Supplementary Table 1. Main risk of bias in the included studies. Study Main risk of bias Anderson, 2009 Differential participation (45% cases, 83% controls) 11% proxy respondents Risk of recall bias Self-reported pancreatitis Few number of exposed subjects Risk of reverse causation (no lag period between pancreatitis and cancer) Treatment outside the region may have resulted in misclassification of exposure or outcome Bang, 2014 No information on tobacco smoking and alcohol consumption Risk of reverse causation (only 1 year lag period between pancreatitis and cancer) Bansal, 1995 Only inpatients included No information on tobacco smoking Considered pseudocyst as manifestation of chronic pancreatitis (risk of misclassification, as this may also be a complication to acute pancreatitis) Risk of reverse causation (only 1 year lag period between pancreatitis and cancer) Treatment outside the Veterans Affairs system may have resulted in misclassification Duell, 2006 33% non-responders in both groups Risk of recall bias Self-reported pancreatitis Few number of exposed subjects Risk of reverse causation (no lag period between pancreatitis and cancer) Treatment outside the region may have resulted in misclassification of exposure or outcome Goldacre, 2008 Only 55% males (risk of selection bias) Only inpatients included Treatment outside the area may have resulted in misclassification No information on tobacco smoking and alcohol consumption Risk of reverse causation (only 1 year lag period between pancreatitis and cancer) Karlson, 1997 Risk of misclassification of exposure (uncertain validity of pancreatitis diagnoses) No information on tobacco smoking Risk of reverse causation (only 1 year lag period between pancreatitis and cancer)
Lowenfels, 1993 Malka, 2002 Pedrazzoli, 2008 Talamini, 1999 Ueda, 2013 Wang, 2011 Wu, 2012 Varying characteristics of the patients in the different centers (risk of different classification of exposure or outcome) Unable to stratify for tobacco smoking and alcohol consumption Questionable quality of pancreatitis diagnoses in early years Few number of cancers 32% lost to follow-up Unable to stratify for tobacco smoking and alcohol consumption Few number of cancers Treatment outside the region may have resulted in misclassification of exposure or outcome Included 6 patients with hereditary pancreatitis (no cancers in this group) Did not standardize by sex Unable to stratify for tobacco smoking and alcohol consumption Few number of cancers High risk of confounding by tobacco smoking Treatment outside the regions may have resulted in misclassification of exposure or outcome Few number of cancers High risk of confounding by alcohol consumption Unable to stratify for tobacco smoking and alcohol consumption Few number of cancers Included 9 patients with hereditary pancreatitis (no cancers in this group) Some information collected in a non-standardized manor Risk of recall bias Few number of cancers Included 4 patients with hereditary pancreatitis (no cancers in this group) Risk of recall bias Few number of exposed subjects Risk of reverse causation (no lag period between pancreatitis and cancer)
Supplementary Table 2: Excluded studies No full-text available (n=20) 1. Adamek HE. Is Chronic Pancreatitis a Risk Factor for Pancreatic Adenocarcinoma? Strahlentherapie und Onkologie 2004;180(4):248-249 2. Bartholomew LG et al. Carcinoma of the pancreas associated with chronic relapsing pancreatitis. Gastroenterol 1958;35(5):473-7 3. Becker V. Carcinoma of the pancreas and chronic pancreatitis--a possible relationship. Acta hepato-gastroenterologica 1978;25(4):257-9 4. Billah MM et al. Chronic calcific pancreatitis and pancreatic cancer. Mymensingh Med J 2014;23(3):485-8 5. Camara SN et al. Etiology, pathology, management and prognosis of chronic pancreatitis in Chinese population: A retrospective study. J Huazhong Univ Sci Technolog Med Sci 2015;35(3):384-9 6. Kamisawa T et al. The incidence of pancreatic and extrapancreatic cancers in Japanese patients with chronic pancreatitis. Hepato- Gastroenterology 2007;54(77):1579-1581 7. Kudo Y et al. Incidence of and risk factors for developing pancreatic cancer in patients with chronic pancreatitis. Hepato- Gastroenterology 2011;58(106):609-611 8. Liang CC et al. Investigation of risk factors for pancreatic carcinoma and chronic pancreatitis. World Chinese Journal of Digestology 2012;20(10):870-874 9. Lin CC et al. Chronic calcifying pancreatitis in Taiwan: A multicentric study and comparison with western countries. Hepato- Gastroenterology 1997;44(15):842-848 10. Lowenfels AB. Chronic pancreatitis, pancreatic cancer, alcohol, and smoking. Gastroenterol Sep 1984;87(3):744-5 11. Lowenfels AB et al. Prognosis of chronic pancreatitis: an international multicenter study. International Pancreatitis Study Group. Am J Gastroenterol 1994;89(9):1467-71
12. Mack et al. Pancreas cancer and smoking, beverage consumption, and past medical history. J Natl Cancer Inst Jan 1986;76(1):49-60 13. Midha S et al. Idiopathic chronic pancreatitis, diabetes, and smoking are significant risk factors for pancreatic cancer: Results of casecontrol and cohort studies. Gastroenterol 2010;138(5):S551 14. Mori M et al. A case-control study on risk factors for pancreatic diseases in Kerala, India. Hepato-Gastroenterology 1999;46(25):25-30 15. Olsen H. Pancreatitis: a prospective clinical evaluation of 100 cases and review of the literature. Am J Dig Dis 1974;19(12):1077-90 16. Ragulin-Coyne E et al. Potential predictors of pancreatic cancer: A population-based screen. J Clin Oncol 2011;29(4): 17. Schlosser W et al. Development of pancreatic cancer in chronic pancreatitis. Zeitschrift fur Gastroenterologie 1996;34(1):3-8 18. Suceveanu AI. Diabetes mellitus, obesity and chronic pancreatitis? Independent risk factors for pancreatic adenocarcinoma (PAC) in Romanian Black Sea coast area. Pancreatology 2015;15(3):S86 19. Takeda Y. The risk factors of pancreatic ductal adenocarcinoma: A hospital-based case-control study in tottori, Japan. Gastroenterol 2013;144(5):S660 20. Vallejo-Senra N et al. Mortality in patients with chronic pancreatitis (CP) with and without exocrine pancreatic insufficiency (EPI). Gastroenterol 2015;148(4):S906 No relevant risk estimate (n=22) 1. Ammann RW et al. Course of alcoholic chronic pancreatitis: a prospective clinicomorphological long-term study. Gastroenterol 1996;111(1):224-31 2. Balakrishnan V et al. Chronic pancreatitis. A prospective nationwide study of 1,086 subjects from India. JOP 2008;9(5):593-600 3. Bhattacharjee PK et al. Demographic and clinicopathological profile of patients with chronic pancreatitis in a tertiary referral teaching hospital of West Bengal: Personal experience. Indian J Gastroenterol 2015;34(5):365-371
4. Dítě, P.; Hermanová, M.; Trna, J.; Novotný, I.; Růžička, M.; Liberda, M.; Bártková, A. The role of chronic inflammation: Chronic pancreatitis as a risk factor of pancreatic cancer. Dig Dis 2012;30(3):277-283 5. Ishii K et al. Chronic calcifying pancreatitis and pancreatic carcinoma in Japan. Digestion 1973;9(5):429-37 6. Kudo Y. High risk group developing pancreatic cancer in patients with chronic pancreatitis. Gastrointest Endosc 2009;69(5):AB271 7. Lankisch PG et al. Natural course in chronic pancreatitis. Pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digestion 1993;54(3):148-155 8. Lankisch PG et al. Epidemiology of pancreatic diseases in Lüneburg County: A study in a defined German population. Pancreatology 2002;2(5):469-477 9. Lo AC et al. Lifestyle, occupational, and reproductive factors in relation to pancreatic cancer risk. Pancreas 2007;35(2):120-9 10. Lu XH et al. Establishment of risk model for pancreatic cancer in Chinese Han population. World J Gastroenterol 2006;12(14):2229-34 11. McWilliams RR et al. Risk Factors for Early-Onset and Very-Early-Onset Pancreatic Adenocarcinoma: A Pancreatic Cancer Case- Control Consortium (PanC4) Analysis. Pancreas 2016;45(2):311-6 12. Midha S et al. Genetically Determined Chronic Pancreatitis but not Alcoholic Pancreatitis Is a Strong Risk Factor for Pancreatic Cancer. Pancreas 2016;45(10):1478-1484 13. Miyake H et al. Clinical course and prognosis of chronic pancreatitis. Pancreas 1987;2(4):378-85 14. Miyake H et al. Prognosis and prognostic factors in chronic pancreatitis. Dig Dis Sci Mar 1989;34(3):449-55 15. Munigala S et al. New diagnosis of chronic Pancreatitis: Risk of missing an underlying pancreatic cancer. Am J Gastroenterol 2014;109(11):1824-1830 16. Robles-Díaz G et al. Chronic pancreatitis in Mexico City. Pancreas 1990;5(4):479-83
17. Rocca G et al. Increased incidence of cancer in chronic pancreatitis. J Clin Gastroenterol 1987;9(2):175-9 18. Ryu JK et al. Clinical features of chronic pancreatitis in Korea: a multicenter nationwide study. Digestion 2005;72(4):207-11 19. Seicean A et al. Mortality risk factors in chronic pancreatitis. J Gastrointestin Liver Dis 2006;15(1):21-26 20. Talamini G et al. Previous cholecystectomy, gastrectomy, and diabetes mellitus are not crucial risk factors for pancreatic cancer in patients with chronic pancreatitis. Pancreas 2001;23(4):364-367 21. Talamini G et al. Outcome and quality of life in chronic pancreatitis. JOP 2001;2(4):117-123 22. Thuluvath PJ et al. Chronic pancreatitis. Long-term pain relief with or without surgery, cancer risk, and mortality. J Clin Gastroenterol 2003;36(2):159-65 No discrimination between acute and chronic pancreatitis (n=11) 1. Bracci PM et al. Pancreatitis and pancreatic cancer in two large pooled case-control studies. Cancer Causes Control 2009;20(9):1723-1731 2. Bueno de Mesquita HB et al. Aspects of medical history and exocrine carcinoma of the pancreas: a population-based case-control study in The Netherlands. Int J Cancer 1992;52(1):17-23 3. Fehringer G et al. The association of family history of cancer and medical history with pancreatic cancer risk. Pancreas 2014;43(5):812-4 4. Fernandez E et al. Family history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Epidemiol Biomarkers Prev 1994 ;3(3):209-12 5. Fernandez E et al. Pancreatitis and the risk of pancreatic cancer. Pancreas 1995;11(2):185-9 6. Hassan MM et al. Risk factors for pancreatic cancer: case-control study. Am J Gastro 2007;102(12):2696-707
7. Kalapothaki V et al. Tobacco, ethanol, coffee, pancreatitis, diabetes mellitus, and cholelithiasis as risk factors for pancreatic carcinoma. Cancer Causes Control 1993;4(4):375-82 8. La Vecchia C et al. Medical history, diet and pancreatic cancer. Oncol 1990;47(6):463-6 9. Lipworth L et al. Diabetes mellitus, other medical conditions and pancreatic cancer: a case-control study. Diabetes Metab Res Rev 2011;27(3):255-61 10. Maisonneuve P et al. Past medical history and pancreatic cancer risk: Results from a multicenter case-control study. Ann Epidemiol 2010;20(2):92-8 11. Partanen TJ et al. Pancreas cancer, tobacco smoking and consumption of alcoholic beverages: a case-control study. Cancer Lett 1997;116(1):27-32 Diabetic population (n=5) 1. Brodovicz KG et al. Impact of diabetes duration and chronic pancreatitis on the association between type 2 diabetes and pancreatic cancer risk. Diabetes Obes Metab 2012;14(12):1123-1128. 2. Lai HC et al. Gallstones, a cholecystectomy, chronic pancreatitis, and the risk of subsequent pancreatic cancer in diabetic patients: A population-based cohort study. J Gastroenterol 2013;48(6):721-727 3. Lin CC et al. Independent and joint effect of type 2 diabetes and gastric and hepatobiliary diseases on risk of pancreatic cancer risk: 10- year follow-up of population-based cohort. Br J Cancer 2014;111(11):2180-6 4. Mansoor E et al. Risk factors for pancreatic cancer in new-onset diabetes mellitus: A population based study. Gastroenterol 2016;150(4):S233 5. Munigala S et al. Higher pancreatic cancer risk following new onset of diabetes mellitus in non-obese patients with chronic pancreatitis. Gastroenterol 2014;79(5):AB191-AB192
Results reported elsewhere (n=2) 1. Duell EJ et al. Pancreatitis and pancreatic cancer risk: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann Oncol 2012;23(11):2964-70 (Reported in: Anderson LN, 2009) 1. Ekbom A et al. Pancreatitis and pancreatic cancer: a population-based study. J Natl Cancer Inst 1994;86(8):625-7 (Reported in: Karlson BM, 1997)
Supplementary Figure 1: Sensitivity analysis. Studies with +50 cancers or exposures and minimum 1 year lag period.
Supplementary Figure 2: Sensitivity analysis. Studies with +50 cancers or exposures and minimum 5 year lag period.
Supplementary Figure 3: Sensitivity analysis. Studies with verified exposure and outcome and minimum 2 year lag period.
Supplementary Figure 4: Sensitivity analysis. Studies adjusting for alcohol consumption and tobacco smoking.