of endometrial cancer in the tibolone-treated women and 2 cases in the placebo group.22
Isolated cases of endometrial proliferation have been reported—eg, 4 of 150 women treated with 2.5 mg daily for 2 years.23 In a 5-year follow-up, 47 of 434 women experienced bleeding, and of these 11 had endometrial polyps, 2 had fibroids, but there were 2 with simple hyperplasia and 2 with endometrial Ca-in-situ.24
Abnormal endometrium is more frequently encountered in patients on combination estrogen-progestin when the patients have previously been treated for a period of time with unopposed estrogen. Breakthrough bleeding or unscheduled bleeding in these patients requires endometrial surveillance because an increased risk for endometrial cancer persists beyond the period of exposure to unopposed estrogen, and it is unknown how effective the subsequent protective exposure to a progestin will be.25-27 It is prudent to assess the endometrium in these patients prior to changing from unopposed to combined therapy. Clinicians should maintain a highly anxious state of mind with patients who have been treated previously with unopposed estrogen. Is it possible that endometrial abnormalities in women using tibolone reflect previous exposure to unopposed estrogen?
The Million Women authors state that their results with tibolone are in "accord with findings from another UK study." The UK case-control study found that tibolone users were more likely to develop endometrial cancer compared with users of estrogen-progestin products, based on 43 cases.28 But it is difficult in these studies to know whether the comparison groups are identical, and again, the important influence of previous exposure to unopposed estrogen may be a factor.
The Million Women Study had no significant variation in characteristics at recruitment, including BMI, socio-economic status, alcohol consumption, and smoking, among the users of the various types of treatment. Despite this similarity, an important question has been raised: Do the results with tibolone reflect preferential prescribing? Using the MediPlus primary care database in the United Kingdom, a comparison of personal characteristics among women prescribed various forms of postmenopausal hormone therapy indicted that clinicians often prescribed tibolone to women at increased risks for breast and endometrial cancer.29 Women prescribed tibolone in the United Kingdom more often had chronic breast disease, a personal history of breast cancer, previous dysfunctional uterine bleeding, hypertension, and previous uterine operations. Most importantly, more women prescribed tibolone had a history of treatment with unopposed estrogen. These data argue strongly that preferential prescribing has occurred in the United Kingdom, and this would affect observational studies like the Million Women cohort, the case-control study, and the case reports noted above. A combined estrogen-progestin program will not totally prevent endometrial cancer,26 and this is probably true for tibolone as well. This underscores the standard clinical principle to investigate persistent vaginal bleeding in any postmenopausal women. Vigilance on the part of the clinician, however, will detect endometrial cancer at an early stage, a stage that can be treated with excellent results.
Conclusion
It is unlikely that clomiphene treatment increases the risk of endometrial cancer. A large body of evidence suggests that tibolone protects the endometrium against excessive growth. Endometrial safety results with the use of tibolone in randomized clinical trials will soon be available. The studies reviewed above should not change current prescribing practices.
Attention Readers
Due to the large amount of references contained within this issue’s Special Feature, and space considerations, Dr. Speroff and the staff at OB/GYN Clinical Alert will provide copies of the references by request only. If you would like to receive the references, please contact Rob Kimball, Managing Editor, at 404-262-5413, or e-mail at [email protected]. We will be happy to provide the full references. Thank you.
Epidemiologists at the National Cancer Institute organized and conducted a retrospective cohort study, recruiting patients treated between 1965 and 1988 from endocrine and infertility practices in 5 academic centers.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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