Pancreatic Enzyme Replacement Therapy After Pancreatoduodenectomy: Are Patients Treated Adequately? A Systematic Review Correlated with a Prospective Cohort
Main Article Content
Abstract
Background: Treatment with pancreatic enzymes is necessary to improve nutrient digestion and to prevent malabsorption in patients with exocrine pancreatic insufficiency (EPI) after pancreatoduodenectomy. Aim of this study was to identify the optimal dosage of pancreatic enzymes in patients with EPI after pancreatoduodenectomy based on studies available and to evaluate if patients in our cohort are treated adequately.
Methods: A systematic review of literature was performed to identify all randomized controlled trials reporting on the effect of treatment with pancreatic enzymes on nutritional parameters after pancreatoduodenectomy. Alongside a prospective observational study was performed, where the administered dosage of pancreatic enzymes was evaluated by a questionnaire in patients after pancreatoduodenectomy with EPI (defined as fat absorption < 85 %), and was compared to their dietary fat intake. Endpoints of this study were (1) the percentage of patients that received an adequate dosage based on the results of the systematic literature study, (2) the ratio between reported dose lipase (PhEur units) and fat intake (g), and reported dose of protease (PhEur units) and protein intake (g).
Results: The systematic review revealed three randomized controlled trials, their results indicate that an effective dosage of pancreatic enzymes to treat EPI following pancreatoduodenectomy should consists of at least 40000 PhEur units lipase per main meal. Twenty-nine patients with EPI after pancreatoduodenectomy were included in the prospective study. The recommended dosage (minimum 40000 PhEur units of lipase) was administered in 52% of the patients. The lowest ratio of the PhEur units of lipase per gram dietary fat intake was observed during dinner (2521 ±1770 units/gram fat) and the highest ratio was observed during breakfast (4441 ± 6936 units/gram fat).
Conclusion: According to the cut-off of minimal 40000 PhEur units of lipase per main meal, only half of the patients are using the minimum dosage of pancreatic enzymes. The variability between the ratios of the reported dose of lipase (PhEur units) and fat intake (g) fat intake per main meals is large and prescribing pancreatic enzymes adjusted to fat intake (as ratio’s) seems more appropriate.
Article Details
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
2. Perez MM, Newcomer AD, Moertel CG, Go VL, Dimagno EP. Assessment of weight loss, food intake, fat metabolism, malabsorption, and treatment of pancreatic insufficiency in pancreatic cancer. Cancer. Jul-15 52(2):346-52.
3. Toouli J, Biankin AV, Oliver MR, Pearce CB, Wilson JS, Wray NH. Management of pancreatic exocrine insufficiency: Australasian Pancreatic Club recommendations. Medical Journal of Australia. Oct 193(8):461-467.
4. Domínguez-Muñoz JE. Pancreatic enzyme replacement therapy: exocrine pancreatic insufficiency after gastrointestinal surgery. HPB : the official journal of the International Hepato Pancreato Biliary Association. 2009-12 2009;11:3-6.
5. Domínguez-Muñoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Current gastroenterology reports. 2007-4 2007;9(2):116-22.
6. J M, V K. Pancreatic enzyme therapy. Deutsches Arzteblatt international. 2010-8 2010;108(34):578-82.
7. Budipramana VS, Witarto AP, Witarto BS, et al. Risk factors for exocrine pancreatic insufficiency after pancreatic surgery: a systematic review and meta-analysis. Can J Surg. Nov-Dec 2022;65(6):E770-e781. doi:10.1503/cjs.010621
8. Whitcomb DC, Lehman GA, Vasileva G, et al. Pancrelipase Delayed-Release Capsules (CREON) for Exocrine Pancreatic Insufficiency Due to Chronic Pancreatitis or Pancreatic Surgery: A Double-Blind Randomized Trial (vol 105, pg 2276, 2010). American Journal of Gastroenterology. Jun 106(6):1177-1178.
9. Kim H, Yoon Y, Han Y, et al. Effects of Pancreatic Enzyme Replacement Therapy on Body Weight and Nutritional Assessments After Pancreatoduodenectomy in a Randomized Trial. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2020-4 2020;18(4):926-934.e4.
10. Halloran CM, Cox TF, Chauhan S, et al. Partial pancreatic resection for pancreatic malignancy is associated with sustained pancreatic exocrine failure and reduced quality of life: a prospective study. Pancreatology. 2011 2011;11(6):535-45.
11. Chaudhary A, Domínguez-Muñoz J, Layer P, Lerch M. Pancreatic Exocrine Insufficiency as a Complication of Gastrointestinal Surgery and the Impact of Pancreatic Enzyme Replacement Therapy. Digestive diseases (Basel, Switzerland). 2020 2020;38(1):53-68.
12. Belyaev O, Herzog T, Chromik AM, Meurer K, Uhl W. Early and late postoperative changes in the quality of life after pancreatic surgery. Langenbecks Arch Surg. Apr 2013;398(4):547-55. doi:10.1007/s00423-013-1076-3
13. Domínguez-Muñoz JE, Nieto-Garcia L, López-Díaz J, Lariño-Noia J, Abdulkader I, Iglesias-Garcia J. Impact of the treatment of pancreatic exocrine insufficiency on survival of patients with unresectable pancreatic cancer: a retrospective analysis. BMC Cancer. May-5 18(1):534.
14. Dutta SK, Bustin MP, Russell RM, Costa BS. Deficiency of fat-soluble vitamins in treated patients with pancreatic insufficiency. Ann Intern Med. Oct 1982;97(4):549-52. doi:10.7326/0003-4819-97-4-549
15. Kalivianakis M, Minich DM, Bijleveld CM, et al. Fat malabsorption in cystic fibrosis patients receiving enzyme replacement therapy is due to impaired intestinal uptake of long-chain fatty acids. Am J Clin Nutr. Jan 1999;69(1):127-34. doi:10.1093/ajcn/69.1.127
16. Lankisch PG, Lembcke B, Göke B, Creutzfeldt W. Therapy of pancreatogenic steatorrhoea: does acid protection of pancreatic enzymes offer any advantage? Z Gastroenterol. Dec 1986;24(12):753-7.
17. Sikkens EC, Cahen DL, Kuipers EJ, Bruno MJ. Pancreatic enzyme replacement therapy in chronic pancreatitis. Best Pract Res Clin Gastroenterol. Jun 2010;24(3):337-47. doi:10.1016/j.bpg.2010.03.006
18. Braga M, Cristallo M, De Franchis R, et al. Pancreatic enzyme replacement therapy in post-pancreatectomy patients. International journal of pancreatology : official journal of the International Association of Pancreatology. 1989 1989;5:37-44.
19. Bruno M, Borm J, Hoek F, et al. Comparative effects of enteric-coated pancreatin microsphere therapy after conventional and pylorus-preserving pancreatoduodenectomy. vol 84. 1997:952-6.
20. Freelove R, Walling AD. Pancreatic cancer: diagnosis and management. Am Fam Physician. Feb 1 2006;73(3):485-92.
21. Sikkens E, Cahen D, van Eijck C, Kuipers E, Bruno M. The daily practice of pancreatic enzyme replacement therapy after pancreatic surgery: a northern European survey: enzyme replacement after surgery. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2012-8 2012;16(8):1487-92.
22. Neoptolemos J, Ghaneh P, Andrén-Sandberg A, et al. Treatment of pancreatic exocrine insufficiency after pancreatic resection. Results of a randomized, double-blind, placebo-controlled, crossover study of high vs standard dose pancreatin. vol 25. 1999:171-80.
23. Phillips M. Pancreatic exocrine insufficiency following pancreatic resection. Pancreatology : official journal of the International Association of Pancreatology (IAP) [et al]. 2015-9 2015;15(5):449-455.
24. Wierdsma NJ, Peters JH, van Bokhorst-de van der Schueren MA, Mulder CJ, Metgod I, van Bodegraven AA. Bomb calorimetry, the gold standard for assessment of intestinal absorption capacity: normative values in healthy ambulant adults. J Hum Nutr Diet. Apr 2014;27 Suppl 2:57-64. doi:10.1111/jhn.12113
25. Vanga RR, Tansel A, Sidiq S, El-Serag HB, Othman MO. Diagnostic Performance of Measurement of Fecal Elastase-1 in Detection of Exocrine Pancreatic Insufficiency: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. Aug 2018;16(8):1220-1228.e4. doi:10.1016/j.cgh.2018.01.027
26. Seiler C, Izbicki J, Varga-Szabó L, et al. Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25000Ph. Eur. minimicrospheres (Creon 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension. Alimentary pharmacology & therapeutics. 2013-4 2013;37(7):691-702.
27. Seiler CM, Izbicki J, Varga-Szabo L, et al. Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrospheres (Creon 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension. Aliment Pharmacol Ther. Apr 2013;37(7):691-702. doi:10.1111/apt.12236
28. Versteijne E, van Dam JL, Suker M, et al. Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial. J Clin Oncol. Apr 10 2022;40(11):1220-1230. doi:10.1200/jco.21.02233
29. Rämö OJ, Puolakkainen PA, Seppälä K, Schröder TM. Self-administration of enzyme substitution in the treatment of exocrine pancreatic insufficiency. Scand J Gastroenterol. Aug 1989;24(6):688-92. doi:10.3109/00365528909093110
30. Keller J, Layer P. Human pancreatic exocrine response to nutrients in health and disease. Gut. Jul 2005;54 Suppl 6(Suppl 6):vi1-28. doi:10.1136/gut.2005.065946
31. JE D-M. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency: when is it indicated, what is the goal and how to do it? Advances in medical sciences. 2011 2011;56(1):1-5.
32. DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med. Apr 19 1973;288(16):813-5. doi:10.1056/nejm197304192881603
33. Lankisch PG, Lembcke B, Wemken G, Creutzfeldt W. Functional reserve capacity of the exocrine pancreas. Digestion. 1986;35(3):175-81. doi:10.1159/000199364
34. Prescott J. Pancreatic enzyme replacement therapy: A view from behind the counter. . 2016;82(10)
35. Forsmark C, Tang G, Xu H, Tuft M, Hughes S, Yadav D. The use of pancreatic enzyme replacement therapy in patients with a diagnosis of chronic pancreatitis and pancreatic cancer in the US is infrequent and inconsistent. Alimentary pharmacology & therapeutics. 2020-5 2020;51(10):958-967.
36. Rothenbacher D, Löw M, Hardt PD, Klör HU, Ziegler H, Brenner H. Prevalence and determinants of exocrine pancreatic insufficiency among older adults: results of a population-based study. Scand J Gastroenterol. Jun 2005;40(6):697-704. doi:10.1080/00365520510023116
37. Collaborative TRSGobotWMR. Pancreatic enzyme replacement therapy in patients with pancreatic cancer: A national prospective study. Pancreatology. May 25 2021. doi:10.1016/j.pan.2021.05.299
38. Jain T, Sharma P, Giri B, et al. Prescription patterns of pancreatic enzyme replacement therapy for patients with pancreatic cancer in the United States. HPB (Oxford). Oct 2022;24(10):1729-1737. doi:10.1016/j.hpb.2022.05.00