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Randomized Double-Blind Trial of Estrogen Replacement Therapy Versus Placebo in Stage I or II Endometrial Cancer: A Gynecologic Oncology Group Study

From the Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York; Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; Division of Gynecologic Oncology, Women's Cancer Center, University of Nevada School of Medicine, Las Vegas, NV; Department of Gynecologic Oncology, Riverside Methodist Hospital; Department of Obstetrics and Gynecology, Ohio State University, Columbus, OH; Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK

Address reprint requests to Denise Mackey, Gynecologic Oncology Group Administrative Office, Four Penn Center, Ste 1020, 1600 John F. Kennedy Blvd, Philadelphia, PA 19103; e-mail: gynbreast{at}mskcc.org

	ABSTRACT

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PURPOSE: To determine the effect of estrogen replacement therapy (ERT) on recurrence rate and survival in women who have undergone surgery for stage I or II endometrial cancer.

PATIENTS AND METHODS: After surgery, eligible patients were allocated to therapy with ERT or placebo after undergoing hysterectomy with or without pelvic and aortic nodal sampling. Planned duration of hormonal versus placebo treatment was 3 years, with an additional 2 years of follow-up.

RESULTS: The median follow-up time for all 1,236 eligible and assessable patients was 35.7 months. Stage, grade, histologic subtype, and percentage of patients receiving adjuvant therapy were similarly distributed between the groups. The median age at diagnosis for the 618 patients randomly assigned to ERT was 57 years (range, 26 to 91 years). Two hundred fifty-one patients (41.1%) were compliant with ERT for the entire treatment period. Disease recurrence was experienced in 14 patients (2.3%). Eight patients (1.3%) developed a new malignancy. There were 26 deaths (4.2%), and five deaths (0.8%) were a result of endometrial cancer. The median age at diagnosis for the 618 patients in the placebo group was 57 years (range, 30 to 88 years). Twelve patients (1.9%) experienced disease recurrence. Ten patients (1.6%) developed a new malignancy. There were 9 deaths (3.1%) in the placebo group, and four deaths (0.6%) were a result of endometrial cancer.

CONCLUSION: Although this incomplete study cannot conclusively refute or support the safety of exogenous estrogen with regard to risk of endometrial recurrence, it is noteworthy that the absolute recurrence rate (2.1%) and the incidence of new malignancy were low.

	INTRODUCTION

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Adenocarcinoma of the endometrium is the most common malignancy of the female genital tract in the United States, with an estimated 40,880 newly diagnosed patients and 7,310 deaths anticipated in 2005.¹ Fortunately, in 75% of patients, the tumor is confined to the uterus at diagnosis, and uncorrected survival rates of 75% or higher are achieved.² Although endometrial adenocarcinoma is primarily a disease of postmenopausal women, 25% of the cases occur in premenopausal patients, and 5% occur in women under the age of 40 years.^3,4 Standard therapy for endometrial cancer includes total abdominal hysterectomy, bilateral salpingo-oophorectomy, and surgical staging. Further treatment is tailored according to the presence or absence of various risk factors.

In the 1970s, reports in the medical literature began to link the use of exogenous estrogen to an increased incidence of endometrial cancer.^5,6 However, these patients were found to have superficial, well-differentiated endometrial cancers that were highly curable. Furthermore, it was subsequently demonstrated that the addition of progestational agents abrogated this increased risk.⁷ Estrogen replacement therapy (ERT) was believed to offer important health benefits to women, including alleviation of hot flashes,⁸ prevention of osteoporosis,^9,10 prevention of genital tract atrophy, and prevention of coronary heart disease.^11,12 The risk of major coronary disease for women taking estrogen had been demonstrated to be 0.56 of the risk for nonusers.¹²

In addition, retrospective data indicated that ERT in women treated for endometrial cancer might actually be safe.^13-15 Despite the potential benefits of ERT, women with a history of endometrial carcinoma were usually denied this therapy because adenocarcinoma of the endometrium is considered an estrogen-dependent neoplasm, and administration of estrogen could stimulate occult disease. However, no scientific data existed to support the contention that ERT was dangerous for this group of patients. Therefore, the Gynecologic Oncology Group (GOG) decided to conduct a randomized trial of estrogen versus placebo in women with early-stage endometrial cancer. The purpose of this trial was to test the hypothesis that ERT has a deleterious effect on the risk of recurrence in patients with endometrial cancer.

	PATIENTS AND METHODS

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Eligibility Criteria
To be eligible for the study, patients had to be diagnosed with primary, histologically confirmed, grade 1, 2, or 3 endometrial adenocarcinoma (endometrioid, villoglandular, mucinous, adenosquamous, papillary serous, clear cell, and not otherwise specified). Surgical management had to consist of, at a minimum, a total hysterectomy (either abdominal or laparoscopically assisted vaginal) and bilateral salpingo-oophorectomy, and the patient had to have surgically staged IA, IB, IC, IIA (occult), or IIB (occult) disease. Pelvic and aortic nodal sampling was performed at the discretion of the treating physician. All patients had to have recovered from the effects of their recent surgery and be entered onto the study within 20 weeks from time of surgery. In addition, the patient had to have an indication for treatment with ERT, including hot flashes, vaginal atrophy, increased risk of cardiovascular disease, or an increased risk of osteoporosis. Before study entry, patients had to have undergone a history, physical, and pelvic examination and chest x-ray. In addition, patients were required to have adequate hepatic function as defined by a serum bilirubin 1.5x normal and AST 3x normal. A normal mammogram or a negative breast biopsy after an abnormal mammogram within 1 year before study entry was also required. Patients provided written informed consent consistent with federal, state, and local requirements before receiving protocol therapy. Patients were ineligible if they had a history of breast malignancy or a known or suspected carcinoma of the breast. Patients with other invasive malignancies, with the exception of nonmelanoma skin cancer, who had any evidence of the other cancer present within the last 5 years or whose previous cancer treatment contraindicated this protocol therapy were also ineligible. Patients with nonmelanoma skin cancer were eligible regardless of the time of diagnosis. The protocol also excluded patients with acute liver disease or a history of thromboembolic disease because these are generally felt to be contraindications to ERT. Finally, patients could not be receiving any form of sex hormonal therapy. Institutional review board approval was obtained before the commencement of this study.

Statistical Considerations
The design for this study was a double-blind, randomized, phase III noninferiority trial of estrogen for 3 years. The assignment of the two therapies was to be balanced across three strata defined by International Federation of Gynecology and Obstetrics stage (IA, IB/IC, and II). The anticipated annual accrual (and recurrence rate based on the Gompertz model¹⁶) for the three strata was as follows: 75 patients per year with stage IA disease ( = .000387, = –.00516), 150 patients per year with stage IB/IC disease ( = .00370, = –.0223), and 75 patients per year with stage II disease ( = .00940, = –.0234). The primary end point was the time to recurrence, and the secondary end point was all-cause mortality. Compliance was monitored using unused tablet counts, patient logs, patient inquiries, and adverse effects that prompt discontinuing estrogen use.

Limiting Accrual of Stage IA Patients
Because the stage IA stratum would contribute negligible information for the formal hypothesis test (recurrences < 2%), it was decided that sufficient numbers of patients should be accrued in strata 2 and 3 to achieve the required statistical power for the formal hypothesis test. The point estimate of the relative risk (RR) from the stage IA stratum was to be compared informally with the other two strata to assess consistency. The consistency of these two estimates is important only for formal testing of the hypothesis that ERT is safe is accepted. We considered it essential to collect direct, albeit limited, evidence that ERT is safe for stage IA patients. However, because of the limited information anticipated to be contained in stratum 1, the accrual to this stratum was limited to 500 eligible patients.

Because this was a noninferiority study, the strategy was to detect any modest increase in risk (ie, 50%), with a type I error set at 0.10 (one sided) and the power to detect this difference set at 0.90. Calculations using strata 2 and 3 only, the Gompertz model with the parameters given earlier, and the control of the type I and II errors yielded a sample size of 1,028 eligible patients with 160 recurrences during the 36 months of follow-up. This number of recurrences would provide the specified control over the type I and II errors with 100% treatment compliance.¹⁷

Patient Compliance
It was anticipated that noncompliance would be a significant but manageable problem during the 3 years of follow-up for the testing of the primary hypothesis. Noncompliance was defined as any patient assigned estrogen tablets who discontinued use for more than 1 month (type 1 crossover) and any patient assigned placebo tablets who obtained estrogen tablets and took them for more than 1 month (type 2 crossover). We defined the degree of noncompliance as the number of months from the occurrence of the cross over to 3 years divided by 36 (eg, cross over at 25th month: 12/36 = 0.33). A patient who was compliant up to the time of her recurrence was considered fully compliant.

It was anticipated that the primary time point for noncompliance would occur within the first couple of months because some patients were not getting any relief from symptoms caused by estrogen deprivation. It is estimated that the percentage of type 1 and type 2 crossovers would not exceed 20%. Applying the method of Lachin and Foulkes¹⁸ gives rise to the need for increasing the sample size by 56% ([1 – 0.2]^–2 1.563). Including the oversampling and the 500 patients with stage IA disease, the total sample size goal for this trial was set at 2,108 eligible patients (1,028 x 1.563 + 500).

For purposes of this report, patients on placebo were considered noncompliant only if they began taking open-label estrogen within 33 months on study. Those assigned to the estrogen regimen were considered noncompliant at the time they stopped taking their prescription if they were on study less than 33 months. Ninety-one patients were missing the off-study form, and consequently, compliance could not be determined unequivocally. For these patients, the date of the latest follow-up from the on-study treatment follow-up form was taken as the date they terminated taking their medication. This assumption reduced the number of patients missing compliance status to 17 patients.

CI
In accordance with the statistical section of this study, a two-sided 80% CI will be reported. The alternative hypothesis on which this study was designed is H_a: RR more than 1, where RR is the RR of ERT to placebo. The associated test statistic is essentially equivalent to whether the lower bound of the CI of RR excludes 1 (reject null hypothesis). That is, if this study had been completed, there would be a 90% chance that the 90% lower confidence boundary would have excluded 1, if the true RR equaled 1.5. Because the study was not completed, it is imperative to assess the evidence of risk associated with ERT, albeit limited, using a CI. It is worthy to note that, if the accrual goal had been achieved, there would have been a 90% chance that the upper boundary of this CI would have excluded 1.5 if the true RR equaled 1.0.

Progression-free survival was defined as the date from protocol registration to the date of reappearance of disease or death, whichever occurred first. Survival was defined as the length of life from entry onto protocol to death or to the date of last contact. All eligible patients were included in the analysis of survival and progression-free survival (intent-to-treat principle for eligible patients). All deaths, regardless of the cause, were included in the calculation of survival rates. All rates (ie, progression-free survival, survival, and compliance) were calculated using the Kaplan-Meier method.¹⁹ RR estimates and CIs of RR were taken from the Cox model procedure.²⁰

On July 9, 2002, it was announced that the estrogen and progestin arm of the Women's Health Initiative (WHI) study was being stopped because it was found that the overall risks exceeded the benefits.²¹ Although the estrogen-only companion trial of the WHI study was not stopped at the same time, the early release of the WHI results prompted the GOG to conduct a review of the ERT protocol. It was concluded that it would be impossible to accrue enough patients experiencing a recurrence in a reasonable amount of time to demonstrate that the use of exogenous estrogen does not increase the recurrence rate in women with endometrial cancer. This conclusion was based on a continually decreasing accrual rate and a much lower recurrence rate than expected among the patients enrolled onto the study. As a result, the Data Monitoring Committee closed the trial. The results presented here represent an analysis of the 1,236 assessable patients enrolled onto the study before its closure.

	RESULTS

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Between June 1997 and January 2003, 1,236 patients were randomly assigned to receive either ERT or placebo after undergoing surgery for early-stage endometrial cancer. The planned duration of hormonal versus placebo treatment was 3 years, with an additional 2 years of follow-up. After the publication of the results of the WHI in July 2002,²¹ enrollment decreased, and the study was closed prematurely after it became clear that the accrual goal of 2,108 patients could not be reached in a reasonable amount of time. This report focuses on the data accrued on the initial 1,236 assessable patients.

The patient characteristics are listed in Table 1. The median age at diagnosis for the eligible patients was 57 years for both treatment groups (ERT range, 26 to 91 years; placebo range, 30 to 88 years). The clinical stage, grade, histologic subtype, and type of surgery performed were similar between the two groups (Table 2). In addition, the percentages of patients receiving adjuvant therapy were similar between the groups, with 8.1% of patients in the ERT group receiving postoperative radiation compared with 11.2% of patients in the placebo group. Only 0.2% of both groups received adjuvant chemotherapy. The indications for ERT are listed in Table 3 and were similar between the two groups. In the ERT group, 251 patients (41.1%) were compliant for the entire treatment period. Compliance with taking the medication was better in the placebo group (305 patients, 50.1%). In terms of noncompliance rates at 6 months, 15.5% of patients discontinued the medication in the ERT group compared with 3.3% of patients who began to take open-label estrogen in the placebo group. By 2 years, these rates were 45.6% and 9.7% for the estrogen and placebo groups, respectively. When considering only patients enrolled in the years 1997 to 1999 (at least 2 years before the WHI publication), the 2-year noncompliance rate was 25.6% for the ERT group and unchanged for the placebo group. In the entire placebo group, 59 patients started taking open-label estrogen and are the basis for the computed rates.

View larger version (13K): [in this window] [in a new window]   Fig 1. Overall survival by clinical/surgical stage.

View larger version (14K): [in this window] [in a new window]   Fig 2. Progression-free (PF) survival by clinical/surgical stage.

	DISCUSSION

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The use of ERT in women with a history of endometrial cancer is controversial. Preclinical data demonstrated that in vitro treatment of Ishikawa endometrial cancer cells with estrogen upregulates estrogen receptor expression and augments growth in endometrial cancer cells.^22,23 Although in vivo growth of residual microscopic endometrial cancer in patients has not been proven to date, there is reluctance among clinicians to prescribe ERT to women with a history of endometrial cancer based on the theoretical concern that exogenous estrogen may stimulate the growth of dormant cells, leading to disease recurrence.

Four retrospective studies have looked at the issue of ERT after surgical treatment of early-stage endometrial adenocarcinoma. In 1986, Creasman et al¹³ reported on 221 patients with stage I endometrial cancer, of whom 47 (22%) received postoperative ERT for a median of 26 months. Multiple regression analysis revealed no increased risk of recurrence or death when adjusting for tumor grade, myometrial invasion, nodal metastasis, peritoneal cytology, and age (survival only) between the 47 patients who received ERT and the 174 patients who did not. In a subsequent report in 1989, Lee et al¹⁴ reported on 44 patients with a history of low-risk (stage IA/B, grade 1 or 2) endometrial carcinoma who were selected to undergo oral ERT for a median of 64 months. Their outcome was compared with 99 similar patients who did not receive ERT. No recurrent endometrial cancers or intercurrent deaths occurred in the treated group, whereas there were eight recurrences and eight intercurrent deaths in the group who did not receive estrogen. More recently, Chapman et al¹⁵ compared 62 women with stage I and II endometrial cancer who received hormone replacement therapy (HRT) after surgery with 61 women who did not. There was no significant increase in recurrences or deaths caused by endometrial cancer in the HRT group. Suriano et al²⁴ reported a retrospective cohort study that involved 75 patients with stage I to III disease who received HRT postoperatively (51% received estrogen alone and 49% received estrogen with added progestin). Among the 150 patients, only eight patients had stage III disease. Patients using HRT had a longer recurrence-free survival compared with nonusers. There were two recurrences (1%) among the 75 estrogen users compared with 11 recurrences (14%) in the 75 patients who did not receive estrogen. Selection bias probably played a role in these retrospective studies, despite the analytic techniques used to eliminate their potential effect. Because the majority of recurrences from endometrial cancer occur within the first 2 years after surgery, these studies may have selected for a good prognosis group of patients who were highly unlikely to experience recurrence regardless of treatment. However, these studies did indicate the need for a randomized trial to determine the safety of ERT in women with a history of surgically treated endometrial cancer.

With this in mind, in June 1997, the GOG initiated protocol 137, which was a prospective, randomized, double-blind trial of estrogen versus placebo in women with early-stage endometrial cancer. The study was powered to determine the effect of ERT on progression-free and overall survival in women with a history of stage I or II endometrial adenocarcinoma. On July 9, 2002, it was announced that the estrogen and progestin arm of the WHI study was being stopped because it was found that the overall risks exceeded the benefits.²¹ The results of the WHI study led the GOG to conduct a review of the ERT protocol and close it prematurely. The statistical office of the GOG noted two problems with the study. First, patients primarily with early, good prognosis tumors were being enrolled. In fact, the majority of patients enrolled onto the ERT arm of the study had a low-risk profile (60% were < age 60 years; 38% and 50% had stage IA and IB disease, respectively, whereas 8% had stage IC disease, and only 7% had grade 3 disease). In the absence of adequate enrollment of more intermediate- and high-risk early-stage endometrial cancer patients, the number of recurrences, which was the basis of the sample size determination, would be insufficient, leading to suboptimal power for the clinical trial.

Second, there was a significant decrease in enrollment after the results of the WHI were published, even though patients enrolled onto this study were receiving estrogen alone and not estrogen and progesterone. The statisticians concluded that it would be impossible to complete the trial and answer the question the trial was designed for, which was to see whether ERT increased the rate of recurrence in women with endometrial cancer. As a result, the statistical office recommended to the Data Monitoring Committee that the trial be closed. The results presented represent an analysis of the 1,236 assessable patients enrolled onto the study before its closure.

In a Committee Opinion by the American College of Obstetricians and Gynecologists Committee of Gynecologic Practice, the members announced that "the decision to use HRT in these women [endometrial cancer patients] should be individualized on the basis of potential benefit and risk to the patient."²⁵ The results of the WHI indicated that, at least with regards to combined hormone treatment, HRT should not be initiated for the primary prevention of coronary heart disease in any patient, whether or not she has a history of endometrial cancer. That trial did not address the short-term risks and benefits of hormones administered for the alleviation of menopausal symptoms, which may be the most important indication for therapy in this group of patients. The benefits of postmenopausal hormones in preventing osteoporosis and colorectal cancer must be weighed against the risk of cardiovascular disease and breast cancer, especially in view of the availability of other agents for the prevention of osteoporosis.

The results of the WHI randomized trial of estrogen alone versus placebo in 10,739 women who have undergone a hysterectomy were recently published.²⁶ The results of that trial suggest that estrogen alone had advantages over estrogen plus progestin for treating postmenopausal women. There was an increased risk of stroke and possibly pulmonary emboli but not of coronary heart disease or breast cancer. The benefit of postmenopausal estrogen in preventing osteoporosis was again confirmed, although the benefit in protection against colorectal cancer was not. However, the study did not address the issue of quality of life in postmenopausal women receiving ERT. These findings are more applicable to GOG 137, which shares an identical treatment arm.

With the closure of this GOG protocol, the safety of exogenous estrogen use in women who have undergone surgical management for stage I or II endometrial cancer may never be fully ascertained. Although this incomplete study cannot conclusively refute or support the safety of exogenous estrogen with regard to risk of endometrial cancer recurrence (RR = 1.27; 80% CI, 0.916 to 1.77), it is noteworthy that, in this low-risk population, the absolute recurrence rate (2.1%) was low. Furthermore, the RR of recurrence for patients randomly assigned to ERT was 1.27, with 55% of patients taking ERT for more than 2 years. It is uncertain what the RR of recurrence would have been if more high-risk patients had been enrolled onto the study. However, these data do have particular relevance to the clinician discussing the overall risk to benefit ratio of ERT in patients with low-risk endometrial cancer.

	Appendix

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The following Gynecologic Oncology Group member institutions participated in this study: Roswell Park Cancer Institute, University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, University of Minnesota Medical School, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group, University of California at Los Angeles, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University Medical Center, Wake Forest University School of Medicine, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-Presbyterian–St Luke's Medical Center, State University of New York Downstate Medical Center, University of Kentucky, The Cleveland Clinic Foundation, State University of New York at Stony Brook, Southwest Oncology Group, Washington University School of Medicine, Memorial Sloan-Kettering Cancer Center, Cooper Hospital/University Medical Center, Columbus Cancer Council, Fox Chase Cancer Center, Women's Cancer Center, University of Oklahoma, University of Virginia, University of Chicago, Tacoma General Hospital, Eastern Collaborative Oncology Group, Thomas Jefferson University Hospital, Mayo Clinic, Case Western Reserve University, Tampa Bay Cancer Consortium, Brookview Research Inc, Ellis Fischel Cancer Center, and the M.D. Anderson Community Clinical Oncology Program.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Richard R. Barakat, Brian N. Bundy Provision of study materials or patients: Richard R. Barakat, Nick M. Spirtos, Jeffrey Bell, Robert S. Mannel Collection and assembly of data: Richard R. Barakat, Brian N. Bundy, Robert S. Mannel Data analysis and interpretation: Brian N. Bundy Manuscript writing: Richard R. Barakat, Brian N. Bundy, Nick M. Spirtos, Robert S. Mannel Final approval of manuscript: Richard R. Barakat, Brian N. Bundy, Nick M. Spirtos, Jeffrey Bell, Robert S. Mannel

 

	NOTES

 
Supported by National Cancer Institute Grant No. CA 27469 to the Gynecologic Oncology Group Administrative Office and Grant No. CA 37517 to the Gynecologic Oncology Group Statistical and Data Center.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
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3. Gallup DG, Stock RJ: Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 64:417-420, 1984[Medline]

4. Whitaker GK, Lee RB, Benson WL: Carcinoma of the endometrium in young women. Mil Med 151:25-31, 1986[Medline]

5. Smith DC Prentice R, Thompson DJ, et al: Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 293:1164-1167, 1975[Abstract]

6. Ziel HK, Finkle WD: Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 293:1167-1170, 1975[Abstract]

7. Gambrell RD Jr, Massey FM, Castaneda TA, et al: Reduced incidence of endometrial cancer among postmenopausal women treated with progestogens. J Am Geriatr Soc 27:389-394, 1979[Medline]

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10. Nachtigall LE, Nachtigall RH, Nachtigall RD, et al: Estrogen replacement therapy: I. A 10-year prospective study in the relationship to osteoporosis. Obstet Gynecol 53:277-281, 1979[Medline]

11. Hammond CB, Jelovsek FR, Lee KL, et al: Effects of long-term estrogen replacement therapy: I. Metabolic effects. Am J Obstet Gynecol 133:525-536, 1979[Medline]

12. Stampfer MJ, Colditz GA, Willett WC, et al: Postmenopausal estrogen therapy and cardiovascular disease: Ten-year follow-up from the nurses' health study. N Engl J Med 325:756-762, 1991[Abstract]

13. Creasman WT, Henderson D, Hinshaw W, et al: Estrogen replacement therapy in the patient treated for endometrial cancer. Obstet Gynecol 67:326-330, 1986[Medline]

14. Lee RB, Burke TW, Park RC: Estrogen replacement therapy following treatment for stage I endometrial carcinoma. Gynecol Oncol 36:189-191, 1990[CrossRef][Medline]

15. Chapman JA, DiSaia PJ, Osann K, et al: Estrogen replacement in surgical stage I and II endometrial cancer survivors. Am J Obstet Gynecol 175:1195-1200, 1996[CrossRef][Medline]

16. Klein JP, Moeschberger ML: Statistics for Biology and Health: Survival Analysis. New York, NY, Springer, 1997

17. Schoenfeld DA: Sample-size formula for the proportional-hazards regression model. Biometrics 39:499-503, 1983[CrossRef][Medline]

18. Lachin JM, Foulkes MA: Evaluation of sample size and power for analyses of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification. Biometrics 42:507-519, 1986[CrossRef][Medline]

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20. Cox DR: Regression model and life tables. J R Stat Soc B 34:187-220, 1972

21. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288:321-333, 2002[Abstract/Free Full Text]

22. Holinka CF, Hata H, Kuramoto H, et al: Responses to estradiol in a human endometrial adenocarcinoma cell line (Ishikawa). J Steroid Biochem 24:85-89, 1986[CrossRef][Medline]

23. Farnell YZ, Ing NH: The effects of estradiol and selective estrogen receptor modulators on gene expression and messenger RNA stability in immortalized sheep endometrial stromal cells and human endometrial adenocarcinoma cells. J Steroid Biochem Mol Biol 84:453-461, 2003[CrossRef][Medline]

24. Suriano KA, McHale M, McLaren CE, et al: Estrogen replacement therapy in endometrial cancer patients: A matched control study. Obstet Gynecol 97:555-560, 2001[CrossRef][Medline]

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26. Anderson GL, Limacher M, Assaf AR, et al: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA 291:1701-1712, 2004[Abstract/Free Full Text]

Submitted May 25, 2005; accepted November 4, 2005.

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