title: Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer.
abstract: BACKGROUND
  Metformin, widely used in the treatment of type 2 diabetes mellitus, reduces the risk of cancer and relapse after treatment. Fertility-sparing treatment for endometrial cancer (EC) with progestin is associated with a high chance of disease regression, and the high relapse rate continues to be a problem. We assessed the efficacy of metformin in preventing recurrence after medroxyprogesterone acetate (MPA) as fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and EC.
  
  
  METHODS
  This phase II study enrolled 17 patients with AEH and 19 patients with EC limited to the endometrium (age, 20-40 years). MPA (400 mg/day) and metformin (750-2250 mg/day) were administered for 24-36 weeks to achieve a complete response (CR). Metformin was administered until conception, even after MPA discontinuation. The primary end point was relapse-free survival (RFS) after remission. We analyzed all efficacy end points in the full analysis set.
  
  
  RESULTS
  The body mass index was ≥25 kg/m(2) in 27 patients (mean, 31 kg/m(2); range, 19-51 kg/m(2)), and the homeostasis model assessment for insulin resistance index was ≥2.5 in 24 patients (mean, 4.7; range, 0.7-21). Two patients showed progression at 12 weeks [6%; 95% confidence interval (CI) 2-18]. At 36 weeks, 29 (81%; 95% CI 65-90) patients achieved CR, and 5 (14%; 95% CI 6-29) patients achieved partial response. During a median follow-up of 38 months (range, 9-66 months) after remission, relapse was confirmed in three of the patients who had achieved CR (relapse rate, 10%). The 3-year estimated RFS rate was 89%. No patients experienced severe toxicity.
  
  
  CONCLUSIONS
  Metformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in EC treatment should be studied further.
  
  
  BACKGROUND
  UMIN 000002210.
authors.affiliation: Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba antira@faculty.chiba-u.jp.
authors.forename: A
authors.initials: A
authors.lastname: Mitsuhashi
authors.affiliation: Clinical Research Center, Chiba University Hospital, Chiba.
authors.forename: Y
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kiyokawa
authors.affiliation: Clinical Research Center, Chiba University Hospital, Chiba.
authors.forename: M
authors.initials: M
authors.lastname: Koshizaka
authors.affiliation: Clinical Research Center, Chiba University Hospital, Chiba.
authors.forename: H
authors.initials: H
authors.lastname: Hanaoka
authors.affiliation: Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba.
authors.forename: M
authors.initials: M
authors.lastname: Shozu
mesh_terms: D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004714:Endometrial Hyperplasia / Q000188:drug therapy*; D016889:Endometrial Neoplasms / Q000188:drug therapy*; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D005260:Female; D005298:Fertility / Q000187:drug effects; D059247:Fertility Preservation / Q000379:methods*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D017258:Medroxyprogesterone Acetate / Q000009:adverse effects / Q000627:therapeutic use*; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D008687:Metformin; D017258:Medroxyprogesterone Acetate
keywords: endometrial cancer; fertility-sparing treatment; insulin resistance; medroxyprogesterone acetate; metformin