Medroxyprogesterone acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and endometrial carcinoma: trial protocol for a prospective, randomised, open, blinded-endpoint design, dose-response trial (FELICIA trial)

Abstract

IntroductionProgestin therapy is the only fertility-sparing treatment option for patients with atypical endometrial hyperplasia (AEH) and endometrial cancer (EC). However, the results of three meta-analyses revealed a high remission rate, as well as an association with a high rate of relapse. We previously conducted a phase II of medroxyprogesterone acetate (MPA) plus metformin as a fertility-sparing treatment for AEH and EC patients, and reported that metformin inhibited disease relapse after remission.Methods and analysisA randomised, open, blinded-endpoint design phase IIb dose response trial was planned to commence in July 2019. The trial aims to identify the appropriate dose of metformin to be combined with MPA therapy for fertility-sparing treatment of patients with AEH and EC. The primary endpoint of the trial is the 3-year relapse-free survival (RFS) rate. The secondary endpoints are RFS rate, the overall rate of response to MPA therapy, the conception rate after treatment, the outcome of pregnancy, toxicity evaluation and changes in insulin resistance and body mass index. A total of 120 patients will be enrolled from 15 Japanese institutions within a 2.5-year period and followed up for at least 3 years.Ethics and disseminationThe protocol was approved by the institutional review board at Chiba University Hospital and boards at 14 other institutions. The trial will be conducted according to the principles of the World Medical Association’s Declaration of Helsinki and in accordance with Good Clinical Practice (GCP) standards. The trial findings will be published in a peer-reviewed journal.Trial registration numberJapan Registry of Clinical Trials (jRCT2031190065).

Overexpression of TICRR and PPIF confer poor prognosis in endometrial cancer identified by gene co-expression network analysis

“…Silencing of TICRR and PPIF led to enhance the expression of epithelial marker E-cadherin and decrease the mesenchymal marker N-cadherin and metastasis associated genes MMP9 as well as proliferation-related marker CCND1, suggesting their involvement in the progression of endometrial cancer ( Figure 6E ). Medroxyprogesterone acetate (MPA) as a conservative therapy is commonly applied to the early stage of endometrial carcinoma [ 19 ]. The knockdown of TICRR resulted in a potent decrease of cell growth and clone formation and enhanced the inhibitory effect of MPA ( Figure 6F ) and the downregulated PPIF yielded the similar results ( Figure 6G ).…”

The results of different fertility-sparing treatment modalities and obstetric outcomes in patients with early endometrial cancer and atypical endometrial hyperplasia: Case series of 30 patients and systematic review

“…However, it was found, that only pretreatment BMI !25 kg/m 2 , not the change in BMI during the treatment is a significant factor in achieving the complete response [11]. The overall effects of metformin on oncological and obstetrical outcomes are planned to be examined in randomized study [35].…”

Clinical Use of Progestins and Their Mechanisms of Action: Present and Future (Review)

“…The dosage forms of gestagens existing in the Russian pharmaceutical market and indications for their use are presented in the Table. Gestagens are successfully used for contraception, pregnancy maintenance, and secondary amenorrhea. They are the front-line therapy for endometrial hyperplasia and cancer [18][19][20]. Gestagens are used in hormone replacement therapy (HRT) to prevent osteoporosis and in ART procedures [21].…”

“…Metformin is a biguanide widely used in the treatment of type 2 diabetes. Analysis of several recent epidemiological studies [ 19 , 69 , 70 ] has shown that metformin reduces the risk of cancer development and mortality in diabetic patients with endometrial hyperplasia and carcinoma.…”