Abstract
Introduction
Although patients with pancreatic ductal adenocarcinoma (PDAC) frequently require medications to treat pre-existing conditions, the impact of these treatments on outcomes post-resection is unknown. The purpose of this study was to determine the impact of preoperative medications on overall survival after pancreatic resection.
Methods
Multi-institutional data on preoperative medications and outcomes in patients undergoing resection for PDAC were analyzed. Univariate and multivariate analyses were performed to determine which medications were predictive of early mortality.
Results
Of the 518 patients resected for PDAC, 13.3% were being treated preoperatively with insulin, 14.8% were on a statin, 1.7% were on steroids, and 7.6% were on thyroxin. On univariate analysis, patients taking preoperative insulin had a higher 90-day mortality rate relative to those not on insulin (13.0% vs. 4.8%, p = 0.024), and those on a statin had a higher 90-day mortality than those who were not (10.8% vs. 4.6%, p = 0.035). Preoperative steroids and thyroxin were not associated with 90-day mortality (p = 0.409 and p = 0.474, respectively). Insulin and statin use was a stronger predictor of 90-day mortality than history of diabetes (p = 0.101), BMI ≥ 30 (p = 0.166), cardiac disease (p = 0.168), pulmonary disease (p = 1.000), or renal dysfunction (p = 1.000). Older patients also had a higher risk of early postoperative death (p = 0.011). On multivariate analysis, only preoperative insulin usage and statin treatment independently predicted early mortality (odds ratio (OR) = 3.043; 95% confidence interval (CI), 1.256–7.372; p = 0.014, and OR = 2.529; 95% CI, 1.048–6.104; p = 0.039, respectively). Based on the beta coefficients, a simple scoring system was devised to predict survival after resection from preoperative medication use. Zero points were assigned to patients who were on neither insulin nor a statin, one point to those who were on one or the other, and two points to those who were on both insulin and a statin. The score correlated with early postoperative survival (90-day mortality rates of 3.4%, 11.5%, and 13.3% for 0, 1, and 2 points, respectively, p = 0.004). Increasing score was also associated with poorer long-term outcomes, with a median overall survival of 19.6, 15.6, and 11.2 months for 0, 1, and 2 points, respectively (p = 0.002, median follow-up 14.4 months).
Conclusions
Patients with PDAC being treated for pre-existing diabetes or hypercholesterolemia with either insulin or statin-based therapy have an increased risk of early postoperative mortality. A simple scoring system based on preoperative medications can be used to predict early and overall survival following resection.
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References
Chari ST, Leibson CL, Rabe KG, Timmons LJ, Ransom J, de Andrade M, et al. Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 2008 Jan;134:95-101.
Pannala R, Leirness JB, Bamlet WR, Basu A, Petersen GM, Chari ST. Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology 2008 Apr;134:981-987.
Everhart J, Wright D. (1995) Diabetes mellitus as a risk factor for pancreatic cancer A meta-analysis. JAMA 273:1605-1609.
Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer 2005 Jun 6;92:2076-2083.
Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB, Derr RL, et al. Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 2008 Dec 17;300:2754-2764.
Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009 Aug;137:482-488.
Li D, Morris JS, Liu J, Hassan MM, Day RS, Bondy ML, et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA 2009 Jun 24;301:2553-2562.
Goldstein MR, Mascitelli L, Pezzetta F. Do statins prevent or promote cancer? Curr Oncol 2008 Apr;15:76-77.
Chu CK, Mazo AE, Sarmiento JM, Staley CA, Adsay NV, Umpierrez GE, et al. Impact of diabetes mellitus on perioperative outcomes after resection for pancreatic adenocarcinoma. J Am Coll Surg 2010 Apr;210:463-473.
Ramos M, Khalpey Z, Lipsitz S, Steinberg J, Panizales MT, Zinner M, et al. Relationship of perioperative hyperglycemia and postoperative infections in patients who undergo general and vascular surgery. Ann Surg 2008 Oct;248:585-591.
Neumayer L, Hosokawa P, Itani K, El-Tamer M, Henderson WG, Khuri SF. Multivariable predictors of postoperative surgical site infection after general and vascular surgery: results from the patient safety in surgery study. J Am Coll Surg 2007 Jun;204:1178-1187.
Frisch A, Chandra P, Smiley D, Peng L, Rizzo M, Gatcliffe C, et al. Prevalence and Clinical Outcome of Hyperglycemia in the Perioperative in non-Cardiac Surgery. Diabetes Care 2010 Aug;33(8):1783–1788.
Calle EE, Murphy TK, Rodriguez C, Thun MJ, Heath CW, Jr. Diabetes mellitus and pancreatic cancer mortality in a prospective cohort of United States adults. Cancer Causes Control 1998 Aug;9:403-410.
Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A. Abnormal glucose metabolism and pancreatic cancer mortality. JAMA 2000 May 17;283:2552-2558.
Chu CK, Mazo AE, Goodman M, Egnatashvili V, Sarmiento JM, Staley CA, et al. Preoperative diabetes mellitus and long-term survival after resection of pancreatic adenocarcinoma. Ann Surg Oncol 2010 Feb;17:502-513.
Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995 Feb;16:3-34.
Giovannucci E, Michaud D. The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology 2007 May;132:2208-2225.
Call R, Grimsley M, Cadwallader L, Cialone L, Hill M, Hreish V, et al. Insulin--carcinogen or mitogen? Preclinical and clinical evidence from prostate, breast, pancreatic, and colorectal cancer research. Postgrad Med 2010 May;122:158-165.
Stoeltzing O, Liu W, Reinmuth N, Fan F, Parikh AA, Bucana CD, et al. Regulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancer. Am J Pathol 2003 Sep;163:1001-1011.
Rensing KL, Houttuijn Bloemendaal FM, Weijers EM, Richel DJ, Buller HR, Koolwijk P, et al. Could recombinant insulin compounds contribute to adenocarcinoma progression by stimulating local angiogenesis? Diabetologia 2010 May;53:966-970.
Basso D, Plebani M, Fogar P, Panozzo MP, Meggiato T, De Paoli M, et al. Insulin-like growth factor-I, interleukin-1 alpha and beta in pancreatic cancer: role in tumor invasiveness and associated diabetes. Int J Clin Lab Res 1995;25:40-43.
Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR. AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res 2001 Jan 15;61:589-593.
Bailey CJ, Turner RC. Metformin. N Engl J Med 1996 Feb 29;334:574-579.
Yang YX. Do diabetes drugs modify the risk of pancreatic cancer? Gastroenterology 2009 Aug;137:412-415.
Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding XZ, et al. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 2001 Apr;120:1263-1270.
Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006 Nov 1;66:10269-10273.
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001 Oct;108:1167-1174.
Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 2007 Feb;9:218-224.
Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 2005 Apr 29;18:283-293.
Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006 Feb;29:254-258.
Bowker SL, Yasui Y, Veugelers P, Johnson JA. (2010) Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure. Diabetologia 53:1631–1637
Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005 Jun 4;330:1304-1305.
Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009 Sep;52:1766-1777.
Batty GD, Kivimaki M, Morrison D, Huxley R, Smith GD, Clarke R, et al. Risk factors for pancreatic cancer mortality: extended follow-up of the original Whitehall Study. Cancer Epidemiol Biomarkers Prev 2009 Feb;18:673-675.
Gbelcova H, Lenicek M, Zelenka J, Knejzlik Z, Dvorakova G, Zadinova M, et al. Differences in antitumor effects of various statins on human pancreatic cancer. Int J Cancer 2008 Mar 15;122:1214-1221.
Friis S, Poulsen AH, Johnsen SP, McLaughlin JK, Fryzek JP, Dalton SO, et al. Cancer risk among statin users: a population-based cohort study. Int J Cancer 2005 Apr 20;114:643-647.
Karp I, Behlouli H, Lelorier J, Pilote L. Statins and cancer risk. Am J Med 2008 Apr;121:302-309.
Kuoppala J, Lamminpaa A, Pukkala E. Statins and cancer: A systematic review and meta-analysis. Eur J Cancer 2008 Oct;44:2122-2132.
Dale KM, Coleman CI, Henyan NN, Kluger J, White CM. Statins and cancer risk: a meta-analysis. JAMA 2006 Jan 4;295:74-80.
Bonovas S, Sitaras NM. Does pravastatin promote cancer in elderly patients? A meta-analysis. CMAJ 2007 Feb 27;176:649-654.
Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002 Nov 23;360:1623-1630.
Bonovas S, Filioussi K, Sitaras NM. Statins are not associated with a reduced risk of pancreatic cancer at the population level, when taken at low doses for managing hypercholesterolemia: evidence from a meta-analysis of 12 studies. Am J Gastroenterol 2008 Oct;103:2646-2651.
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Chagpar, R.B., Martin, R.C.G., Ahmad, S.A. et al. Medically Managed Hypercholesterolemia and Insulin-Dependent Diabetes Mellitus Preoperatively Predicts Poor Survival after Surgery for Pancreatic Cancer. J Gastrointest Surg 15, 551–557 (2011). https://doi.org/10.1007/s11605-011-1448-3
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DOI: https://doi.org/10.1007/s11605-011-1448-3