Abstract
Purpose
Some clinical studies have suggested that metformin improved prognoses in several cancers. This study aimed to identify prognostic factors for pancreatic ductal adenocarcinoma (PDAC) and determine the utility of metformin administration.
Methods
Between January 2007 and December 2015, 373 consecutive patients underwent curative surgery for PDAC. Among the patients, 121 were diagnosed as having diabetes mellitus (DM) before surgery. The characteristics and overall survival (OS) between patients with and without DM were compared retrospectively. Based on their metformin intake, patients with DM were divided into two groups. OS rates between patients with and without metformin intake were compared. Univariate and multivariate analyses were performed to identify prognostic factors for OS among all patients and those with PDAC and DM.
Results
No significant differences in the 5-year survival rates between patients with and without DM were observed. Among the 121 patients with DM, 18 received metformin and 103 did not (other medications group). The 5-year survival rate was significantly better in the metformin group than in the other medications group (66.7% and 24.4%, respectively; p = 0.034). Multivariate analysis identified pN1 (p = 0.002), metformin administration (p = 0.022), and microvascular invasion (p = 0.023) as independent prognostic factors for OS in the patients with DM. Matched-pair analysis showed that OS tended to be better in the metformin group than in the other medications group (p = 0.067).
Conclusions
History of metformin intake may contribute to favorable prognosis in patients with PDAC and pre-existing DM.
Similar content being viewed by others
References
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69:7–34
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108
Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y (2016) Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet 388:248–257
Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H (2013) Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 310:1473–1481
Magruder JT, Elahi D, Andersen DK (2011) Diabetes and pancreatic cancer: chicken or egg? Pancreas 40:339–351
Margel D, Urbach DR, Lipscombe LL, Bell CM, Kulkarni G, Austin PC, Fleshner N (2013) Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol 31:3069–3075
Coyle C, Cafferty FH, Vale C, Langley RE (2016) Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Ann Oncol 27:2184–2195
Kumar S, Meuter A, Thapa P, Langstraat C, Giri S, Chien J, Rattan R, Cliby W, Shridhar V (2013) Metformin intake is associated with better survival in ovarian cancer: a case-control study. Cancer 119:555–562
Xu H, Chen K, Jia X, Tian Y, Dai Y, Li D, Xie J, Tao M, Mao Y (2015) Metformin use is associated with better survival of breast cancer patients with diabetes: a meta-analysis. Oncologist 20:1236–1244
Bridgewater J, Lopes A, Wasan H, Malka D, Jensen L, Okusaka T, Knox J, Wagner D, Cunningham D, Shannon J, Goldstein D, Moehler M, Bekaii-Saab T, McNamara MG, Valle JW (2016) Prognostic factors for progression-free and overall survival in advanced biliary tract cancer. Ann Oncol 27:134–140
Wan G, Sun X, Li F, Wang X, Li C, Li H, Yu X, Cao F (2018) Survival benefit of metformin adjuvant treatment for pancreatic cancer patients: a systematic review and meta-analysis. Cell Physiol Biochem 49:837–847
Zhou PT, Li B, Liu FR, Zhang MC, Wang Q, Li YY, Xu C, Liu YH, Yao Y, Li D (2017) Metformin is associated with survival benefit in pancreatic cancer patients with diabetes: a systematic review and meta-analysis. Oncotarget 8:25242–25250
Dong YW, Shi YQ, He LW, Cui XY, Su PZ (2017) Effects of metformin on survival outcomes of pancreatic cancer: a meta-analysis. Oncotarget 8:55478–55488
Jang WI, Kim MS, Kang SH, Jo AJ, Kim YJ, Tchoe HJ, Park CM, Kim HJ, Choi JA, Choi HJ, Paik EK, Seo YS, Yoo HJ, Kang JK, Han CJ, Kim YJ, Kim SB, Ko MJ (2017) Association between metformin use and mortality in patients with type 2 diabetes mellitus and localized resectable pancreatic cancer: a nationwide population-based study in Korea. Oncotarget 8:9587–9596
Amin S, Mhango G, Lin J, Aronson A, Wisnivesky J, Boffetta P, Lucas AL (2016) Metformin improves survival in patients with pancreatic ductal adenocarcinoma and pre-existing diabetes: a propensity score analysis. Am J Gastroenterol 111:1350–1357
Choi Y, Kim TY, Oh DY, Lee KH, Han SW, Im SA, Kim TY, Bang YJ (2016) The impact of diabetes mellitus and metformin treatment on survival of patients with advanced pancreatic cancer undergoing chemotherapy. Cancer Res Treat 48:171–179
Ambe CM, Mahipal A, Fulp J, Chen L, Malafa MP (2016) Effect of metformin use on survival in resectable pancreatic cancer: a single-institution experience and review of the literature. PLoS One 11:e0151632
Wang Z, Lai ST, Xie L, Zhao JD, Ma NY, Zhu J, Ren ZG, Jiang GL (2014) Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract 106:19–26
Sadeghi N, Abbruzzese JL, Yeung SC et al (2012) Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res 18:2905–2912
Currie CJ, Poole CD, Jenkins-Jones S, Gale EAM, Johnson JA, Morgan CL (2012) Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care 35:299–304
Chaiteerakij R, Petersen GM, Bamlet WR, Chaffee KG, Zhen DB, Burch PA, Leof ER, Roberts LR, Oberg AL (2016) Metformin use and survival of patients with pancreatic cancer: a cautionary lesson. J Clin Oncol 34:1898–1904
Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW (2015) Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 16:839–847
Hwang AL, Haynes K, Hwang WT, Yang YX (2013) Metformin and survival in pancreatic cancer: a retrospective cohort study. Pancreas 42:1054–1059
(2006) Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia. World Health Organization, Geneva
(2011) Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus: abbreviated report of a WHO consultation. World Health Organization, Geneva
Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, de Santibañes E, Pekolj J, Slankamenac K, Bassi C, Graf R, Vonlanthen R, Padbury R, Cameron JL, Makuuchi M (2009) The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 250:187–196
Bassi C, Marchegiani G, Dervenis C, Sarr M, Abu Hilal M, Adham M, Allen P, Andersson R, Asbun HJ, Besselink MG, Conlon K, del Chiaro M, Falconi M, Fernandez-Cruz L, Fernandez-del Castillo C, Fingerhut A, Friess H, Gouma DJ, Hackert T, Izbicki J, Lillemoe KD, Neoptolemos JP, Olah A, Schulick R, Shrikhande SV, Takada T, Takaori K, Traverso W, Vollmer CR, Wolfgang CL, Yeo CJ, Salvia R, Buchler M, International Study Group on Pancreatic Surgery (ISGPS) (2017) The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after. Surgery 161:584–591
Ohgi K, Yamamoto Y, Sugiura T, Okamura Y, Ito T, Ashida R, Aramaki T, Uesaka K (2017) Is pancreatic head cancer with portal venous involvement really borderline resectable? Appraisal of an upfront surgery series. Ann Surg Oncol 24:2752–2761
Brierley JGM, Wittekind C (2017) UICC TNM classification of malignant tumours, Eighth edn. Wiley, Chichester
Andersen DK, Korc M, Petersen GM, Eibl G, Li D, Rickels MR, Chari ST, Abbruzzese JL (2017) Diabetes, pancreatogenic diabetes, and pancreatic cancer. Diabetes 66:1103–1110
Hwang A, Narayan V, Yang Y-X (2013) Type 2 diabetes mellitus and survival in pancreatic adenocarcinoma: a retrospective cohort study. Cancer 119:404–410
McWilliams RR, Matsumoto ME, Burch PA et al (2010) Obesity adversely affects survival in pancreatic cancer patients. Cancer 116:5054–5062
Chu CK, Mazo AE, Goodman M, Egnatashvili V, Sarmiento JM, Staley CA, Galloway JR, Adsay NV, Jacobs S, Kooby DA (2010) Preoperative diabetes mellitus and long-term survival after resection of pancreatic adenocarcinoma. Ann Surg Oncol 17:502–513
Cannon RM, LeGrand R, Chagpar RB, Ahmad SA, McClaine R, Kim HJ, Rupp C, Cho CS, Brinkman A, Weber S, Winslow ER, Kooby DA, Chu CK, Staley CA, Glenn I, Hawkins WG, Parikh AA, Merchant NB, McMasters KM, Martin RCG, Callender GG, Scoggins CR (2012) Multi-institutional analysis of pancreatic adenocarcinoma demonstrating the effect of diabetes status on survival after resection. HPB 14:228–235
Mao Y, Tao M, Jia X, Li D (2015) Diabetes associated with short survival in pancreatic cancer. J Clin Oncol 33:2120–2121
Roeyen G, Jansen M, Chapelle T, Bracke B, Hartman V, Ysebaert D, de Block C (2016) Diabetes mellitus and pre-diabetes are frequently undiagnosed and underreported in patients referred for pancreatic surgery. A prospective observational study. Pancreatology 16:671–676
Warburg O (1956) On the origin of cancer cells. Science 123:309–314
Jalving M, Gietema JA, Lefrandt JD et al (2010) Metformin: taking away the candy for cancer? Eur J Cancer 46:2369–2380
Yue W, Yang CS, DiPaola RS et al (2014) Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prev Res (Phila) 7:388–397
Singh P, Alex JM, Bast F (2014) Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer. Med Oncol 31:805
Pan YH, Jiao L, Lin CY, Lu CH, Li L, Chen HY, Wang YB, He Y (2018) Combined treatment with metformin and gefitinib overcomes primary resistance to EGFR-TKIs with EGFR mutation via targeting IGF-1R signaling pathway. Biologics 12:75–86
Han G, Gong H, Wang Y, Guo S, Liu K (2015) AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell. Cancer Biol Ther 16:77–87
Tan XL, Bhattacharyya KK, Dutta SK, Bamlet WR, Rabe KG, Wang E, Smyrk TC, Oberg AL, Petersen GM, Mukhopadhyay D (2015) Metformin suppresses pancreatic tumor growth with inhibition of NFkappaB/STAT3 inflammatory signaling. Pancreas 44:636–647
Kourelis TV, Siegel RD (2012) Metformin and cancer: new applications for an old drug. Med Oncol 29:1314–1327
Bridges HR, Jones AJ, Pollak MN et al (2014) Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J 462:475–487
Memmott RM, Dennis PA (2009) LKB1 and mammalian target of rapamycin as predictive factors for the anticancer efficacy of metformin. J Clin Oncol 27:e226
Author information
Authors and Affiliations
Contributions
Study conception and design: FT and TS. Acquisition of data: FT and TS. Analysis and interpretation of data: FT, TS, and YY. Drafting of manuscript: FT, TS, and KU. Critical revision of manuscript: all authors.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study. Our study protocols can be obtained from our institutional website.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Terasaki, F., Sugiura, T., Okamura, Y. et al. Oncological benefit of metformin in patients with pancreatic ductal adenocarcinoma and comorbid diabetes mellitus. Langenbecks Arch Surg 405, 313–324 (2020). https://doi.org/10.1007/s00423-020-01874-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00423-020-01874-3