The Effect of Neoadjuvant Depot Medroxyprogesterone Acetate on Glandular Cellularity in Women With Complex Atypical Hyperplasia or Grade 1-2 Endometrial Adenocarcinoma Awaiting Hysterectomy

BACKGROUND/INTRODUCTION:

Recently, multiple modalities of progesterone analogues have been investigated and successfully used to treat complex atypical hyperplasia (CAH) and stage 1A, grade 1 endometrial adenocarcinoma. This body of research focuses on pre-menopausal women with the primary goal of preserving fertility by delaying or avoiding surgical therapy. Across multiple case series, the average time to complete response (CR: typically defined as the absence of hyperplasia, atypia or neoplasia on a follow-up biopsy specimen) is 5-9 months with 60-70% overall complete response rate and approximately 50% durable complete response rate (defined as complete histologic response with no relapse of disease over the period of time studied). There have been no published randomized controlled trials to evaluate which modality of progesterone therapy is the most efficacious, and there is no consistent retrospective data to suggest superiority of any given progesterone analogue or method of administration.

Multiple pathologic predictors of complete response to progesterone therapy have been identified. In a recent study, Gunderson found that an interval decrease in glandular cellularity on endometrial biopsy after treatment with progesterone therapy was an independent predictor of future complete response. While both decreased mitotic index and decreased glandular cellularity were significant findings in this study, only decreased glandular cellularity was independently predictive of future complete response on multivariate analysis.

Despite this growing body of evidence supporting the safety and feasibility of progesterone analogues as medical management for CAH and early-stage endometrial adenocarcinoma, little is known about its potential role as neoadjuvant chemotherapy. A recent multicenter collaborative trial coordinated by the Gynecologic Oncology Group evaluated the effect of 400mg intramuscular medroxyprogesterone acetate administered 21-24 days prior to scheduled hysterectomy for endometrioid adenocarcinoma of the uterus. Upon comparing patients' post-hysterectomy slides to pre-treatment slides, this study found a partial histologic response rate of 63% among the 59 study subjects using pre-defined criteria modified from Wheeler 2007. A down-regulation of progesterone receptor, progesterone receptor beta, Bcl-2, and Ki-67 was also noted in post-hysterectomy specimens, with lower pre-treatment levels of Ki-67 being significantly associated with increased likelihood of histologic response. No clinical data such as patient characteristics, final tumor stage, or specific surgical procedure (ie lymphadenectomy) were collected.

The question of progesterone analogues as neoadjuvant chemotherapy is especially important given recent data showing that delayed time to surgery for endometrial cancer (defined as greater 12 weeks) was significantly associated with decreased 5-year survival rates. The same group of authors also found, alarmingly, that wait times in their province of Ontario, Canada more than doubled between 2000 and 2009. In this study, more than half of hysterectomies performed for endometrial cancer were not within the recommended limit of six weeks from diagnosis to surgery.