Grade 1 Endometrial Endometrioid Adenocarcinoma Clinical Trial
Official title:
The Effect of Neoadjuvant Depot Medroxyprogesterone Acetate on Glandular Cellularity in Women With Complex Atypical Hyperplasia or Grade 1-2 Endometrial Adenocarcinoma Awaiting Hysterectomy
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.
;
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Active, not recruiting |
NCT01686126 -
Improving the Treatment for Women With Early Stage Cancer of the Uterus
|
Phase 2 |