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

Official title

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

Overview

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

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.

Interventions

• Drug Megestrol Acetate 160 MG Oral Tablet
  At a dosage of 160 mg/day
• Drug Medroxyprogesterone Acetate 500 MG
  At a dosage of 500 mg/day
• Drug Triprorelin Acetate
  Intramuscular injection of 3.75mg was given 4 weeks apart and the maximum use are 6 courses
• Drug Letrozole 2.5mg
  At a dosage of 2.5mg/day and no more than 24 weeks

Primary outcome measures

• Complete response rates within 16 weeks of treatment [Time frame: From date of treatment initiation until the date of CR, assessed up to 16 weeks.]

Secondary outcome measures (7)

• Complete response rates within 28 weeks of treatment [Time frame: From date of treatment initiation until the date of CR, assessed up to 28 weeks.]
• Time to achieve complete response [Time frame: 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 [Time frame: 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 [Time frame: From date of randomization until 12 weeks after treatment is over.]
• Relapse rates [Time frame: up to 2 years after the treatment for each patient]
• Change of AMH (anti-mullerian hormone ) serum level [Time frame: From date of randomization until 24 weeks after treatment is over.]
• The rates of fertility outcomes [Time frame: up to 2 years after the treatment for each patient]

Eligibility criteria

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Obstetrics and Gynecology Hospital, Fudan University — Shanghai

Publications

• Zhou H, Cao D, Yang J, Shen K, Lang J. Gonadotropin-Releasing Hormone Agonist Combined With a Levonorgestrel-Releasing Intrauterine System or Letrozole for Fertility-Preserving Treatment of Endometrial Carcinoma and Complex Atypical Hyperplasia in Young Women. Int J Gynecol Cancer. 2017 Jul;27(6):1178-1182. doi: 10.1097/IGC.0000000000001008. PMID 28562472
• Rackow BW, Arici A. Endometrial cancer and fertility. Curr Opin Obstet Gynecol. 2006 Jun;18(3):245-52. doi: 10.1097/01.gco.0000193012.11523.c5. PMID 16735822
• Trimble CL, Kauderer J, Zaino R, Silverberg S, Lim PC, Burke JJ 2nd, Alberts D, Curtin J. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer. 2006 Feb 15;106(4):812-9. doi: 10.1002/cncr.21650. PMID 16400639
• Corzo C, Barrientos Santillan N, Westin SN, Ramirez PT. Updates on Conservative Management of Endometrial Cancer. J Minim Invasive Gynecol. 2018 Feb;25(2):308-313. doi: 10.1016/j.jmig.2017.07.022. Epub 2017 Aug 3. PMID 28782618
• Gressel GM, Parkash V, Pal L. Management options and fertility-preserving therapy for premenopausal endometrial hyperplasia and early-stage endometrial cancer. Int J Gynaecol Obstet. 2015 Dec;131(3):234-9. doi: 10.1016/j.ijgo.2015.06.031. Epub 2015 Sep 8. PMID 26384790
• Baek JS, Lee WH, Kang WD, Kim SM. Fertility-preserving treatment in complex atypical hyperplasia and early endometrial cancer in young women with oral progestin: Is it effective? Obstet Gynecol Sci. 2016 Jan;59(1):24-31. doi: 10.5468/ogs.2016.59.1.24. Epub 2016 Jan 15. PMID 26866032
• Gunderson CC, Fader AN, Carson KA, Bristow RE. Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review. Gynecol Oncol. 2012 May;125(2):477-82. doi: 10.1016/j.ygyno.2012.01.003. Epub 2012 Jan 11. PMID 22245711
• Chen M, Jin Y, Li Y, Bi Y, Shan Y, Pan L. Oncologic and reproductive outcomes after fertility-sparing management with oral progestin for women with complex endometrial hyperplasia and endometrial cancer. Int J Gynaecol Obstet. 2016 Jan;132(1):34-8. doi: 10.1016/j.ijgo.2015.06.046. Epub 2015 Oct 1. PMID 26493012

Identifiers

NCT: NCT05247268 · 53211032

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗