Background for Fast Fact #500     Almost two-thirds of patients with pancreatic head tumors have exocrine pancreatic insufficiency (EPI), and the likelihood increases to 9 out of 10 over the course of the illness. EPI impacts quality of life. However, in one study only 22% of patients with EPI were prescribed its standard therapy: pancreatic enzyme replacement therapy (PERT) (1,2).  This Fast Fact discusses EPI and PERT.

Pathophysiology Most pancreatic tumors arise from the ductal epithelium of the pancreatic head, causing mechanical obstruction of the flow of pancreatic juice, resulting in EPI (3). Symptoms include diarrhea, foul-smelling flatulence, abdominal bloating, indigestion, steatorrhea (excessive undigested fat in stool), weight loss, anorexia, and abdominal pain (4). Symptoms are typically exacerbated by eating (4). The inability to digest fat due to a lack of pancreatic enzymes can lead to malabsorption and associated fat-soluble vitamin deficiencies (vitamins A, D, E and K) (5).

Evaluation     EPI is mostly diagnosed clinically given its high prevalence among patients with pancreatic cancer. Clinicians should consider the diagnosis of EPI in any patient with a pancreatic tumor who is exhibiting diarrhea, bloating, weight loss, and/or stools that are pale, loose, abnormally smelly, and/or difficult to flush. If the diagnosis is not clear, the fecal elastase test is the most sensitive and specific test of pancreatic exocrine function (6,7). Values of 100–200 micrograms/gram of stool signify mild to moderate pancreatic insufficiency, while less than 100 micrograms/gram of stool indicate severe EPI.

PERT    PERT is the foundational treatment of EPI. The basic approach to treatment is that patients take sufficient PERT while eating to eliminate, or at least greatly reduce, their EPI symptoms. PERT capsules contain a combination of lipases, proteases, and amylases that catalyze the hydrolysis of fats into glycerol and fatty acids, proteins into peptides and amino acids, and starch into dextrins and short-chain sugar, respectively (8). Most PERT capsules are enteric coated to minimize gastric destruction in the low pH environment of the stomach. The enzymes are only released when the capsule reaches the higher pH duodenum (pH >5.5 (9)). Pancreatic enzymes need to be mixed with food, so patients should take PERT right at the time of food consumption, as well as additional doses during a meal because the replacement enzymes degrade within 10 minutes of intake.  Additional doses should be taken approximately every 10 minutes while eating. Take note: the total number of capsules taken depends both on the enzyme dose an individual patient needs, as well as how long it takes a patient to eat any given meal. A proton pump inhibitor can be added to decrease gastric acidity if symptoms are not adequately controlled.

Dosing     PERT dosing is based on lipase units. The starting dose for complete lack of enzyme (e.g., post-pancreatectomy) is 500 lipase units per kilogram of body weight per meal. Unlike patients who have undergone pancreatectomy, patients with pancreatic cancer usually have variable levels of exocrine function remaining. Dosage requirements vary based on the fat content of the meal, body weight, size of the meal, clinical symptoms, and severity of EPI (11,12). As a practical matter, patients should be instructed to start with one capsule of a lower lipase dose capsule every 10 minutes while eating. This dose can be titrated to clinical effect (cessation of EPI symptoms) weekly. Patients should be instructed to monitor themselves for their known EPI symptoms and clinicians should arrange close follow up and guidance (e.g., increase to 2 capsules at a time, or prescribe a higher lipase dose). Patients often will need to take more capsules if they are eating a particularly high fat meal. The maximum dose is 2,500 lipase units per kilogram of body weight per meal (or less than or equal to 10,000 lipase units/kg of body weight per day) (13). The Food and Drug Administration has approved five enteric-coated formulations: CREON®, ZENPEP®, PANCREAZE®, PERTZYE® and RELIZORB®. The latter two agents are designed for use in gastrostomy tubes.  The dosage formulations differ in their concentrations of lipase, protease, and amylase. PERT are not bioequivalent and are not interchangeable. Registered dieticians and many gastroenterologists can assist clinicians with diagnosing and treating EPI if needed.

Patient education     Patients should be made aware that nutritional or shake-style supplements and vitamin D supplements (a fat-soluble vitamin) require PERT use. No foods are contraindicated when using PERT, and PERT is not needed for a snack of simple sugars (ex. sugar, honey, fruit juice or fruit) or non-starchy vegetables (ex. lettuce, cucumbers, spinach). Keeping a food diary when starting PERT is recommended.  Instructional handouts should be provided outlining the following: 

1. Gather pancreatic enzyme capsules before meals and snacks.
2. Take the prescribed number of pancreatic enzyme capsules with cold or room temperature liquids with the first bite of food or nutritional drink (e.g., Ensure or Glucerna). Take the capsule/s whole. Do not crush or chew PERT capsules.
3. Set timer for 10 min. If you are still eating after 10 min, take another dose and repeat until you are finished with your meal (10). Example: if you eat for 35 minutes, then you would take 4 doses total during that meal (at the start, 10 min, 20 min, at 30 min).

Precautions PERT has a low risk of systemic side effects as it is not significantly absorbed in the bloodstream. There have been no reports of overdose, but it can produce diarrhea and stomach upset if higher than necessary doses are used (11). Rare cases of fibrosing colonopathy have been described in patients with cystic fibrosis (13). Patients with pork dietary restrictions should be advised that the enzyme is derived from porcine sources. There are currently no alternatives to porcine-derived PERT (14). Financial burden due to high cost of PERT is another cause of under-prescribing.

Summary EPI can significantly impact quality of life in patients with pancreatic cancer. Improvement in symptoms can occur as early as five days after initiation of PERT (15). Effectiveness is highly dependent on proper timing of PERT administration, which requires appropriate patient education.

References: 

1. Sikkens EC, Cahen DL, de Wit J, et al. A prospective assessment of the natural course of the exocrine pancreatic function in patients with a pancreatic head tumor. J. Clin Gastroenterol. 2014;48: e43–e46. doi: 10.1097/MCG.0b013e31829f56e7.  
2. Roberts K, Bannister C, Schrem H. Enzyme replacement improves survival among patients with pancreatic cancer: Results of a population-based study. Pancreatology. 2019;19: 114–121. doi: 10.1016/j.pan.2018.10.010.  
3. Vujasinovic M, Valente R, Del Chiaro M, et al. Pancreatic exocrine insufficiency in pancreatic cancer. Nutrients. 2017;9: 183. doi: 10.3390/nu9030183.  
4. Porta M, Fabregat X, Malats N, et al. Exocrine pancreatic cancer: Symptoms at presentation and their relation to tumour site and stage. Clin Transl Oncol. 2005;7: 189-97. doi: 10.1007/BF02712816. 
5. Carnie LE, Lamarca A, McNamara MG, et al. The assessment of pancreatic exocrine function in patients with inoperable pancreatic cancer: In need of a new gold-standard. Pancreatology. 2020;20: 668-75. doi: 10.1016/j.pan.2020.03.020. 
6. Damerla V, Gotlieb V, Larson H, et al. Pancreatic enzyme supplementation in pancreatic cancer. Support Oncol. 2008;6(8): 393-396.
7. Loser C, Mollgaard A, Folsch UR. Faecal elastase 1: A novel, highly sensitive, and specific tubeless pancreatic function test. Gut. 1996; 39:58-6. doi: 10.1136/gut.39.4.580.
8. Muñoz JED. Diagnosis of chronic pancreatitis: functional testing. Best Pract Res Clin Gastroenterol.     2010;24: 233-41. doi: 10.1016/j.bpg.2010.03.008. 
9. Balaban EP, Mangu PB, Khorana AA, et al. Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34: 2654-68. doi: 10.1200/JCO.2016.67.5561. 
10. Garcia MA, Braun U, Bearden D, Sada Y, Mbue J, Imam S, Jackson L. Appropriate use of pancreatic enzymes in veterans with pancreatic cancer. J. Pain Symptom Manag. 2022;63: 1149. doi: 10.1016/j.jpainsymman.2022.04.158. 
11. Creon. Food and Drug Administration. Available at:  https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020725s000lbl.pdf.  Accessed Jan 2, 2025.
12. Hammer HF. Pancreatic exocrine insufficiency: diagnostic evaluation and replacement therapy with pancreatic enzymes. Dig Dis. 2010;28: 339-43. doi: 10.1159/000319411. 
13. Gooden HM, White KJ. Pancreatic cancer and supportive care—Pancreatic exocrine insufficiency negatively impacts on quality of life. Support Care Cancer. 2013;21: 1835-41. doi: 10.1007/s00520-013-1729-3. 
14. The Clatterbridge Cancer Centre. NHS Foundation Trust Pancreatic Enzyme Replacement Therapy (PERT) Guidance. Available at: https://www.clatterbridgecc.nhs.uk/application/files/3914/3504/9642/PancreaticEnzymeReplacementTherapyPERTGuidanceV1.pdf. Accessed Nov 29, 2024.
15. Trapnell BC, Maguiness K, Graff GR, et al. Efficacy and safety of Creon 24,000 in subjects with exocrine pancreatic insufficiency due to cystic fibrosis. J Cyst Fibros. 2009;8: 370-7. doi: 10.1016/j.jcf.2009.08.008. 

Authors’ Affiliations: Michael E. DeBakey VA Medical Center, Houston, TX (LJ, MAG, UB, SI); Baylor College of Medicine, Houston, TX (LJ, MAG, UB, SI); Methodist Hospital, Houston, Texas USA (IP); Texas Southern University, Houston, Texas, USA (IP).  
Conflicts of Interest:  The authors have disclosed no relevant conflicts of interest.
Version History:  First electronically published in January 2025; originally edited by Drew A Rosielle MD