Endometrial Adenocarcinoma, Endometrial Atypical Hyperplasia
Conditions
Keywords
Endometrial Atypical Hyperplasia, Endometrial Adenocarcinoma, Conservative Medication
Brief summary
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
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.
Interventions
DRUGMegestrol acetate and metformin
Patients will receive metformin 500 mg by mouth third daily and megestrol acetate 160 mg by mouth daily for 3 months.
DRUGMegestrol acetate
Patients will receive megestrol acetate 160 mg by mouth daily for 3 months.
Sponsors
Fudan University
Shanghai 6th People's Hospital
Zhejiang Cancer Hospital
Shanghai Changning Maternity & Infant Health Hospital
Xiaojun Chen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative CR Rates Within 16 Weeks | 16 weeks after initial treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative CR Rates Within 32 Weeks | 32 weeks after initial treatment | 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. |
| Recurrence Rate | through study completion, a median time of 33 months | 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. |
| Pregnancy Rate | through study completion, a median time of 33 months | All patients were followed up till February 2019. The pregnancy rate was calculated only in women who planned for parenthood immediately after achieving CR. |
Countries
China
Participant flow
Recruitment details
307 patients from Obstetrics and Gynaecology Hospital of Fudan University (Shanghai, China) were enrolled to this study between October 2013 to October 2017, including 237 patients with atypical endometrial hyperplasia (AEH) and 70 patients with well-differentiated endometrioid endometrial cancer (EEC).
Pre-assignment details
157 of 307 enrolled patients were deemed ineligible, including 28 patients with hysterectomy history, 31 patients with AEH/EEC history, 67 patients with progestin use history, 10 patients refusing to attend this trial, 21 patients transferred to other hospital were excluded from this trial.
Participants by arm
| Arm | Count |
|---|---|
| Megestrol Acetate and Metformin 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.
Megestrol acetate and metformin: Patients will receive metformin 500 mg by mouth third daily and megestrol acetate 160 mg by mouth daily for 3 months. | 76 |
| Megestrol Acetate 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.
Megestrol acetate: Patients will receive megestrol acetate 160 mg by mouth daily for 3 months. | 74 |
| Total | 150 |
Baseline characteristics
| Characteristic | Megestrol Acetate and Metformin | Total | Megestrol Acetate |
|---|---|---|---|
| Age, Continuous | 32.0 years STANDARD_DEVIATION 4.5 | 32.6 years STANDARD_DEVIATION 4.9 | 33.4 years STANDARD_DEVIATION 5.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 76 Participants | 150 Participants | 74 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 76 participants | 150 participants | 74 participants |
| Sex: Female, Male Female | 76 Participants | 150 Participants | 74 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 76 | 0 / 74 |
| other Total, other adverse events | 47 / 76 | 46 / 74 |
| serious Total, serious adverse events | 0 / 76 | 0 / 74 |
Outcome results
Primary
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.
Time frame: 16 weeks after initial treatment
Population: In MA+metformin group, 9 cases were excluded in primary analysis for 1 asking for surgery and 8 missing hysteroscopic evaluation.~In MA group, 16 cases were excluded for 1 asking for surgery and 15 missing hysteroscopic evaluation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Megestrol Acetate and Metformin | Cumulative CR Rates Within 16 Weeks | 23 Participants |
| Megestrol Acetate | Cumulative CR Rates Within 16 Weeks | 12 Participants |
Secondary
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.
Time frame: 32 weeks after initial treatment
Population: In MA+metformin group, 6 cases were excluded in this analysis for 3 asking for surgery and 3 missing hysteroscopic evaluation.~In MA group, 8 cases were excluded for 2 asking for surgery and 6 missing hysteroscopic evaluation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Megestrol Acetate and Metformin | Cumulative CR Rates Within 32 Weeks | 52 Participants |
| Megestrol Acetate | Cumulative CR Rates Within 32 Weeks | 45 Participants |
Secondary
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.
Time frame: through study completion, a median time of 33 months
Population: In MA+metformin group only 31 cases wanted to have a baby, and that in MA group were 37.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Megestrol Acetate and Metformin | Pregnancy Rate | 19 Participants |
| Megestrol Acetate | Pregnancy Rate | 15 Participants |
Secondary
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.
Time frame: through study completion, a median time of 33 months
Population: In MA+metformin group, 3 cases were excluded in this analysis for surgery, 3 for lost to follow-up, and 1 for still in treatment.~In MA group, 2 cases were excluded for surgery and 6 for lost to follow-up.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Megestrol Acetate and Metformin | Recurrence Rate | 7 Participants |
| Megestrol Acetate | Recurrence Rate | 6 Participants |