Gonadotropin-releasing Hormone Agonist (GnRHa) Plus Letrozole In Young Women With Early Endometrial Cancer

Study Overview
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Brief Summary
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To see if Gonadotropin-releasing hormone analogue (GnRHa) combined with aromatase inhibitors (AIs) will achieve better complete response rate than megestrol acetate or medroxyprogesterone acetate (MA/MPA) alone as fertility-sparing treatment for patients with early endometrial carcinoma.

Detailed Description
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This will be a multicenter randomized controlled study to evaluate the treatment effects and adverse events of GnRHa plus AIs compared with MA/MPA in primary EEC patients.In this study, young patients (18-45 years) diagnosed as EEC for the first time seeking for fertility preserving treatment at the Obstetrics and Gynecology Hospital of Fudan University were screened. Patients were randomly assigned (1:1) to GnRHa+letrozole group (triprorelin acetate, intramuscular injection of 3.75mg was given 4 weeks apart and the maximum use are 6 courses. letrozole, 2.5mg oral daily and no more than 24 weeks) or MA/MPA group (160 mg oral MA daily or 500 mg oral MPA daily). Hysteroscopy will be performed every 3 months during treatment to evaluate the treatment effects. For patients with EEC, complete response (CR) is defined as the reversion of endometrial carcinoma to proliferative or secretory endometrium; partial response (PR) is defined as regression to simple or complex hyperplasia with or without atypia; Stable disease (SD) is defined as the persistence of the disease; and progressive disease (PD) is defined as the progression of endometrial lesions. Continuous therapies will be needed in PR, SD or PD.The primary endpoint was cumulative complete response (CR) rate at 16 weeks of treatment. The secondary endpoints were cumulative CR rate at 28weeks of treatment, adverse events, recurrent rate, pregnancy rate, effects on ovarian function and quality of life of patients.

Official Title
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Gonadotropin-releasing Hormone Agonist Combined With Letrozole Compared With Megestrol Acetate or Medroxyprogesterone Acetate Alone as Fertility-sparing Treatment in Early Endometrial Cancer

Conditions
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Endometrial Neoplasm Malignant Stage I

Intervention / Treatment
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* Drug: Megestrol Acetate 160 MG Oral Tablet
* Drug: Medroxyprogesterone Acetate 500 MG
* Drug: Triprorelin Acetate
* Drug: Letrozole 2.5mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consent informed and signed Primarily have a confirmed diagnosis of early-stage endometrial cancer (endometrioid, grade I, without myometrial inva- sion) ) based upon endometrial biopsy, diagnostic curettage or hysteroscopy No signs of suspicious myometrial invasion or extrauterine metastasis by enhanced magnetic resonance imaging (MRI), enhanced computed tomography (CT) or transvaginal ultrasonography (TVUS) Have a strong desire for remaining reproductive function or uterus Have good compliance and follow-up conditions, and patients are willing to follow up in Obstetrics and Gynecology Hospital of Fudan University in time Exclusion Criteria: Pathologically confirmed as endometrial cancer with suspicious myometrial invasion or extrauterine metastasis Recurrent endometrial cancer Combined with severe medical disease or severely impaired liver and kidney function Patients with other types of endometrial cancer or other malignant tumors of the reproductive system; patients with breast cancer or other hormone- dependent tumors that cannot be used with progesterone Those who require hysterectomy or other methods other than conservative treatment with drugs Known or suspected pregnancy Contraindication for Medroxyprogesterone Acetate, Megestrol Acetate, Triprorelin Acetate, Letrozole or pregnancy Hormone treatment within 3 months before entering the trial; Acute severe disease such as stroke or heart infarction or a history of thrombosis disease Smoker(>15 cigarettes a day)

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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Accepts Healthy Volunteers

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: GnRHa+letrozole<br>Patients will be stratified into BMI≥28kg/m2 group and BMI<28kg/m2 group. Patients in BMI≥28kg/m2 or BMI<28kg/m2 group will be randomly assigned (1:1) to GnRHa+letrozole group or MA/MPA group. Patients who will be assigned to GnRHa+letrozole group will receive triprorelin acetate (intramuscular injection of 3.75mg was given 4 weeks apart and the maximum use are 6 courses) plus letrozole (2.5mg oral daily and no more than 24 weeks). Then every 3 months, an hysteroscope will be used to evaluate the endometrial condition, and the findings will be recorded. | Drug: Triprorelin Acetate<br>* Intramuscular injection of 3.75mg was given 4 weeks apart and the maximum use are 6 courses<br>Drug: Letrozole 2.5mg<br>* At a dosage of 2.5mg/day and no more than 24 weeks<br>* Other names: Letrozole;|
| Active Comparator: MA/MPA<br>Patients will be stratified into BMI≥28kg/m2 group and BMI<28kg/m2 group. Patients in BMI≥28kg/m2 or BMI<28kg/m2 group were randomly assigned (1:1) to GnRHa+letrozole group or MA/MPA group.Patients assigned to MA/MPA group will receive MA/MPA (160 mg oral MA daily or 500 mg oral MPA daily).Then every 3 months, an hysteroscopy will be used to evaluate the endometrial condition, and the findings will be recorded. | Drug: Megestrol Acetate 160 MG Oral Tablet<br>* At a dosage of 160 mg/day<br>* Other names: Megestrol Acetate;Drug: Medroxyprogesterone Acetate 500 MG<br>* At a dosage of 500 mg/day<br>* Other names: Medroxyprogesterone Acetate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rates within 16 weeks of treatment | The cumulative 16-week CR rates will be calculated in two groups | From date of treatment initiation until the date of CR, assessed up to 16 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rates within 28 weeks of treatment | The cumulative 28-week CR rates will be calculated in two groups | From date of treatment initiation until the date of CR, assessed up to 28 weeks. | 
| Time to achieve complete response | The median CR time will be calculated in two groups | From date of treatment initiation until the date of CR or date of hysterectomy,From date of randomization until the date of CR, assessed up to 2 years | 
| Adverse events | Adverse events related with Medroxyprogesterone Acetate, Megestrol Acetate, Triprorelin Acetate and Letrozole. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 will be recorded, as well as incidence of adverse events. | From date of treatment initiation until the date of CR, assessed up to 2 years | 
| Quality of life during the treatment accessed by WHOQOL-BREF | Quality of life will be assessed at baseline, 4 weeks and every 12-16 weeks of treatment, using WHOQOL-BREF scale including assessment on pain, energy,sleep,mobil,activity,medication,work,positive feeling,think,esteem,body,negtivity,spirit,relationship,support,sex,safety,home,finance,service,information, environment,leisure,transport | From date of randomization until 12 weeks after treatment is over. | 
| Relapse rates | All enrolled patients will be followed up for 2 years. During the following-up period, if patients recur after complete response, they will be counted and the number of recurrence will be divided by number of patients followed up, then we can get the relapse rates. Comparison will be performed between two groups. | up to 2 years after the treatment for each patient | 
| Change of AMH (anti-mullerian hormone ) serum level | AMH (anti-mullerian hormone ) will be assessed at baseline and every 12-16 weeks. | From date of randomization until 24 weeks after treatment is over. | 
| The rates of fertility outcomes | The percentage of pregnancy and live-birth will be counted. | up to 2 years after the treatment for each patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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early endometrial carcinoma, fertility-preserving treatment, gonadotropin-releasing hormone analogue, aromatase inhibitors