Megestrol Acetate Plus Metformin to Megestrol Acetate in Patients With Endometrial Atypical Hyperplasia or Early Stage Endometrial Adenocarcinoma

Study Overview
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Brief Summary
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The purpose of this study is to see if megestrol acetate plus metformin will be more effective in returning the endometrial tissue to a normal state than megestrol acetate alone in patients with endometrial atypical hyperplasia or early stage endometrial adenocarcinoma.

Detailed Description
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After diagnosed of endometrial atypical hyperplasia(EAH) or type I endometrial cancer(EC) by dilatation and curettage (D&C) or hysteroscopy, patients will be enrolled. Age, waist circumstances, blood pressure, basic history of infertility, blood pressure, serum lipid level and side effects will be collected. Blood tests, including triglycerides, high density lipoprotein-cholesterol, fasting blood glucose, liver and kidney function will be performed before treatment to evacuate their metabolic conditions. Patients are randomized to 1 of 2 treatment groups. Patients will receive metformin 500 mg by mouth third daily and megestrol acetate 160 mg by mouth daily for 3 months on Arm I. Patients will receive megestrol acetate 160 mg PO daily for 3 months on Arm II. Then an hysteroscope will be used to evaluate the endometrial condition, and the findings will be recorded. For patients with EAH, complete response (CR) is defined as the reversion of endometrial atypical hyperplasia to proliferative or secretory endometrium; partial response (PR) is defined as regression to simple or complex hyperplasia without atypia; no response (NR) is defined as the persistence of the disease; and progressive disease (PD) is defined as the appearance of endometrial cancer in patients. EAH after treatment will be defined as PR in patients with EC. Continuous therapies will be needed in PR, NR or PD. After completion of study treatment, 3 months of maintenance treatment will be recommended for patients with CR, and they will be followed up for 2 years. In addition, we've already had a pilot study in 19 patients primarily diagnosed of endometrial atypical hyperplasia from August 2012 to April 2013. 10 patients were in Arm I and 9 patients were in Arm II. Metabolic syndrome were evaluated among all subjects. After treatment, megestrol acetate plus metformin worked better than megestrol acetate alone. But two arms showed no difference in NR patients, which may suggest metformin just worked as an antitumor drug more than an insulin sensitizer. More supportive researches are needed to verify it.

Official Title
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Megestrol Acetate Plus Metformin to Megestrol Acetate in Patients With Endometrial Atypical Hyperplasia or Early Stage Endometrial Adenocarcinoma

Conditions
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Endometrial Atypical Hyperplasia, Endometrial Adenocarcinoma

Intervention / Treatment
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* Drug: Megestrol acetate and metformin
* Drug: Megestrol acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be between the ages of 18-45 years old Primarily have a confirmed diagnosis of endometrial atypical hyperplasia based upon D&C or hysteroscopy OR primarily have a confirmed diagnosis of endometrial adenocarcinoma(G1, low tumor grade), based upon D&C or hysteroscopy, and three MRI parameters shows there's no myometrial invasion, extension beyond corpus, or enlarged lymph nodes Have a desire for remaining reproductive function or uterus Need to be able to undergo correlative treatment and follow-up Exclusion Criteria: Have a history of serious liver or renal dysfunction Have a confirmed diagnosis of malignant tumor in genital system Have taken oral contraceptive or other medicine for the treatment of endometrial hyperplasia in the past 6 months Ask for removal of the uterus or other conservative treatment serum CA-125 > 35 Um/L

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Megestrol acetate and metformin<br>Patients will receive metformin 500 mg by mouth third daily and megestrol acetate 160 mg by mouth daily for 3 months.Then an hysteroscope will be used to evaluate the endometrial condition, and the findings will be recorded. | Drug: Megestrol acetate and metformin<br>* Patients will receive metformin 500 mg by mouth third daily and megestrol acetate 160 mg by mouth daily for 3 months.<br>* Other names: Metformin: Fortamet, Glucophage;|
| Experimental: Megestrol acetate<br>Patients will receive megestrol acetate 160 mg by mouth daily for 3 months.Then an hysteroscope will be used to evaluate the endometrial condition, and the findings will be recorded. | Drug: Megestrol acetate<br>* Patients will receive megestrol acetate 160 mg by mouth daily for 3 months.<br>* Other names: Megestrol acetate: Megace;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative CR Rates Within 16 Weeks | The primary objective was to determine whether metformin plus MA would be associated with a higher CR rate at 3 months of treatment compared with MA alone. However, for patients who eventually underwent the first and second hysteroscopies for endometrium evaluation within 16 weeks of the treatment, the cumulative CR rates within 16 weeks (16w-CR) were analysed as first end point instead of the CR rate at 3 months. Complete response was defined as the reversion of AEH/EEC to proliferative or secretory endometrium in pathology. | 16 weeks after initial treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence Rate | All patients were followed up till February 2019. Statistics of patients who didn't accept hysterectomy and were not lost to follow up were analyzed. | through study completion, a median time of 33 months | 
| Pregnancy Rate | All patients were followed up till February 2019. The pregnancy rate was calculated only in women who planned for parenthood immediately after achieving CR. | through study completion, a median time of 33 months | 
| Cumulative CR Rates Within 32 Weeks | One of the secondary objectives was between-group comparisons of the cumulative CR rate at 6 months treatment. However, for patients who eventually underwent the second hysteroscopies for endometrium evaluation within 32 weeks of the treatment, the cumulative CR rates within 32 weeks (32w-CR rates) were analysed as secondary end point instead of the CR rate at 6 months. | 32 weeks after initial treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endometrial Atypical Hyperplasia, Endometrial Adenocarcinoma, Conservative Medication