Abstract
Preclinical evidence has demonstrated anti-tumorigenic effects of metformin. The effects of metformin following pancreatic cancer, however, remain undefined. We sought to assess the association between metformin use and survival using a large, nationally representative sample of patients undergoing surgery for pancreatic cancer. Patients undergoing a pancreatic resection between January 01, 2010, and December 31, 2012, were identified using the Truven Health MarketScan database. Clinical data, including history of metformin use, as well as operative details and information on long-term outcomes were collected. Multivariable Cox proportional hazards regression analysis was performed to assess the effect of metformin use on overall survival (OS). A total of 3393 patients were identified. The mean age of patients was 54.2 years (SD = 9.1 years). Roughly one half of patients were female (n = 1735, 51.1 %); 49.1 % (n = 1665) presented with a Charlson comorbidity index of 3 or greater (CCI ≥3); and 19.6 % (n = 664) had diabetes. At the time of surgery, 60.0 % (n = 2034) of patients underwent a pancreaticoduodenectomy, 35.7 % (n = 1212) a partial/distal pancreatectomy, while 4.3 % (n = 147) had a total pancreatectomy. On pathology, 1057 (31.2 %) had lymph node metastasis. Metformin use was identified in 456 patients (13.4 %) and was more commonly administered among patients without locally advanced disease (14.3 vs. 11.6 %, p = 0.038). While OS was comparable between patients within the first year of surgery (OS at 1 year 65.4 % [95 % confidence interval (CI) 63.4–67.3 %] vs. 69.2 % [95 % CI 64.2–73.4 %]), patients who received metformin demonstrated an improved OS beginning at 18 months following surgery. On multivariable analysis adjusting for patient and clinicopathologic characteristics, metformin use was independently associated with a decreased risk of mortality (hazard ratio [HR] = 0.79, 95 % CI 0.67–0.93, p = 0.005). Metformin use was associated with an improved overall survival among patients undergoing pancreatic surgery for pancreatic cancer. Further work is necessary to better understand its role in modifying cancer-specific and overall health outcomes.
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Tempero MA, Malafa MP, Behrman SW, et al. Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2014;12(8):1083-1093.
Mayo SC, Nathan H, Cameron JL, et al. Conditional survival in patients with pancreatic ductal adenocarcinoma resected with curative intent. Cancer. 2012;118(10):2674-2681. doi:10.1002/cncr.26553.
Gillen S, Schuster T, Meyer zum Büschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7(4):e1000267–15. doi:10.1371/journal.pmed.1000267.
Singh S, Singh PP, Singh AG, Murad MH, McWilliams RR, Chari ST. Anti-Diabetic Medications and Risk of Pancreatic Cancer in Patients With Diabetes Mellitus: A Systematic Review and Meta-Analysis. The American Journal of Gastroenterology. 2013;108(4):510-519. doi:10.1038/ajg.2013.7.
Li D, Mao Y, Chang P, et al. Impacts of new-onset and long-term diabetes on clinical outcome of pancreatic cancer. Am J Cancer Res. 2015;5(10):3260-3269.
Bosetti C, Rosato V, Li D, et al. Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium. Ann Oncol. 2014;25(10):2065-2072. doi:10.1093/annonc/mdu276.
Kozak MM, Anderson EM, Eyben von R, et al. Statin and Metformin Use Prolongs Survival in Patients With Resectable Pancreatic Cancer. Pancreas. 2016;45(1):64-70. doi:10.1097/MPA.0000000000000470.
Wang Z, Lai S-T, Xie L, et al. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Research and Clinical Practice. 2014;106(1):19-26. doi:10.1016/j.diabres.2014.04.007.
Li D, Yeung S-CJ, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137(2):482-488. doi:10.1053/j.gastro.2009.04.013.
Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304-1305. doi:10.1136/bmj.38415.708634.F7.
Franciosi M, Lucisano G, Lapice E, Strippoli GFM, Pellegrini F, Nicolucci A. Metformin Therapy and Risk of Cancer in Patients with Type 2 Diabetes: Systematic Review. Federici M, ed. PLoS ONE. 2013;8(8):e71583–12. doi:10.1371/journal.pone.0071583.
Incio J, Suboj P, Chin SM, et al. Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages. Xie K, ed. PLoS ONE. 2015;10(12):e0141392–23. doi:10.1371/journal.pone.0141392.
Goel G, Sun W. Novel approaches in the management of pancreatic ductal adenocarcinoma: potential promises for the future. J Hematol Oncol. 2015;8(1):44. doi:10.1186/s13045-015-0141-5.
Kordes S, Pollak MN, Zwinderman AH, et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015;16(7):839-847. doi:10.1016/S1470-2045(15)00027-3.
Reni M, Dugnani E, Cereda S, et al. (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: an open-label, randomized phase 2 trial. Clin Cancer Res. October 2015. doi:10.1158/1078-0432.CCR-15-1722.
Hansen L, Chang S. Health Research Data for the Real World: the MarketScan® Databases. Truven Health Analytics. Ann Arbor; 2013.
Stagg V. CHARLSON: Stata module to calculate Charlson index of comorbidity. Statistical Software Components. 2006.
Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. Biometrics. 1983;39(2):499-503.
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials. 1996;17(4):343-346.
Davidson MB, Peters AL. An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med. 1997;102(1):99-110.
Tian RH, Zhang YG, Wu Z, Liu X, Yang JW, Ji HL. Effects of metformin on survival outcomes of lung cancer patients with type 2 diabetes mellitus: a meta-analysis. Clinical and Translational Oncology. October 2015:1-9. doi:10.1007/s12094-015-1412-x.
Jang EK, Kim WG, Kwon H, et al. Metformin Is Associated with a Favorable Outcome in Diabetic Patients with Cervical Lymph Node Metastasis of Differentiated Thyroid Cancer. Eur Thyroid J. 2015;4(3):181-188. doi:10.1159/000437365.
Mei Z-B, Zhang Z-J, Liu C-Y, et al. Survival Benefits of Metformin for Colorectal Cancer Patients with Diabetes: A Systematic Review and Meta-Analysis. Moschetta A, ed. PLoS ONE. 2014;9(3):e91818-e91818. doi:10.1371/journal.pone.0091818.
Xiao Y, Zhang S, Hou G, Zhang X, Hao X, Zhang J. Clinical pathological characteristics and prognostic analysis of diabetic women with luminal subtype breast cancer. Tumor Biol. 2013;35(3):2035-2045. doi:10.1007/s13277-013-1270-5.
Barone BB, Yeh H-C, Snyder CF, et al. Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA. 2008;300(23):2754-2764. doi:10.1001/jama.2008.824.
Yang Y-X, Rustgi AK. Impact of Metformin on Advanced Pancreatic Cancer Survival: Too Little, Too Late? Clin Cancer Res. 2015. doi:10.1158/1078-0432.CCR-15-2494.
Choi Y, Kim T-Y, Oh D-Y, et al. The Impact of Diabetes Mellitus and Metformin Treatment on Survival of Patients with Advanced Pancreatic Cancer Undergoing Chemotherapy. Cancer Res Treat. March 2015:1-9. doi:10.4143/crt.2014.292.
Sadeghi N, Abbruzzese JL, Yeung SCJ, Hassan M, Li D. Metformin Use Is Associated with Better Survival of Diabetic Patients with Pancreatic Cancer. Clin Cancer Res. 2012;18(10):2905-2912. doi:10.1158/1078-0432.CCR-11-2994.
Walter U, Kohlert T, Rahbari NN, Weitz J, Welsch T. Impact of preoperative diabetes on long-term survival after curative resection of pancreatic adenocarcinoma: a systematic review and meta-analysis. Ann Surg Oncol. 2014;21(4):1082-1089. doi:10.1245/s10434-013-3415-6.
Chu CK, Mazo AE, Goodman M, et al. Preoperative diabetes mellitus and long-term survival after resection of pancreatic adenocarcinoma. Ann Surg Oncol. 2010;17(2):502-513. doi:10.1245/s10434-009-0789-6.
Haut ER, Pronovost PJ, Schneider EB. Limitations of administrative databases. JAMA. 2012;307(24):2589–authorreply2589–90. doi:10.1001/jama.2012.6626.
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Complementary log-log plots for strata of metformin use. (GIF 174 KB)
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Cerullo, M., Gani, F., Chen, S.Y. et al. Metformin Use Is Associated with Improved Survival in Patients Undergoing Resection for Pancreatic Cancer. J Gastrointest Surg 20, 1572–1580 (2016). https://doi.org/10.1007/s11605-016-3173-4
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DOI: https://doi.org/10.1007/s11605-016-3173-4