No Effect of Metformin on Ovarian Cancer Survival: A Systematic Review and Meta-Analysis of Cohort Studies

Author(s): Yongbo Wang, Xiaoxue Liu, Pengfei Yan, Yongyi Bi, Yu Liu, Zhi-Jiang Zhang*

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 23 , 2019

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Abstract:

Background: A number of observational studies examined the association between metformin therapy and ovarian cancer survival outcomes, but the results are inconsistent.

Objective: The study aimed to investigate the effect of metformin on survival for ovarian cancer patients.

Method: PubMed, Embase and Web of Science databases were searched for relevant studies from the inception to June 11, 2019. The strength of the relationship was assessed using summary of hazard ratios (HRs) with corresponding 95% confidence intervals (CI). Statistical analyses were carried out using the random-effects model.

Results: Totally, 6 retrospective cohort studies involving 2,638 ovarian cancer patients were included. Metformin was not associated with improved overall survival (HR=0.78, 95% CI 0.54-1.12, P=0.175, I2= 61.6%) and disease- free survival (HR=0.49, 95% CI 0.20-1.17, P=0.106, I2=82.1%) in ovarian cancer patients compared to nonmetformin users.

Conclusion: The current study provides preliminary evidence that metformin may not be associated with a survival benefit for ovarian cancer patients. More studies with rigorous designs are needed.

Keywords: Metformin, ovarian cancer, overall survival, diabetes mellitus, immortal time bias, statistical analyses.

[1]
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62(1): 10-29.
[http://dx.doi.org/10.3322/caac.20138] [PMID: 22237781]
[2]
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65(2): 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[3]
Wang L, Wang L, Zhang J, Wang B, Liu H. Association between diabetes mellitus and subsequent ovarian cancer in women: A systematic review and meta-analysis of cohort studies. Medicine (Baltimore) 2017; 96(16)e6396
[http://dx.doi.org/10.1097/MD.0000000000006396] [PMID: 28422831]
[4]
Zhang D, Li N, Xi Y, Zhao Y, Wang T. Diabetes mellitus and risk of ovarian cancer. A systematic review and meta-analysis of 15 cohort studies. Diabetes Res Clin Pract 2017; 130: 43-52.
[http://dx.doi.org/10.1016/j.diabres.2017.04.005] [PMID: 28554142]
[5]
Zhang D, Zhao Y, Wang T, Xi Y, Li N, Huang H. Diabetes mellitus and long-term mortality of ovarian cancer patients. A systematic review and meta-analysis of 12 cohort studies. Diabetes Metab Res Rev 2017; 33(4): 33.
[http://dx.doi.org/10.1002/dmrr.2868] [PMID: 27860198]
[6]
Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: Update regarding thiazolidinediones: A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2008; 31(1): 173-5.
[http://dx.doi.org/10.2337/dc08-9016] [PMID: 18165348]
[7]
Morley LC, Tang T, Yasmin E, Norman RJ, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev 2017; 11CD003053
[http://dx.doi.org/10.1002/14651858.CD003053.pub6] [PMID: 29183107]
[8]
Zhang ZJ, Li S. The prognostic value of metformin for cancer patients with concurrent diabetes: A systematic review and meta-analysis. Diabetes Obes Metab 2014; 16(8): 707-10.
[http://dx.doi.org/10.1111/dom.12267] [PMID: 24460896]
[9]
Zhang ZJ, Yuan J, Bi Y, Wang C, Liu Y. The effect of metformin on biomarkers and survivals for breast cancer- a systematic review and meta-analysis of randomized clinical trials. Pharmacol Res 2019; 141: 551-5.
[http://dx.doi.org/10.1016/j.phrs.2019.01.036] [PMID: 30664988]
[10]
Moher D, Liberati A, Tetzlaff J, Altman DG, Grp P. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009; 6(7)e1000097
[http://dx.doi.org/10.1371/journal.pmed.1000097] [PMID: 19621072]
[11]
Wei M, Liu Y, Wang C, et al. The need for differentiating diabetes-specific mortality from total mortality when comparing metformin with insulin regarding cancer survival. Acta Diabetol 2017; 54(2): 219-20.
[http://dx.doi.org/10.1007/s00592-016-0933-2] [PMID: 27796654]
[12]
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25(9): 603-5.
[http://dx.doi.org/10.1007/s10654-010-9491-z] [PMID: 20652370]
[13]
Parmar MKB, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998; 17(24): 2815-34.
[http://dx.doi.org/10.1002/(SICI)1097-0258(19981230)17:24<2815:AID-SIM110>3.0.CO;2-8] [PMID: 9921604]
[14]
Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21(11): 1539-58.
[http://dx.doi.org/10.1002/sim.1186] [PMID: 12111919]
[15]
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315(7109): 629-34.
[http://dx.doi.org/10.1136/bmj.315.7109.629] [PMID: 9310563]
[16]
Bar D, Lavie O, Stein N, Feferkorn I, Shai A. The effect of metabolic comorbidities and commonly used drugs on the prognosis of patients with ovarian cancer. Eur J Obstet Gynecol Reprod Biol 2016; 207: 227-31.
[http://dx.doi.org/10.1016/j.ejogrb.2016.09.005] [PMID: 27890326]
[17]
Garcia C, Yao A, Camacho F, Balkrishnan R, Cantrell LA. A SEER-Medicare analysis of the impact of metformin on overall survival in ovarian cancer. Gynecol Oncol 2017; 146(2): 346-50.
[http://dx.doi.org/10.1016/j.ygyno.2017.05.006] [PMID: 28499649]
[18]
Romero IL, McCormick A, McEwen KA, et al. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet Gynecol 2012; 119(1): 61-7.
[http://dx.doi.org/10.1097/AOG.0b013e3182393ab3] [PMID: 22183212]
[19]
Shah MM, Erickson BK, Matin T, et al. Diabetes mellitus and ovarian cancer: More complex than just increasing risk. Gynecol Oncol 2014; 135(2): 273-7.
[http://dx.doi.org/10.1016/j.ygyno.2014.09.004] [PMID: 25220626]
[20]
Urpilainen E, Marttila M, Hautakoski A, et al. Prognosis of ovarian cancer in women with type 2 diabetes using metformin and other forms of antidiabetic medication or statins: A retrospective cohort study. BMC Cancer 2018; 18(1): 767.
[http://dx.doi.org/10.1186/s12885-018-4676-z] [PMID: 30055585]
[21]
Wang SB, Lei KJ, Liu JP, Jia YM. Continuous use of metformin can improve survival in type 2 diabetic patients with ovarian cancer: A retrospective study. Medicine (Baltimore) 2017; 96(29)e7605
[http://dx.doi.org/10.1097/MD.0000000000007605] [PMID: 28723808]
[22]
Dilokthornsakul P, Chaiyakunapruk N, Termrungruanglert W, Pratoomsoot C, Saokaew S, Sruamsiri R. The effects of metformin on ovarian cancer: A systematic review. Int J Gynecol Cancer 2013; 23(9): 1544-51.
[http://dx.doi.org/10.1097/IGC.0b013e3182a80a21] [PMID: 24172091]
[23]
Li L, Qi X, Xu M, et al. The effects of metformin on ovarian cancer: An updated systematic review and meta-analysis. Int J Clin Exp Med 2016; 9: 17559-68.
[24]
Shi J, Liu B, Wang H, Zhang T, Yang L. Association of metformin use with ovarian cancer incidence and prognosis: A systematic review and meta-analysis. Int J Gynecol Cancer 2019; 29(1): 140-6.
[http://dx.doi.org/10.1136/ijgc-2018-000060] [PMID: 30640696]
[25]
Gong TT, Wu QJ, Lin B, Ruan SK, Kushima M, Takimoto M. Observational Studies on the Association Between Post-diagnostic Metformin Use and Survival in Ovarian Cancer: A Systematic Review and Meta-Analysis. Front Oncol 2019; 9: 458.
[http://dx.doi.org/10.3389/fonc.2019.00458] [PMID: 31192140]
[26]
Currie CJ, Poole CD, Jenkins-Jones S, Gale EAM, Johnson JA, Morgan CL. Mortality after incident cancer in people with and without type 2 diabetes: Impact of metformin on survival. Diabetes Care 2012; 35(2): 299-304.
[http://dx.doi.org/10.2337/dc11-1313] [PMID: 22266734]
[27]
Wei M, Liu Y, Bi Y, Zhang ZJ. Metformin and pancreatic cancer survival: Real effect or immortal time bias? Int J Cancer 2019; 145(7): 1822-8.
[http://dx.doi.org/10.1002/ijc.32254] [PMID: 30848544]
[28]
Zhang ZJ, Bi Y, Li S, et al. Reduced risk of lung cancer with metformin therapy in diabetic patients: A systematic review and meta-analysis. Am J Epidemiol 2014; 180(1): 11-4.
[http://dx.doi.org/10.1093/aje/kwu124] [PMID: 24920786]
[29]
Zhang ZJ, Zheng ZJ, Kan H, et al. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: A meta-analysis. Diabetes Care 2011; 34(10): 2323-8.
[http://dx.doi.org/10.2337/dc11-0512] [PMID: 21949223]
[30]
Zhang ZJ, Zheng ZJ, Shi R, Su Q, Jiang Q, Kip KE. Metformin for liver cancer prevention in patients with type 2 diabetes: A systematic review and meta-analysis. J Clin Endocrinol Metab 2012; 97(7): 2347-53.
[http://dx.doi.org/10.1210/jc.2012-1267] [PMID: 22523334]
[31]
Zhang ZJ. Metformin and reduced risk of cancer in the Hong Kong Diabetes Registry: Real effect or immortal time bias? J Gen Intern Med 2019; 34(7): 1154-7.
[http://dx.doi.org/10.1007/s11606-019-04982-z] [PMID: 31025306]
[32]
Zhang F, Chen H, Du J, Wang B, Yang L. Anticancer activity of metformin, an antidiabetic drug, against ovarian cancer cells involves inhibition of cysteine-rich 61 (Cyr61)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Med Sci Monit 2018; 24: 6093-101.
[http://dx.doi.org/10.12659/MSM.909745] [PMID: 30171812]
[33]
Zheng Y, Zhu J, Zhang H, Liu Y, Sun H. Metformin inhibits ovarian cancer growth and migration in vitro and in vivo by enhancing cisplatin cytotoxicity. Am J Transl Res 2018; 10(10): 3086-98.
[PMID: 30416652]
[34]
Muoio DM, Newgard CB. Mechanisms of disease: Molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 2008; 9(3): 193-205.
[http://dx.doi.org/10.1038/nrm2327] [PMID: 18200017]
[35]
Pulito C, Sanli T, Rana P, Muti P, Blandino G, Strano S. Metformin: On ongoing journey across diabetes, cancer therapy and prevention. Metabolites 2013; 3(4): 1051-75.
[http://dx.doi.org/10.3390/metabo3041051] [PMID: 24958265]


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VOLUME: 25
ISSUE: 23
Year: 2019
Page: [2595 - 2601]
Pages: 7
DOI: 10.2174/1381612825666190716113126
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