EDITORIAL Can We Prevent Pancreatic Disease? hree diseases, acute pancreatitis, chronic pancreatitis, and pancreatic cancer, constitute the major afflictions of the pancreas requiring treatment by gastroenterologists. Although these diseases are separate entities, there is a temporal relationship between them: acute attacks of pancreatitis generally precede chronic pancreatitis, and a small fraction of patients with chronic pancreatitis eventually develop pancreatic cancer. The frequency, morbidity, and mortality of these diseases differ markedly: acute pancreatitis is a common gastrointestinal disorder, with a mortality rate of approximately 2%. Chronic pancreatitis has a much lower incidence than acute pancreatitis but is a progressive, debilitating, often painful disorder with limited therapeutic options. Pancreatic cancer, with fewer than 200,000 new cases per year in the United States, fits the definition of a rare disease, and, although uncommon, is highly lethal. Despite the best efforts of surgeons and oncologists, current therapy adds only months, rather than years, to pancreatic cancer survival statistics, which have remained relatively unchanged over several decades.1 For many common illnesses, current health strategies focus on prevention because maintaining a person’s health is a more effective approach than treating patients after they have become ill.2 Much of the gain in life expectancy over the past several decades has been the result of prevention of both childhood and adult disease. To what extent are pancreatic diseases avoidable? In the current issue of Clinical Gastroenterology and Hepatology, Alsamarrai et al3 examined factors such as tobacco, obesity, or diet that might alter the risk of pancreatic diseases. Their aim was to focus on these factors rather than nonmodifiable factors such as blood group and various rare genetic disorders. They used a meta-analytic approach, an increasing popular technique that combines and summarizes results from previously published studies. The advantage of this approach is the increased power obtained by combining multiple small studies. The disadvantages include difficulty controlling for confounding, and the problem of selection bias because positive studies are more likely to be published than negative studies. Alsamarrai et al3 attempted to strengthen their results by selecting only cohort studies in which information about exposure to putative risk factors was collected at baseline when the participant was disease free, thereby avoiding recall bias, a common problem for casecontrol studies. One potential disadvantage of this type of study is that patterns of exposure can change over time and the initial assessment obtained many years before the onset of disease may not reflect current exposure.
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From more than 6000 initial reports, Alsamarrai et al3 selected 32 high-quality population-based studies, about 1% of the potentially available reports, for their meta-analysis. The diagnosis of pancreatic disease can be difficult, especially if based on administrative data4; excluding studies coming from referral centers for pancreatic diseases somewhat weakens the validity of the current study. By using the search terms “meta-analysis,” “etiology,” along with “acute pancreatitis,” “chronic pancreatitis,” or “pancreatic cancer,” the investigators retrieved 87 articles on acute pancreatitis, 30 articles on chronic pancreatitis and 184 reports on pancreatic cancer. What new information does this current report add? Most published meta-analytic reports are diseasespecific, but this report combines risk factors for all 3 major pancreatic diseases. This certainly provides a comprehensive overview, but raises questions about the validity of such an unusual approach. Furthermore, readers should bear in mind that the results in this report for the association between various risk factors and combined benign and malignant pancreatic disease are heavily weighted by the inclusion of larger numbers of reports on pancreatic cancer, with only a few studies on benign pancreatic disease. In fact, the analysis for tobacco, alcohol, and obesity includes only 2 studies on acute pancreatitis and a single study on chronic pancreatitis. For acute pancreatitis, several previous publications have shown a temporal increase in this disease,1,5 which most commonly is caused by either alcohol or by gallstones. In most countries, alcohol consumption has remained relatively constant or has decreased, implying that the increase in the frequency of acute pancreatitis most likely is related to an increased frequency of gallstones, for which obesity is a major risk factor. Thus, controlling obesity, a rapidly increasing global problem,6 should reduce the frequency of acute pancreatitis. We already know from many reports that smoking is a major risk factor for pancreatic cancer. What this report shows is that smoking is just as strong a risk factor for benign pancreatic diseases as is heavy alcohol consumption. These findings are in agreement with results from previous meta-analyses that have reported an association between tobacco smoking and both pancreatic cancer (relative risk, 1.7; 95% confidence interval [CI], 1.6–1.9),7 and chronic pancreatitis (relative risk, 2.5; 95% CI, 1.3–4.6).8 For some clinicians, the concept of a link between smoking and benign pancreatic disease may be surprising, and implies that physicians who manage patients with acute or chronic pancreatitis should advise patients about smoking cessation along with guidance about reducing alcohol consumption. Drinking more than 5 alcoholic drinks per day has long been associated with benign pancreatic disease. The Clinical Gastroenterology and Hepatology 2014;-:-–-
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Lowenfels and Maisonneuve
2 cohort studies included in the current report showed an association between pancreatic cancer and heavy alcohol consumption. This last finding had been noted previously in both cohort and case-control studies, with heavy alcohol consumption being associated with an approximately 20% increased risk of pancreatic cancer.9,10 Are nonalcoholic beverages such as coffee or tea a risk factor for pancreatic cancer? A pooled analysis of 14 cohort studies and another more recent large cohort study found no risk for these substances.11,12 The evidence for the protective benefits of selected dietary items against various types of cancer has always been controversial. Although case-control studies often report a favorable effect of fruits or vegetables, the results from stronger studies such as cohort studies or randomized controlled trials are less impressive. In this report, fruits or vegetables afforded an approximately 30% reduction in the overall risk of pancreatic disorders, but with less consistent disease-specific results. However, such a reduction was not established in a pooled analysis of original data from 14 independent cohort studies, with a summary relative risk of 0.89 (95% CI, 0.77–1.04) for high vs low fruit intake and 1.03 (95% CI, 0.87–1.23) for high vs low vegetable intake.13 Although Alsamarrai et al3 did not present information on the fraction of pancreatic disease caused by preventable risk factors, other reports have suggested that a combination of healthy lifestyle measures (nonsmoking, limited alcohol use, adherence to the Mediterranean dietary pattern, body weight control, and regular physical activity) might prevent a substantial fraction of all pancreatic cancers14 and perhaps a similar proportion of benign pancreatic disease. With the alarming increase in the costs associated with hospitalization, this report reminds us of the importance of avoiding known risk factors for pancreatic diseases, and the potential benefit of increasing our intake of preventive substances such as fruits and vegetables. This is especially true of pancreatic cancer, for which, in the United States, the estimated costs are anticipated to increase to 2.8 billion dollars by the year 2020.15 Based on this and similar reports, we can add pancreatic diseases to such illnesses as stroke and heart disease, for which preventive efforts are likely to be effective. ALBERT B. LOWENFELS, MD Departments of Surgery and Family and Community Medicine New York Medical College Valhalla, New York PATRICK MAISONNEUVE, DiplEng Division of Epidemiology and Biostatistics European Institute of Oncology Milan, Italy
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References 1. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 2013;144:1252–1261. 2. World Health Assembly. Global action plan for the prevention and control of noncommunicable diseases 2013-2020. Available at: http://www.who.int/nmh/events/ncd_action_plan/en/. Accessed January 30 2014. 3. Alsamarrai A, Das SLM, Windsor JA, et al. Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies. Clin Gastroenterol Hepatol 2014 Feb 5. Epub ahead of print. 4. Saligram S, Lo D, Saul M, et al. Analyses of hospital administrative data that use diagnosis codes overestimate the cases of acute pancreatitis. Clin Gastroenterol Hepatol 2012; 10:805–811. 5. Spanier BW, Dijkgraaf MG, Bruno MJ. Epidemiology, aetiology and outcome of acute and chronic pancreatitis: an update. Best Pract Res Clin Gastroenterol 2008;22:45–63. 6. Lehnert T, Sonntag D, Konnopka A, et al. Economic costs of overweight and obesity. Best Pract Res Clin Endocrinol Metab 2013;27:105–115. 7. Iodice S, Gandini S, Maisonneuve P, et al. Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbecks Arch Surg 2008;393:535–545. 8. Andriulli A, Botteri E, Almasio PL, et al; ad hoc Committee of the Italian Association for the Study of the Pancreas. Smoking as a cofactor for causation of chronic pancreatitis: a meta-analysis. Pancreas 2010;39:1205–1210. 9. Genkinger JM, Spiegelman D, Anderson KE, et al. Alcohol intake and pancreatic cancer risk: a pooled analysis of fourteen cohort studies. Cancer Epidemiol Biomarkers Prev 2009; 18:765–776. 10. Lucenteforte E, La Vecchia C, Silverman D, et al. Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann Oncol 2012;23:374–382. 11. Genkinger JM, Li R, Spiegelman D, et al. Coffee, tea, and sugarsweetened carbonated soft drink intake and pancreatic cancer risk: a pooled analysis of 14 cohort studies. Cancer Epidemiol Biomarkers Prev 2012;21:305–318. 12. Bhoo-Pathy N, Uiterwaal CS, Dik VK, et al. Intake of coffee, decaffeinated coffee, or tea does not affect risk for pancreatic cancer: results from the European Prospective Investigation into Nutrition and Cancer Study. Clin Gastroenterol Hepatol 2013; 11:1486–1492. 13. Koushik A, Spiegelman D, Albanes D, et al. Intake of fruits and vegetables and risk of pancreatic cancer in a pooled analysis of 14 cohort studies. Am J Epidemiol 2012;176:373–386. 14. Jiao L, Mitrou PN, Reedy J, et al. A combined healthy lifestyle score and risk of pancreatic cancer in a large cohort study. Arch Intern Med 2009;169:764–770. 15. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst 2011;103:117–128.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.02.032
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From more than 6000 initial reports, Alsamarrai et al3 selected 32 high-quality population-based studies, about 1% of the potentially available reports, for their meta-analysis. The diagnosis of pancreatic disease can be difficult, especially if based on administrative data4; excluding studies coming from referral centers for pancreatic diseases somewhat weakens the validity of the current study. By using the search terms “meta-analysis,” “etiology,” along with “acute pancreatitis,” “chronic pancreatitis,” or “pancreatic cancer,” the investigators retrieved 87 articles on acute pancreatitis, 30 articles on chronic pancreatitis and 184 reports on pancreatic cancer. What new information does this current report add? Most published meta-analytic reports are diseasespecific, but this report combines risk factors for all 3 major pancreatic diseases. This certainly provides a comprehensive overview, but raises questions about the validity of such an unusual approach. Furthermore, readers should bear in mind that the results in this report for the association between various risk factors and combined benign and malignant pancreatic disease are heavily weighted by the inclusion of larger numbers of reports on pancreatic cancer, with only a few studies on benign pancreatic disease. In fact, the analysis for tobacco, alcohol, and obesity includes only 2 studies on acute pancreatitis and a single study on chronic pancreatitis. For acute pancreatitis, several previous publications have shown a temporal increase in this disease,1,5 which most commonly is caused by either alcohol or by gallstones. In most countries, alcohol consumption has remained relatively constant or has decreased, implying that the increase in the frequency of acute pancreatitis most likely is related to an increased frequency of gallstones, for which obesity is a major risk factor. Thus, controlling obesity, a rapidly increasing global problem,6 should reduce the frequency of acute pancreatitis. We already know from many reports that smoking is a major risk factor for pancreatic cancer. What this report shows is that smoking is just as strong a risk factor for benign pancreatic diseases as is heavy alcohol consumption. These findings are in agreement with results from previous meta-analyses that have reported an association between tobacco smoking and both pancreatic cancer (relative risk, 1.7; 95% confidence interval [CI], 1.6–1.9),7 and chronic pancreatitis (relative risk, 2.5; 95% CI, 1.3–4.6).8 For some clinicians, the concept of a link between smoking and benign pancreatic disease may be surprising, and implies that physicians who manage patients with acute or chronic pancreatitis should advise patients about smoking cessation along with guidance about reducing alcohol consumption. Drinking more than 5 alcoholic drinks per day has long been associated with benign pancreatic disease. The Clinical Gastroenterology and Hepatology 2014;-:-–-
2
Lowenfels and Maisonneuve
2 cohort studies included in the current report showed an association between pancreatic cancer and heavy alcohol consumption. This last finding had been noted previously in both cohort and case-control studies, with heavy alcohol consumption being associated with an approximately 20% increased risk of pancreatic cancer.9,10 Are nonalcoholic beverages such as coffee or tea a risk factor for pancreatic cancer? A pooled analysis of 14 cohort studies and another more recent large cohort study found no risk for these substances.11,12 The evidence for the protective benefits of selected dietary items against various types of cancer has always been controversial. Although case-control studies often report a favorable effect of fruits or vegetables, the results from stronger studies such as cohort studies or randomized controlled trials are less impressive. In this report, fruits or vegetables afforded an approximately 30% reduction in the overall risk of pancreatic disorders, but with less consistent disease-specific results. However, such a reduction was not established in a pooled analysis of original data from 14 independent cohort studies, with a summary relative risk of 0.89 (95% CI, 0.77–1.04) for high vs low fruit intake and 1.03 (95% CI, 0.87–1.23) for high vs low vegetable intake.13 Although Alsamarrai et al3 did not present information on the fraction of pancreatic disease caused by preventable risk factors, other reports have suggested that a combination of healthy lifestyle measures (nonsmoking, limited alcohol use, adherence to the Mediterranean dietary pattern, body weight control, and regular physical activity) might prevent a substantial fraction of all pancreatic cancers14 and perhaps a similar proportion of benign pancreatic disease. With the alarming increase in the costs associated with hospitalization, this report reminds us of the importance of avoiding known risk factors for pancreatic diseases, and the potential benefit of increasing our intake of preventive substances such as fruits and vegetables. This is especially true of pancreatic cancer, for which, in the United States, the estimated costs are anticipated to increase to 2.8 billion dollars by the year 2020.15 Based on this and similar reports, we can add pancreatic diseases to such illnesses as stroke and heart disease, for which preventive efforts are likely to be effective. ALBERT B. LOWENFELS, MD Departments of Surgery and Family and Community Medicine New York Medical College Valhalla, New York PATRICK MAISONNEUVE, DiplEng Division of Epidemiology and Biostatistics European Institute of Oncology Milan, Italy
Clinical Gastroenterology and Hepatology Vol.
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No.
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References 1. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 2013;144:1252–1261. 2. World Health Assembly. Global action plan for the prevention and control of noncommunicable diseases 2013-2020. Available at: http://www.who.int/nmh/events/ncd_action_plan/en/. Accessed January 30 2014. 3. Alsamarrai A, Das SLM, Windsor JA, et al. Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies. Clin Gastroenterol Hepatol 2014 Feb 5. Epub ahead of print. 4. Saligram S, Lo D, Saul M, et al. Analyses of hospital administrative data that use diagnosis codes overestimate the cases of acute pancreatitis. Clin Gastroenterol Hepatol 2012; 10:805–811. 5. Spanier BW, Dijkgraaf MG, Bruno MJ. Epidemiology, aetiology and outcome of acute and chronic pancreatitis: an update. Best Pract Res Clin Gastroenterol 2008;22:45–63. 6. Lehnert T, Sonntag D, Konnopka A, et al. Economic costs of overweight and obesity. Best Pract Res Clin Endocrinol Metab 2013;27:105–115. 7. Iodice S, Gandini S, Maisonneuve P, et al. Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbecks Arch Surg 2008;393:535–545. 8. Andriulli A, Botteri E, Almasio PL, et al; ad hoc Committee of the Italian Association for the Study of the Pancreas. Smoking as a cofactor for causation of chronic pancreatitis: a meta-analysis. Pancreas 2010;39:1205–1210. 9. Genkinger JM, Spiegelman D, Anderson KE, et al. Alcohol intake and pancreatic cancer risk: a pooled analysis of fourteen cohort studies. Cancer Epidemiol Biomarkers Prev 2009; 18:765–776. 10. Lucenteforte E, La Vecchia C, Silverman D, et al. Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann Oncol 2012;23:374–382. 11. Genkinger JM, Li R, Spiegelman D, et al. Coffee, tea, and sugarsweetened carbonated soft drink intake and pancreatic cancer risk: a pooled analysis of 14 cohort studies. Cancer Epidemiol Biomarkers Prev 2012;21:305–318. 12. Bhoo-Pathy N, Uiterwaal CS, Dik VK, et al. Intake of coffee, decaffeinated coffee, or tea does not affect risk for pancreatic cancer: results from the European Prospective Investigation into Nutrition and Cancer Study. Clin Gastroenterol Hepatol 2013; 11:1486–1492. 13. Koushik A, Spiegelman D, Albanes D, et al. Intake of fruits and vegetables and risk of pancreatic cancer in a pooled analysis of 14 cohort studies. Am J Epidemiol 2012;176:373–386. 14. Jiao L, Mitrou PN, Reedy J, et al. A combined healthy lifestyle score and risk of pancreatic cancer in a large cohort study. Arch Intern Med 2009;169:764–770. 15. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst 2011;103:117–128.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.02.032
