Continuous Combined Estrogen Plus Progestin and Endometrial Cancer

The Women's Health Initiative Randomized Trial

R. T. Chlebowski; G. L. Anderson; G. E. Sarto; R. Haque; C. D. Runowicz; A. K. Aragaki; C. A. Thomson; B. V. Howard; J. Wactawski-Wende; C. Chen; T. E. Rohan; M. S. Simon; S. D. Reed; J. E. Manson

Disclosures

J Natl Cancer Inst. 2016;108(3) 

In This Article

Methods

Study Design and Participants

Trial methodology has been described.[16,17] Briefly, postmenopausal women age 50 to 79 years with an intact uterus were enrolled at 40 US clinical centers. Exclusions were prior breast cancer, anticipated survival of less than 3 years, and previous invasive cancer within 10 years. A three-month wash-out period was required for hormone therapy users at screening. Institutional review board approval was obtained at each clinical center, and all participants provided written, informed consent.

Women were randomly allocated to daily combined conjugated equine estrogens (0.625mg/day) plus medroxyprogesterone acetate (2.5mg/day) (n = 8506) as a single pill (Prempro; Wyeth-Ayerst, Collegeville, PA) or an identical-appearing placebo (n = 8102) using a computerized, permuted-block algorithm, stratified by age group and clinical center. Random assignment and double-blind study drug dispensing utilizing a secured database system were implemented by the WHI Clinical Coordinating Center (Seattle, WA). The trial protocol can be accessed at whi.org. This trial is registered with clinicaltrials.gov, number NCT000000611.

Data Collection

Baseline characteristics were collected using standardized questionnaires or by interview. Nonstudy drug use was accessed by interviewer-administered questionnaire serially. Study medication adherence was annually measured initially by pill counts and later by weighing return bottles. Health status was accessed twice yearly.

Endometrial Cancer

Endometrial cancer was one of the prospectively identified main study outcomes, which also included coronary heart disease (CHD), invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, and a global index of these outcomes. Initial outcomes reports were confirmed locally by centrally trained physician adjudicators after medical record review. Final cancer adjudication was conducted at the Clinical Coordinating Center.[17] Reasons for hysterectomy were prospectively collected.

Clinical Trial Course

After 5.6 years of median follow-up, the intervention was stopped when overall risks exceeded benefits and participants were instructed to discontinue study drug on July 8, 2002.[16] Protocol-defined follow-up continued through March 31, 2005, the prospectively determined trial completion date. Follow-up after that date required reconsent, obtained from 12 788 (83%) of 15 408 surviving participants. The participant flow is described in a CONSORT diagram (Figure 1).[18] Deaths were documented by death certificate and medical record review by centrally trained physician adjudicators. Additionally, linkage to the National Death Index linkage was conducted on December 31, 2008.

Figure 1.

Participant flow diagram of the Women's Health Initiative randomized trial of continuous combined estrogen plus progestin through extended follow-up. Estrogen indicates conjugated equine estrogens, and progestin indicates medroxyprogesterone acetate. The intervention phase ran from November 15, 1993 to July 7, 2002. The postintervention phase began July 8, 2002, the day after participants were instructed to stop study medication use (conjugated equine estrogens plus medroxyprogesterone acetate or placebo), and continued through the original trial completion date (March 31, 2005). The extension phase began on April 1, 2005 and includes follow-up for participants who reconsented (83% of those eligible) through September 30, 2010. During this period, 2.8% dropped out.

Endometrial Evaluation

For safety, endometrial biopsies were required prior to study entry. Biopsy reports of endometrial cancer and complex adenomatous hyperplasia, with or without atypia, precluded study entry. Women with simple hyperplasia were not eligible but could subsequently enter with resolution of histologic abnormality. A cohort of 5% of participants was randomly identified to undergo scheduled biopsies at three years of follow-up. Biopsies were performed by WHI clinical staff[13] and read by pathologists blinded to random assignment. During follow-up, other endometrial biopsies and vaginal ultrasounds were performed for medical indications. Women with persistent or heavy bleeding were evaluated by clinical center gynecologists. If biopsy was indicated, gynecologist unblinding was permitted. Diagnosis of endometrial cancer and complex or adenomatous hyperplasia, with or without atypia, required discontinuation of study medications. For simple hyperplasia, placebo group participants had study medication discontinued and received referral to their health care providers for further management. Estrogen plus progestin group participants with simple hyperplasia were continued on study medication with additional 20mg/day of medroxyprogesterone acetate with biopsies repeated in three to six months.

Statistical Analysis

The target sample size of 15 125 was based primarily on projected coronary heart disease benefit. Results for endometrial cancer incidence and deaths directly attributed to endometrial cancer were assessed with time-to-event methods based on the intent-to-treat principle, which included all 16 608 randomly assigned participants. Cancer incidence rate comparisons, presented as hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazard models, were stratified by age and randomization groups in the WHI dietary trial, and proportionality was verified with the Grambsch and Therneau's test.[19]

Analyses were conducted for three time periods: the intervention phase from random assignment through July 7, 2002, the postintervention phase beginning July 8, 2002, and for cumulative results (through September 30, 2010). Participants were included in postintervention phase analyses if they were alive, in follow-up, and had no prior endometrial cancer as of July 8, 2002. Censoring was defined by the earliest date of death and last follow-up date.

Analyses of cumulative results begin at random assignment with censoring as above and included all randomly assigned participants. The heterogeneity of hazard ratios across endometrial cancer subtypes was assessed with competing risk methods.[19] In analyses examining deaths from endometrial cancer, women were censored at last contact date.

Exploratory interactions were examined for eleven baseline characteristics potentially related to endometrial cancer risk[20] within the primary Cox model, expanded to include the designated baseline factors, random assignment, and interaction term(s). At most, one interaction was expected to be statistically significant at the .05 level by chance alone.

When initiated in 1993, the trial originally included random assignment to an estrogen alone arm. When clinical trial results indicated estrogen alone increased endometrial epithelial proliferation,[4] that arm was dropped and the 331 women in the estrogen alone group were added to the combined therapy group.

All analyses were conducted using SAS version 9.3 (SAS Institute Inc., Cary, NC). Figures were created using R 2.15 (R Foundation for Statistical Computing, Vienna, Austria). All P values are two-sided, and P values of .05 or less were regarded as statistically significant.

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