Metformin plus megestrol acetate compared with megestrol acetate alone as fertility-sparing treatment in patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer: a randomised controlled trial

B-Y Yang^{1

2}, Y Gulinazi^{1

2}, Y Du³, C-C Ning^{1

2}, Y-L Cheng^{1

2}, W-W Shan^{1

2}, X-Z Luo^{1

2}, H-W Zhang⁴, Q Zhu⁵, F-H Ma⁶, J Liu⁶, L Sun⁷, M Yu⁸, J Guan^{1

2

9}, X-J Chen^{1

2}

Affiliations

¹ Department of Gynaecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
² Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
³ Department of Clinical Epidemiology, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
⁴ Department of Cervical Diseases, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
⁵ Department of Pathology, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
⁶ Department of Radiology, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
⁷ Department of Sonography, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
⁸ Shanghai JiAi Genetics and IVF Institute, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
⁹ Department of Gynaecology, Campus Virchow Clinic, Charite Medical University of Berlin, corporate member of Free University Berlin, Humboldt-University Berlin, Berlin Institute of Health, Berlin, Germany.

PMID: 31961463
DOI: 10.1111/1471-0528.16108

Randomized Controlled Trial

Metformin plus megestrol acetate compared with megestrol acetate alone as fertility-sparing treatment in patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer: a randomised controlled trial

B-Y Yang et al. BJOG. 2020 Jun.

. 2020 Jun;127(7):848-857.

doi: 10.1111/1471-0528.16108. Epub 2020 Feb 16.

Authors

Affiliations

¹ Department of Gynaecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
² Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
³ Department of Clinical Epidemiology, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
⁴ Department of Cervical Diseases, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
⁵ Department of Pathology, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
⁶ Department of Radiology, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
⁷ Department of Sonography, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
⁸ Shanghai JiAi Genetics and IVF Institute, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China.
⁹ Department of Gynaecology, Campus Virchow Clinic, Charite Medical University of Berlin, corporate member of Free University Berlin, Humboldt-University Berlin, Berlin Institute of Health, Berlin, Germany.

PMID: 31961463
DOI: 10.1111/1471-0528.16108

Abstract

Objective: To assess the efficacy of metformin in megestrol acetate (MA)-based fertility-sparing treatment for patients with atypical endometrial hyperplasia (AEH) and endometrioid endometrial cancer (EEC).

Design: A randomised, single-centre, open-label, controlled trial conducted between October 2013 and December 2017.

Setting: Shanghai OBGYN Hospital of Fudan University, China.

Population: A total of 150 patients (18-45 years old) with primary AEH or well-differentiated EEC were randomised into an MA group (n = 74) and an MA plus metformin group (n = 76).

Methods: Patients with AEH or EEC were firstly stratified, then randomised to receive MA (160 mg orally, daily) or MA (160 mg orally, daily) plus metformin (500 mg orally, three times a day).

Main outcomes and measures: The primary efficacy parameter was the cumulate complete response (CR) rate within 16 weeks of treatment (16w-CR rate); the secondary efficacy parameters were 30w-CR rate and adverse events.

Results: The 16w-CR rate was higher in the metformin plus MA group than in the MA-only group (34.3 versus 20.7%, odds ratio [OR] 2.0, 95% confidence interval [CI] 0.89-4.51, P = 0.09) but the difference was more significant in 102 AEH patients (39.6 versus 20.4%, OR 2.56, 95% CI 1.06-6.21, P = 0.04). This effect of metformin was also significant in non-obese (51.4 versus 24.3%, OR 3.28, 95% CI 1.22-8.84, P = 0.02) and insulin-sensitive (54.8 versus 28.6%, OR 3.04, 95% CI 1.03-8.97, P = 0.04) subgroups of AEH women. No significant result was found in secondary endpoints.

Conclusion: As a fertility-sparing treatment, metformin plus MA was associated with a higher early CR rate compared with MA alone in AEH patients.

Tweetable abstract: For AEH patients, metformin plus MA might be a better fertility-sparing treatment to achieve a higher early CR rate compared with MA alone.

Keywords: Atypical endometrial hyperplasia; endometrioid endometrial cancer; fertility-sparing; megestrol acetate; metformin.

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Comment in

Is there any move to use metformin for endometrial hyperplasia in routine clinical practice?
Atiomo W. Atiomo W. BJOG. 2020 Jun;127(7):858. doi: 10.1111/1471-0528.16183. Epub 2020 Mar 16. BJOG. 2020. PMID: 32096892 No abstract available.

References

1. Gallos ID, Yap J, Rajkhowa M, Luesley DM, Coomarasamy A, Gupta JK. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2012;207:266.e1-12.
1. Ushijima K, Yahata H, Yoshikawa H, Konishi I, Yasugi T, Saito T, et al. Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women. J Clin Oncol 2007;25:2798-803.
1. Lee TY, Martinez-Outschoorn UE, Schilder RJ, Kim CH, Richard SD, Rosenblum NG, et al. Metformin as a therapeutic target in endometrial cancers. Front Oncol 2018;8:341.
1. Liu X, Romero IL, Litchfield LM, Lengyel E, Locasale JW. Metformin targets central carbon metabolism and reveals mitochondrial requirements in human cancers. Cell Metab 2016;24:728-39.
1. Lord SR, Cheng WC, Liu D, Gaude E, Haider S, Metcalf T, et al. Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer. Cell Metab 2018;28:679-8.e4.

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Metformin plus megestrol acetate compared with megestrol acetate alone as fertility-sparing treatment in patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer: a randomised controlled trial

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Metformin plus megestrol acetate compared with megestrol acetate alone as fertility-sparing treatment in patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer: a randomised controlled trial

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