Objective: To compare pre- and post-treatment glandular cellularity in women with complex atypical hyperplasia or grade 1-2 endometrial adenocarcinoma who are treated with intramuscular depot medroxyprogesterone acetate (DMPA) versus placebo injection prior to hysterectomy. The secondary objective is to compare various other outcomes including molecular, histologic, pathologic and clinical endpoints in women treated with DMPA versus placebo prior to hysterectomy.

Hypothesis: Patients treated with DMPA will have significantly decreased glandular cellularity post-treatment when compared to patients treated with placebo injection. Patients treated with DMPA will exhibit previously described changes in molecular tumor marker expression patterns and other characteristic histologic changes. Patients treated with DMPA will report less bothersome vaginal bleeding prior to surgery when compared to patients treated with placebo injection.

Study Design: Double blinded randomized controlled trial

Population: Women being treated at the Women and Infants Program in Women's Oncology who have a biopsy-proven diagnosis of complex atypical hyperplasia or grade 1-2 endometrial adenocarcinoma with disease clinically confined to the uterus, with a plan to undergo hysterectomy.

Study Period: February 2015 to June 2016

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.

Considering the above data, treatment with a progesterone analogue prior to hysterectomy can be viewed as either a maintenance therapy or a temporizing measure, with the primary goal of preventing disease progression in those awaiting surgery rather than curative intent. This potential application of progesterone analogues may be particularly relevant in settings where women can expect a long wait time prior to definitive surgical management. There is empiric basis for this usage of DMPA, as one particularly intriguing study found that in vivo injection of MPA elevated the expression of a known metastasis suppressor gene in a murine breast cancer model.

Depot medroxyprogesterone acetate is a safe, well-studied and well-tolerated method of contraception that has been used globally since the 1960s. It does not require refrigeration and can be safely administered in remote settings with poor infrastructure, as demonstrated by its widespread use as contraception in the developing world. A history of using DMPA for contraception is believed by the World Health Organization to reduce the prevalence of endometrial cancer by 80%, with a protective period of at least 8 years after cessation. Apart from GOG 211, depot medroxyprogesterone acetate's role as a potential neoadjuvant chemotherapeutic agent has not been studied in isolation; rather it has been grouped with other progesterone analogues in retrospective trials of fertility-sparing agents for CAH or endometrial cancer.

Depot medroxyprogesterone acetate is used in the 150mg dose for contraception, however it has been used at higher doses of up to 1000mg weekly for several months in the setting of malignancy with no short-term side effects noted in these studies. More recently, a single dose of 400mg DMPA was compared to venlafaxine to treat women with bothersome hot flashes; at 6 weeks DMPA was superior at reducing hot flashes and associated with less short-term toxicity. GOG 211 used a one-time 400mg dose for maximal progestin effect.

DATA COLLECTION/INTERPRETATION: All data will be collected by the research assistant or study physician. The study drug will be administered during the patient's first visit at the Program in Women's Oncology after the decision is made to undergo hysterectomy for complex atypical hyperplasia or grade 1 or grade 2 endometrioid adenocarcinoma. Prior to injection with the study drug, a questionnaire will be completed by the patient to identify any factors that may influence histologic response to depot medroxyprogesterone acetate as well as baseline demographic information: age, race/ethnicity, education level, gravidity and parity, height/weight and body mass index, diabetes, hypertension, polycystic ovarian syndrome, history of irregular menses, history of oral contraceptive use, menopausal status, age at menarche, family history of uterine or ovarian malignancy, family history of colorectal cancer, smoking history, personal history of malignancy and type, history of abnormal uterine bleeding and duration, recent weight loss, recent symptoms of abdominal distension, and recent symptoms of nausea/vomiting.

FACILITIES: All patient related aspects of the study will transpire in the Women and Infants Program in Women's Oncology outpatient clinic, Women and Infants Hospital inpatient facilities, and the Women and Infants Pathology Department. Data will initially be collected at the patient's first visit with the Women and Infants Program in Women's Oncology when the decision is made to proceed with hysterectomy. Data will be collected one more time while the patient is being prepared for surgery as an inpatient at Women and Infants Hospital. Biopsy specimens and hysterectomy specimens will be reviewed by two study pathologists at the Women and Infants Hospital Department of Pathology. Data processing and interpretation will take place at Women and Infants Hospital in conjunction with the Division of Research.

CONFIDENTIALITY: The patients enrolled in the study will be asked permission for access to their medical records. To ensure patient confidentiality, all forms will be marked with only the participant ID number, with a key containing identifying information kept separately in a locked cabinet that only research personnel will have access to. Electronic data will be stored on the Care New England file server, a file server that is located in a physically secured data center. Access to Care New England data center is card-controlled and all access to the server room is recorded. Care New England computer account management policies and practices ensure that computer access to the study database will be limited to key study personnel.

SAFETY: Study personnel will meet to review safety issues and logistics at 25%, 50% and 75% recruitment. Adverse events and complications will be recorded on the data collection sheet which will be reviewed by the PI on a rolling basis. Any adverse events associated with depot medroxyprogesterone acetate use will be reported to the IRB and the FDA by the PI or co-investigators. Depot medroxyprogesterone acetate is a routinely used medication for birth control and as medical treatment for uterine fibroids and early endometrial cancer.

Inclusion Criteria:

• Patient at the Women and Infants Program in Women's Oncology
• Biopsy-proven complex atypical hyperplasia or grade 1 or grade 2 endometrial adenocarcinoma with endometrioid histology
• Disease clinically confined to the uterus (no physical exam findings or imaging to suggest extrauterine disease)
• Ages 18 and older
• Plan for hysterectomy at Women and Infants Hospital of Rhode Island
• Able to read English or Spanish
• Able to give informed consent for involvement in the study

Exclusion Criteria:

• Allergic to medroxyprogesterone acetate
• Known sensitivity to any component of depot medroxyprogesterone acetate
• History of breast cancer, hepatic disease, uncontrolled hypertension, osteoporosis or strong osteoporotic risk factors including anorexia nervosa, rheumatoid arthritis and chronic glucocorticoid use
• Treatment with any progesterone or progesterone analogue in past 12 months