Long-term outcomes of progestin plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer patients

Akira Mitsuhashi, Yuji Habu, Tatsuya Kobayashi, Yoshimasa Kawarai, Hiroshi Ishikawa, Hirokazu Usui, Makio Shozu, Akira Mitsuhashi, Yuji Habu, Tatsuya Kobayashi, Yoshimasa Kawarai, Hiroshi Ishikawa, Hirokazu Usui, Makio Shozu

Abstract

Objective: The present study investigated long-term outcomes of medroxyprogesterone acetate (MPA) plus metformin therapy in terms of control of atypical endometrial hyperplasia (AEH) and endometrial cancer (EC), and post-treatment conception.

Methods: We retrospectively analyzed 63 patients (42 with EC; 21 with AEH) who underwent fertility-sparing management using MPA plus metformin. MPA (400 mg/day) and metformin (750-2,250 mg/day) were administered to achieve complete response (CR). Metformin was administered until conception, even after MPA discontinuation.

Results: Of the total patients, 48 (76%) had a body mass index (BMI) ≥25 kg/m² and 43 (68%) showed insulin resistance. Sixty-one patients (97%) achieved CR within 18 months. CR rates at 6, 8-9, and 12 months were 60%, 84%, and 90%, respectively. During a median follow-up period of 57 months (range, 13-115 months), relapse occurred in 8 of 61 patients (13.1%) who had achieved CR. Relapse-free survival (RFS) in all patients at 5 years was 84.8%. Upon univariate analysis, patients with BMI ≥25 kg/m² had significantly better prognoses than did those with BMI <25 kg/m² (odds ratio=0.19; 95% confidence interval=0.05-0.66; p=0.009). Overall pregnancy and live birth rates per patient were 61% (19/31) and 45% (14/31), respectively.

Conclusions: MPA plus metformin is efficacious in terms of RFS and post treatment conception. Moreover, metformin may be more efficacious for patients with BMI ≥25 kg/m².

Keywords: Atypical Endometrial Hyperplasia; Endometrial Cancer; Fertility Preservation; Insulin Resistance; Medroxyprogesterone Acetate; Metformin.

Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.

Figures

Fig. 1. RFS in 63 patients who…
Fig. 1. RFS in 63 patients who underwent fertility-sparing treatment with metformin plus medroxyprogesterone acetate. RFS was measured from the date of initial treatment until the date of event occurrence, defined as recurrence, progression, or not reaching remission.
AEH, atypical endometrial hyperplasia; CR, complete response; EC, endometrial cancer; RFS, relapse-free survival.
Fig. 2. Relapse-free survival of 63 patients…
Fig. 2. Relapse-free survival of 63 patients who underwent fertility-sparing treatment with metformin plus medroxyprogesterone acetate, with respect to BMI (A), status of IR (B), AGM (C), and infertility treatment (D).
AGM, abnormal glucose metabolism; BMI, body mass index; IR, insulin resistance; N.S., not significant.
Fig. 3. Relapse-free survival of the patients…
Fig. 3. Relapse-free survival of the patients with endometrial cancer treated with metformin plus MPA compared with historical control treated with MPA alone.
CR, complete response; MET, metformin; MPA, medroxyprogesterone acetate.

References

    1. National Comprehensive Cancer Network (US) Uterine neoplasms [Internet] Plymouth Meeting, PA: National Comprehensive Cancer Network; c2018. [cited 2018 May 25]. Available from: .
    1. Rodolakis A, Biliatis I, Morice P, Reed N, Mangler M, Kesic V, et al. European Society of Gynecological Oncology task force for fertility preservation: clinical recommendations for fertility-sparing management in young endometrial cancer patients. Int J Gynecol Cancer. 2015;25:1258–1265.
    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.e1–266.e12.
    1. 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;125:477–482.
    1. Zhang Q, Qi G, Kanis MJ, Dong R, Cui B, Yang X, et al. Comparison among fertility-sparing therapies for well differentiated early-stage endometrial carcinoma and complex atypical hyperplasia. Oncotarget. 2017;8:57642–57653.
    1. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:1304–1305.
    1. Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 2010;3:1451–1461.
    1. Quinn BJ, Kitagawa H, Memmott RM, Gills JJ, Dennis PA. Repositioning metformin for cancer prevention and treatment. Trends Endocrinol Metab. 2013;24:469–480.
    1. Dowling RJ, Niraula S, Stambolic V, Goodwin PJ. Metformin in cancer: translational challenges. J Mol Endocrinol. 2012;48:R31–43.
    1. Ko EM, Walter P, Jackson A, Clark L, Franasiak J, Bolac C, et al. Metformin is associated with improved survival in endometrial cancer. Gynecol Oncol. 2014;132:438–442.
    1. Chu D, Wu J, Wang K, Zhao M, Wang C, Li L, et al. Effect of metformin use on the risk and prognosis of endometrial cancer: a systematic review and meta-analysis. BMC Cancer. 2018;18:438.
    1. Mitsuhashi A, Sato Y, Kiyokawa T, Koshizaka M, Hanaoka H, Shozu M. Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer. Ann Oncol. 2016;27:262–266.
    1. Falcone F, Laurelli G, Losito S, Di Napoli M, Granata V, Greggi S. Fertility preserving treatment with hysteroscopic resection followed by progestin therapy in young women with early endometrial cancer. J Gynecol Oncol. 2017;28:e2.
    1. Gonthier C, Walker F, Luton D, Yazbeck C, Madelenat P, Koskas M. Impact of obesity on the results of fertility-sparing management for atypical hyperplasia and grade 1 endometrial cancer. Gynecol Oncol. 2014;133:33–37.
    1. Yang B, Xie L, Zhang H, Zhu Q, Du Y, Luo X, et al. Insulin resistance and overweight prolonged fertility-sparing treatment duration in endometrial atypical hyperplasia patients. J Gynecol Oncol. 2018;29:e35.
    1. Park JY, Kim DY, Kim JH, Kim YM, Kim KR, Kim YT, et al. Long-term oncologic outcomes after fertility-sparing management using oral progestin for young women with endometrial cancer (KGOG 2002) Eur J Cancer. 2013;49:868–874.
    1. Pernicova I, Korbonits M. Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10:143–156.
    1. Lee CH, Woo YC, Wang Y, Yeung CY, Xu A, Lam KS. Obesity, adipokines and cancer: an update. Clin Endocrinol (Oxf) 2015;83:147–156.
    1. Fuentes-Mattei E, Velazquez-Torres G, Phan L, Zhang F, Chou PC, Shin JH, et al. Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer. J Natl Cancer Inst. 2014;106:dju158.
    1. Tebbe C, Chhina J, Dar SA, Sarigiannis K, Giri S, Munkarah AR, et al. Metformin limits the adipocyte tumor-promoting effect on ovarian cancer. Oncotarget. 2014;5:4746–4764.
    1. Algire C, Amrein L, Bazile M, David S, Zakikhani M, Pollak M. Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene. 2011;30:1174–1182.
    1. Klein J, Westphal S, Kraus D, Meier B, Perwitz N, Ott V, et al. Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes. J Endocrinol. 2004;183:299–307.
    1. Catalano S, Giordano C, Rizza P, Gu G, Barone I, Bonofiglio D, et al. Evidence that leptin through STAT and CREB signaling enhances cyclin D1 expression and promotes human endometrial cancer proliferation. J Cell Physiol. 2009;218:490–500.
    1. Mitsuhashi A, Kiyokawa T, Sato Y, Shozu M. Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial. Cancer. 2014;120:2986–2995.
    1. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med. 1998;338:1876–1880.
    1. Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med. 2008;358:47–54.
    1. Bonny AE, Ziegler J, Harvey R, Debanne SM, Secic M, Cromer BA. Weight gain in obese and nonobese adolescent girls initiating depot medroxyprogesterone, oral contraceptive pills, or no hormonal contraceptive method. Arch Pediatr Adolesc Med. 2006;160:40–45.
    1. Mangan SA, Larsen PG, Hudson S. Overweight teens at increased risk for weight gain while using depot medroxyprogesterone acetate. J Pediatr Adolesc Gynecol. 2002;15:79–82.

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