Evidence-Based Treatment of Digestive Symptoms in Pancreatic Cancer Patients

A review of the literature

By Heather Wright, ND, FABNO, and Kamorin Samson, RD

Printer Friendly PagePrinter Friendly Page

Abstract

Patients with pancreatic cancer experience symptoms of disease and treatment-related symptoms that can reduce quality of life and negatively impact survival. This paper discusses practical tools for supporting patients in digestive tract symptom reduction with safe interventions such as nutritional counseling and evidence-based supplements. Patients and caregivers who are provided knowledge about digestive tract physiology, nutritional education, and detailed instructions for use of pancreatic enzymes may more effectively utilize treatment plans at home. Supporting overall nutritional status and maximizing digestive function with use of pancreatic enzymes and supplements such as probiotics and melatonin may help reduce suffering in pancreatic cancer patients and support quality of life. 

Introduction

Pancreatic cancer is projected to become the second leading cause of cancer death in the United States by the year 2030.1 Most people with pancreatic cancer are diagnosed with advanced-stage disease and fewer than 20% survive the first year.2 Risk factors include BMI > 25, low socioeconomic status, smoking, type 2 diabetes mellitus, obesity, chronic pancreatitis, genetic status, and previous cancer diagnosis.3-5 Other risk factors include exposures to chemicals (eg, pesticides), consumption of red meat, chronic alcohol intake, consuming more than 2 sodas per week, and history of partial gastrectomy.6-10 Though no curative treatment other than surgery (performed in early stage or local-only disease, in fewer than 10% of patients) has been found, chemotherapy and radiation treatments are used in standard oncology care and offer some survival benefit. There are also palliative care and surgical procedures (eg, biliary decompression) that are used to support functional status, enhance quality of life (QOL), and reduce pain. Higher QOL levels, as indicated by measures such as pain and fatigue during treatment, are associated with improved survival.11-14 While standard antineoplastic agents work toward extending survival, they may also cause side effects that reduce QOL. It is well-known that QOL reported by pancreatic cancer patients is largely determined by digestive symptoms.15 Treatments such as digestive enzymes, nutritional interventions, and supplements offer a pragmatic approach to support improved nutritional status and quality of life. 
Pancreatic cancer is projected to become the second leading cause of cancer death in the United States by the year 2030
In a large national survey conducted by the National Institutes of Health, 65% of respondents who had been diagnosed with cancer reported use of natural approaches for general wellness, immune enhancement, and pain management.16 Integrative healthcare professionals such as naturopathic physicians and nutritionists have the opportunity to educate patients about measures that may reduce the risk of pancreatic cancer, and support optimal digestive function and improved QOL in patients who have pancreatic cancer. By first educating their patients about digestive organs, physiology, and diet, then working with each patient to prioritize safe interventions that address their individual symptoms and disease picture, in coordination with their antineoplastic therapy, integrative clinicians can maximize digestive function, reduce symptoms, and help each patient achieve the highest quality of life possible. 

Normal Digestive Physiology

Normal digestive physiology is a synchronized process that involves the release of a number of digestive hormones. Cholecystokinin (CCK), produced in the duodenum, stimulates pancreatic enzyme secretion and gallbladder contraction, potentiates secretin-induced bicarbonate efflux from the pancreas, and controls the gastric emptying rate.17-18 When acidic chyme leaves the stomach and enters the duodenum, the release of the hormone secretin signals water and bicarbonate ion secretion in the pancreas, which helps carry enzymes through the pancreatic duct. Gastric chyme has a pH of 3 to 4; if the acidity of chyme is not modified by adequate bicarbonate secretion, the acidic envrionment may inactivate enzymes and denature bile salts in the duodenum.19-20 Pancreatic enzymes are activated at a pH of 5 to 6 in the duodenum in the presence of adequate bicarbonate and bile salts. The pancreas secretes enzymes to digest fats, proteins, and carbohydrates. The liver produces bile to help absorb fat. The gallbladder stores and concentrates bile and secretes it in response to foods consumed. The enzymes, bicarbonate, and bile all pass through ducts into the duodenal bulb. Optimal digestion, including absorption of fat-soluble vitamins, depends on an adequately alkalinized environment in the duodenum in which enzymes and bile can remain bioactive.15,18,21,22

Asynchrony of Digestion

The synchrony of hormones, enzymes, bicarbonate, and bile production can be disrupted by surgery, tumor displacement of normal tissue, pancreatic duct obstruction, and/or fibrosis from inflammation or radiation treatment to the pancreas. This disruption results in exocrine pancreatic insufficiency (EPI) and associated digestive symptoms.20,23 In patients with pancreatic insufficiency, decreased production of pancreatic enzymes coupled with low gastric and duodenal pH values are found to correlate negatively with fat absorption.24 In addition to high prevalence of exocrine insufficiency in nonsurgical pancreatic patients (90%-95%), postoperative exocrine insufficiency is reported in 80% of patients who have had pancreatic surgery.20 A pancreatico-cibal asynchrony occurs after classic partial-preserving as well as pylorus-preserving duodenopancreatectomy; pancreatic enzymes may be secreted but the duodenum is missing the gastric chyme. In addition, the release of hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), induced by the rapid passage of food into the ileum, leads to inhibition of pancreatic secretion and reduction in appetite.15 Exocrine pancreatic insufficiency can also cause or exacerbate motility disorders.18 Production of CCK and pancreatic polypeptide are adversely affected by undigested food in the intestines, which can lead to rapid gastric emptying and altered antro-duodenal and gallbladder motility with resultant diarrhea, nausea, and anorexia. Patients with EPI also have shorter fed patterns and faster intestinal transit that is largely ameliorated with enzyme therapy. Generally, the symptoms resulting from asynchrony and disruption of digestion in pancreatic cancer patients are difficult-to-treat diarrhea, weight loss, postprandial pain, and malabsorption of nutrients critical to energy production and host homeostasis.

Exocrine Pancreatic Insufficiency 

The majority of pancreatic cancer patients are thought to experience digestive tract symptoms of exocrine pancreatic insufficiency (EPI) at diagnosis.21,25,18 Exocrine pancreatic insufficiency is failure to produce pancreatic enzymes or inadequate digestive synchrony due to tumor interruption of normal pancreatic and digestive functions. The condition leads to symptoms that include postprandial discomfort and pain, gas and bloating, steatorrhea, and diarrhea. Other symptoms include general abdominal pain, back pain, pale/greasy/floating stools, weight loss, nausea, anorexia, and fatigue. One of the earliest manifestations of EPI is thought to be decreased bicarbonate secretion associated with postprandial gas and bloating.26 Many patients with EPI experience worsening of overall symptoms in relation to food intake.18 History of pancreatic surgery, radiation treatment, location of primary tumor, liver or peritoneal involvement, and functional status of the gallbladder and liver are important contributing factors to EPI.3 In pancreatic cancer, diagnosis of EPI is presumptive based on clinical suspicion of 2 components: 1. Identified cause of insufficiency (such as pancreatic head tumor or pancreatic surgery) and 2. Symptoms indicating <10% exocrine function: post prandial discomfort or pain, gas and bloating, steatorrhea, or diarrhea. These symptoms may contribute to weight loss and fatigue due to inadequate absorption and utilization.27,26 Estimates indicate that 90% of patients diagnosed with pancreatic cancer, 50% of patients with cystic fibrosis, 35% of patients with type 2 diabetes, and 20% of patients with irritable bowel disease (IBD) have EPI.18 Studies conducted across these populations have allowed researchers to interpret the impact of interventions to treat EPI on a greater scale. 

Pancreatic Enzyme Replacement Therapy

Pancreatic enzyme replacement therapy (PERT) may benefit overall nutritional status and QOL and is considered the standard of care for pancreatic cancer patients.18 The goal of pancreatic enzyme therapy is to restore fat absorption by delivering a sufficient amount of active lipase to the right place (the duodenum and proximal jejunum) at the right time (parallel with gastric emptying of nutrients).21 Replacement therapy includes formulations of lipase-based enzymes providing 500 to 1000 units lipase per kg body weight per meal (up to 2500 units/kg/meal).15,20 The initial total dose should be 25,000 to 50,000 units lipase per meal and 5,000 to 25,000 units lipase per snack.15,18-20 The dose of lipase is titrated to achieve symptom relief, but the recommendation is not to exceed 10,000 units lipase per kg body weight per day.18 Even with significant EPI, protein and starch digestion are usually maintained. However, once EPI progresses, lipid malabsorption becomes the cause of clinical symptoms and nutrient deficiencies.
Pancreatic enzyme replacement therapy (PERT) may benefit overall nutritional status and QOL and is considered the standard of care for pancreatic cancer patients
Patients with dysphagia or difficulty swallowing pills may benefit from over-the-counter supplement and prescription lipase-based enzyme formulations, available in a range of dosages (and capsule sizes). Enzyme doses greater than 36,000 units per meal are not associated with statistically significant further benefit in the literature.21,26 Despite this, in general, the standard of care is to recommend titration above this dose if patients continue to experience symptoms. In normal pancreatic physiology, enzymes are secreted gradually throughout meal intake with peak enzyme secretion occurring 20 minutes after a meal.18 Several studies have reported use of incremental dosing throughout a meal to achieve total standard dose with encouraging results; for example, taking 3 capsules of 12,000 units over the course of a meal (for a total dose of 36,000 units).21,28 Incremental dosing may simulate synchrony of digestion with pulsed delivery. Patients who tried incremental dosing reported fewer digestive symptoms, decreased fat excretion (improved fat absorption), and improvement in postprandial symptoms, with the added benefit of ease of swallowing smaller capsules. Some enzyme formulations include enteric coating and timed-release delivery.
 
Other studies have reported benefit (symptom improvement, less fecal fat excretion, and weight loss) with enteric-coated bicarbonate and enzymes given prior to titration of enzyme total dose.17,29 Use of enteric bicarbonate may help ensure enzyme activation in the duodenum. In these studies, participants took 325 mg or 650 mg bicarbonate before meals, and investigators reported that bicarbonate administration was safe and beneficial for pancreatic patients.
 
In patients on PERT, markers of persistent nutrient deficiencies may persist.18-19 Consequences of abnormal lipid digestion are malnutrition; depletion of lipid-soluble vitamins (A,D,E,K), selenium, zinc, B12, calcium, and iron; and decreased circulating lipoproteins.15,18-19,30 Patients with symptoms of fat malabsorption who experience benefit from PERT are also reported to replete deficiencies when supplemented.18-20,28 
 
Durie et al (1980) reported that fat excretion per gram of intake fell from 12 times the normal level to normal in EPI patients receiving bicarbonate and pancreatic enzyme treatment.28 Studies that compared the combination of bicarbonate with PERT to treatment with PERT alone found that combination therapy was more effective in reducing symptoms and improving nutritional status. The improvement is attributed to bicarbonate’s alkalinization of the intraduodenal environment.17,27 Enteric bicarbonate or proton pump inhibitors (PPIs) may help ensure a pH that is sufficient for enzyme activation in the duodenal bulb and optimize PERT regimens.15,20

Nutrition

Replacement therapy with pancreatic enzymes has improved symptoms in human studies, but treatment with enzymes alone has not yielded outcomes that significantly impact overall nutritional status via parameters such as weight loss.18,25 Weight stabilization is associated with improved survival duration and QOL in unresectable pancreatic cancer.31 Careful monitoring and early follow-up of symptoms may help reduce weight loss in advanced pancreatic cancer.25
 
For cases of unremitting postprandial EPI symptoms, some clinicians may recommend reducing fat intake, or they may encounter patients who self-restrict fat intake without trial of pancreatic enzymes. Decreased calorie and fat intake can result in decreased circulating lipoproteins and overall increased weight loss, which is one of the strongest predictors of short survival in this population.20 Reduced fat intake may also result in deficiency of fat-soluble vitamins, micronutrients, and essential fatty acids.15,18-19,28
Weight stabilization is associated with improved survival duration and QOL in unresectable pancreatic cancer.
Diets that provide at least 30% to 35% of daily calories from fat are positively correlated with survival and QOL in patients with pancreatic cancer.25,29 For these patients to best tolerate and absorb dietary fat, PERT may be implemented along with dietary counseling to incorporate recommendations for small frequent meals, adequate hydration, and abstinence from alcoholic beverages.32 Medium-chain triglycerides (MCTs), found in coconut oil, may be more easily absorbed by the lining of the small intestine33 and can be considered for use to support calorie needs.26,30 In other patient populations with fat malaborption and EPI, such as those with cystic fibrosis and chronic pancreatitis, MCT is reported to improve serum essential fatty acid parameters, modulate CCK levels, and reduce symptoms such as steatorrhea.34-36 Further dietary considerations may include reducing or eliminating short-chain carbohydrates,37 including foods or supplements that act luminally to decrease diarrhea (eg, probiotics, adsorbants),38 and incorporating nutrient-rich plant-based foods. Counseling for adequate hydration and electrolytes is also important. Due to the intensity of symptoms of pancreatic cancer and the speed of progression, patients and their care providers may benefit from nutritional counseling. Care providers can help patients adhere to recommended dietary advice and PERT schedules. 

Natural Agents That may Benefit Pancreatic Cancer Patients

Pancreatic cancer patients with EPI are more prone to deficiency of fat-soluble vitamins A, D, E, and K as well as selenium, zinc, vitamin B12, calcium, and iron.19,39 Symptoms of vitamin deficiency may contribute to decreased QOL.29 Patients who experience benefit from PERT are also reported to replete vitamin deficiencies when supplemented in addition to pancreatic enzymes.19-21,29
 
Supplemental probiotics may also be a beneficial addition to treatment plans for pancreatic cancer patients. Studies report that probiotics improve gut barrier function and reduce postoperative infectious complications in this patient population.40-41 Human clinical trials report that probiotics are safe and beneficial for various patient populations, including the critically ill, patients with infections, presurgical, postsurgical, and pediatric patients; however, large prospective trials in pancreatic cancer patients are lacking.40,42-43 Proposed mechanisms of action for probiotics include the induction of antibacterial secretion, such as mucins from human epithelial cells and defensins from paneth cells in the small intestine, modulation of fecal microbiota, strengthening of epithelial junction proteins, maintainenance of epithelial cellular polarization, and reduction of cell apoptosis in the gut lining.44-45 Limited data also suggest probiotics may help restore the “gut barrier effect” in patients chronically treated with PPIs and reduce bacterial overgrowth in the stomach and duodenum.46 
 
Melatonin (MLT) supplementation shows promise for cancer patients who are also receiving chemotherapy, radiotherapy, supportive therapy, or palliative therapy. Data suggest that melatonin may improve survival and ameliorate side effects of chemotherapy.47 There is also promising evidence that supports the use of melatonin in reflux disorder or as a motility aid.48-50
 
Fish oil supplements (omega-3 polyunsaturated fatty acids) are reported to improve clinical outcomes and prognosis in pancreatic cancer patients.51
 
Viscum (mistletoe), a subcutaneous injectable, is a potentially effective adjunct or second-line therapy that may prolong overall survival, reduce disease-related symptoms, and improve QOL for patients with locally advanced or metastatic pancreatic cancer. However, currently there are few prospective clinical trials to support its use.52-53
 
Vitamin E delta tocotrienol (VEDT), hypothesized to be pro-apoptotic, is reported to be safe and well- tolerated when taken before to surgery for pancreatic cancer, but evidence is extremely limited.54 
 
L-carnitine treatment is reported to improve nutritional status, reduce weight loss, and improve QOL in pancreatic cancer patients though data is limited.5
 
Homeopathy studies adjunctive to standard antineoplastic treatments in cancer patients report safety and tolerability with clinical improvement in well-being and possible survival benefit in a variety of tumor types including pancreatic, but prospective data is lacking.56-57 One uncontrolled observational trial testing homeopathic Psorinum (concurrent with supportive care) as a primary treatment for patients with advanced liver, pancreatic, gastric, and gallbladder cancers reported some tumor response and survival benefit.58
 
Medical marijuana, including dronabinol and oral mucosal canibidiols, is reported to be safe and well-tolerated with potential to positively impact QOL parameters of insomnia, pain, and fatigue in advanced cancer patients though data is limited.59-62
 
Another agent with further application for symptom management in pancreatic cancer patients is vitamin D3 which may be a possible treatment for cancer-related fatigue.63 
 
Diarrhea may persist in patients on PERT despite adequate lipase supplementation. Endogenous bile salts may be delivered too profusely or continuously to the duodenum in some patients, resulting in frequent watery diarrhea.64 Some dietary fibers such as pectin and cellulose may decrease primary bile acid effects or decrease secondary bile acid concentrations in fecal water, thereby reducing the fecal water toxicity that leads to diarrhea.65-66 Additional agents that act luminally and therefore do not require systemic absorption to help reduce diarrhea include opiate analogues, bile acid binding agents, probiotics, bismuth compounds, berberine, and bupleurum.38
 
Current standard of care recommends cholestyramine for unremitting diarrhea. Cholestyramine is an effective bile sequestrant but carries the risks of constipation, possible bowel blockage, and side effects such as gas, bloating, nausea, and abdominal discomfort.51 Use of pectin-enriched cholestyramine may modulate these risks. Consideration for any potential benefits with the least side effects by use of a pectin-only approach prior to cholestyramine or pectin-enriched cholestyramine may be supportive. While a significant percentage of patients with unremitting diarrhea improve with cholestyramine treatment, estimates indicate that 40% to 70% of patients discontinue the treatment due to side effects.51

Conclusion

Mortality from pancreatic cancer is expected to increase dramatically by the year 2030. It is imperative that integrative providers work within all public health and clinical settings to provide critical teaching on lowering risk factors for pancreatic cancer and to provide nutritional counseling and guide use of evidence-based natural medicine alongside conventional therapies. This would offer patients supportive comanagement to reduce symptoms of disease, enhance nutritional status, and improve QOL. Pancreatic enzyme replacement therapy given in incremental doses per meal, with or without enteric-coated bicarbonate, and in combination with fat-soluble vitamins are safe considerations in supportive care along with several supplements that have shown to be safe and potentially effective.
 
Further research on therapies to improve QOL and reduce digestive symptoms in patients with pancreatic cancer is warranted. More research is needed on natural agents as adjunctive or stand-alone therapies. The development of a pancreatic cancer–specific symptom inventory tool to best monitor clinical benefit from interventions such as PERT; nutritional counseling; and adjunctive natural agents may improve our ability to assess patient-reported benefits both inside and outside of clinical trials.

About the Authors

Heather Wright, ND is Vice President for the Oncology Association of Naturopathic Physicians and is the Research Director for KNOWoncology.org, a database of integrative oncology research. Dr. Wright is a regular contributor to the Natural Medicine Journal and a speaker providing continuing education to her colleagues and other medical professionals. Dr. Wright's expertise focuses on pancreatic, digestive tract, glioblastoma and breast cancer. She currently sees patients at CAMAcenter.com in Philadelphia, Pennsylvania and via telemedicine through goodapplewellness.com.

Kamorin Samson, RD, is a clinical oncology registered dietitian at CTCA at Eastern Regional Medical Center. Samson earned a Bachelor of Science in Nutrition from La Salle University in Philadelphia and completed an internship with ARAMARK at Riddle Hospital. She obtained board certification as a specialist in oncology nutrition in September 2015. Samson helped develop a department protocol for use of the indirect calorimetry machine in the inpatient setting, in addition to creating a pre-operative nutrition protocol. While at CTCA, utilizing the A3 Problem Solving tool, Samson partnered with the culinary department to develop goals for sustainability in food procurement and production, achieving recognition from the Healthy Food in Health Care initiative.

References

  1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913-2921.
  2. Sener SF, Fremgen A, Menck HR, Winchester DP. Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985-1995, using the National Cancer Database. J Am Coll Surg. 1999;189:1-7.
  3. Hippisley-Cox J, Coupland C. Development and validation of risk prediction algorithms to estimate future risk of common cancers in men and women: prospective cohort study. BMJ Open. 20155(3): e007825.
  4. National Cancer Institute. Pancreatic Cancer Treatment (PDQ) Health Professional Version.  http://www.cancer.gov/types/pancreatic/hp/pancreatic-treatment-pdq. Accessed: 5/25/2016.
  5. Axilbund J, Wiley E. Genetic testing by cancer site: pancreas. Cancer J. 2012;18(4):350-354.
  6. Andreotti G, Beane Freeman LE, Hou L, et al. Agricultural pesticide use and pancreatic cancer risk in the agricultural health study cohort. Intl J Cancer. 2009;124(10):2495-2500. 
  7. Larsson S, Wolk A. Red and processed meat consumption and risk of pancreatic cancer: meta-analysis of prospective studies. Br J Cancer. 2012;106(3):603–607.
  8. Gupta S, Wang F, Holly EA, Bracci PM. Risk of pancreatic cancer by alcohol dose, duration, and pattern of consumption, including binge drinking: a population-based study. Cancer Causes Control . 2010;21(7):1047-1059. 
  9. Mueller NT, Odegaard A, Anderson K, et al. Soft drink and juice consumption and risk of pancreatic cancer: the Singapore Chinese Health Study. Cancer Epidemiol Biomarkers Prev. 2010;19(2):447-455. 
  10. van Rees  BP, Tascilar M, Hruban RH, Giardiello FM, Tersmette AC, Offerhaus GJ. Remote partial gastrectomy as a risk factor for pancreatic cancer: potential for preventive strategies. Ann Oncol. 1999;10(Suppl 4):204-207.
  11. Bernhard J, Dietrich D, Glimelius B, et al. Estimating prognosis and palliation based on tumour marker CA 19-9 and quality of life indicators in patients with advanced pancreatic cancer receiving chemotherapy. Br J of Cancer. 2010;103(9):1318-1324. 
  12. Montazeri A. Quality of life data as prognostic indicators of survival in cancer patients: an overview of the literature from 1982 to 2008. Health Qual Life Outcomes. 2009;7:102.
  13. Quinten C, Coens C, Mauer M, et al. Baseline quality of life as a prognostic indicator of survival: a meta-analysis of individual patient data from EORTC clinical trials. Lancet Oncol. 2009;10:865–871.
  14. Gupta D, Lis CG, Grutsch JF. The European organization for research and treatment of cancer quality of life questionnaire: implications for prognosis in pancreatic cancer. Int J Gastrointest Cancer. 2006;37(2-3):65–73.
  15. Butt Z, Parikh ND, Beaumont JL, et al. Development and validation of a symptom index for advanced hepatobiliary and pancreatic cancers: the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy (NCCN-FACT) Hepatobiliary-Pancreatic Symptom Index (NFHSI). Cancer.  2012;118(23):5997-6004.
  16. National Institutes of Health. National Center for Complementary and Integrative Health. Cancer: In Depth. https://nccih.nih.gov/health/cancer/camcancer.htm. Updated: July 2014. Accessed: June 7 2016.
  17. Mossner J, Keim V. Pancreatic enzyme therapy. Dtsch Arztebl Int. 2011:108(34-35): 578-582. 
  18. Herrington MK, Adrian TE. On the role of cholecystokinin in pancreatic cancer. Int Jl  Pancreatol. 1995.;17(2):121-138.
  19. Vukovic M, Jojic N. Effect of enteric coated sodium bicarbonate, enzymes and bile combination on the absorption of fat in chronic pancreatitis. Ann Gastroenterol. 2000;13(2):113-117.
  20. Feiker A, Philpott J, Armand M. Enzyme replacement therapy for pancreatic insufficiency: present and future. Clin Exp Gastroenterol. 2011;4:55-73.
  21. Damerla V, Gotlieb V Larson H, Saif M. Pancreatic enzyme supplementation in pancreatic cancer. J Support Oncol. 2008;6(8):393-396.
  22. Keim V, Klar E, Poll M, Schoenberg M. Postoperative care following pancreatic surgery: surveillance and treatment. Dtsch Arztebl Int. 2009;106(48):789-794.
  23. Domínguez-Muñoz JE. Pancreatic exocrine insufficiency: diagnosis and treatment. J Gastroenterol Hepatol. 2011;26 (Suppl 2):12-16.
  24. Graham DY. Enzyme replacement therapy of exocrine insufficiency in man. N Engl J Med. 1977; 296(23):1314-1317.
  25. Sikkens EC, Cahen DL, de Wit J, Looman CW, van Eijck C, Bruno MJ. J Clin Gastroenterol . 2014;48(5):e43-46.
  26. Pelley J, Gordon S, Gardner T. Abnormal duodenal [HCO3-] following secretin stimulation develops sooner than endocrine insufficiency in minimal change chronic pancreatitis. Pancreas. 2012;42(3):481-484.
  27. Bye A, Jordhoy M, Skjegstad G, Ledsaak O, Iversen P, Hjermstad M. Symptoms in advanced pancreatic cancer are of importance for energy intake. Support Care Cancer. 2013;21(1):219-227.    
  28. Trang T, Chang J, Graham D. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21st century. World J Gastroenterol. 2014;20(33): 11467–11485.
  29. Durie PR, Bell L, Linton W, Corey ML, Forstner GG. Effect of cimetidine and sodium bicarbonate on pancreatic replacement therapy in cystic fibrosis. Gut. 1980;21(9):778-786.
  30. Armstrong T, Walters E, Varshney S, Johnson C. Deficiencies or micronutrients, altered bowel function, and quality of life during late follow-up after pancreaticoduodenectomy for malignancy. Pancreatology.  2002;2(6):528-534.
  31. Davidson W, Ash S, Capra S, Bauer J; Cancer Cachexia Study Group. Weight stabilization is associated with improved survival duration and quality of life in unresectable pancreatic cancer. Clin Nutr. 2004;23(2):239-247.
  32. Toouli J, Biankin AV, Oliver MR, Pearce CB, Wilson JS, Wray NH; Australasian Pancreatic Club. Management of pancreatic exocrine insufficiency: Australasian Pancreatic Club recommendations. Med J Aust. 2010;193(8):461-467.
  33. Marina AM, Che Man YB, Amin I. Virgin coconut oil: emerging functional food oil. Trends Food Sci Technol. 2009;20(10):481-487.
  34. Christophe A, Verdonk G, Robberecht E, Mahathanakhun R. Effect of supplementing medium chain triglycerides with linoleic acid-rich monoglycerides on severely disturbed serum lipid fatty acid patterns in patients with cystic fibrosis. Ann Nutr Metab. 1985;29(4):239-245.
  35. Widhalm K, Götz M. Long-term use of medium chain triglycerides in cystic fibrosis [in German]. Wien Klin Wochenschr. 1976;88(17):557-561.
  36. Shea JC, Bishop MD, Parker EM, Gelrud A, Freedman SD. An enteral therapy containing medium-chain triglycerides and hydrolyzed peptides reduces postprandial pain associated with chronic pancreatitis. Pancreatology. 2003;3(1):36-40.
  37. Barrett JS. Extending our knowledge of fermentable, short-chain carbohydrates for managing gastrointestinal symptoms. Nutr Clin Pract. 2013;28(3):300-306. 
  38. Menees S, Saad R, Chey WD. Agents that act luminally to treat diarrhea and constipation. Nat Rev Gastroenterol Hepatol. 2012.;9(11):661-674.
  39. Timofte D, Livadariu R, Bintintan V, et al. Metabolic disorders in patients operated for pancreatic cancer. Rev Med Chir Soc Med Nat Iasi. 2014;118(2):392-398.
  40. Jones C, Badger SA, Regan M, et al. Modulation of gut barrier function in patients with obstructive jaundice using probiotic LP299v. Eur J Gastroenterol Hepatol. 2013;25(12):1424-1430. 
  41. Nomura T, Tsuchiya Y, Nashimoto A, et al. Probiotics reduce infectious complications after pancreaticoduodenectomy. Hepatogastroenterology. 2007;54(75):661-663.
  42. Miloh T. Probiotics in Pediatric Liver Disease. J Clin Gastroenterol. 2015;49(Suppl 1):S33-36. 
  43. Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE. Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials. Lancet Infect Dis. 2006;6(6):374–382.
  44. Sherman PM, Ossa JC, Johnson-Henry K. Unraveling mechanisms of action of probiotics. Nutr Clin Pract. 2009;24(1):10-14.
  45. Garrido D, Suau A, Pochart P, Cruchet S, Gotteland M. Modulation of the fecal microbiota by the intake of a Lactobacillus johnsonii La1-containing product in human volunteers. FEMS Microbiol Lett. 2005;248(2):249-256.
  46. Del Piano M, Anderloni A, Balzarini M, et al. The innovative potential of Lactobacillus rhamnosus LR06, Lactobacillus pentosus LPS01, Lactobacillus plantarum LP01, and Lactobacillus delbrueckii subsp. Delbrueckii LDD01 to restore the “gastric barrier effect” in patients with chronically treated PPI: a pilot study. J Clin Gastroenterol. 2012;46(Supp): S18-26.
  47. Seely D, Wu P, Fritz H, et al. Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integr Cancer Ther. 2012;11(4):293-303. 
  48. Konturek SJ, Konturek PC, Brzozowski T, Bebenik GA. Role of melatonin in upper gastrointestinal tract.  J Physiol Pharmacol. 2007;58(Suppl 6):23-52.
  49. Pereira RS. Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and amino acids: comparison with omeprazole. J Pineal Res. 2006;41(3):195-200.
  50. Brzozowska I, Strzalka M, Drozdowicz D, Konturek SJ, Brzozowski T. Mechanisms of esophageal protection, gastroprotection and ulcer healing by melatonin: implications for the therapeutic use of melatonin in gastroesophageal reflux disease (GERD) and peptic ulcer disease. Curr Pharm Des. 2014;20(30):4807-4815.
  51. Ma YJ, Yu J, Xiao J, Cao BW. The consumption of omega-3 polyunsaturated fatty acids improves clinical outcomes and prognosis in pancreatic cancer patients: a systematic evaluation. Nutr Cancer. 2015;67(1):112-118.
  52. Tröger W, Galun D, Reif M, Schumann A, Stankovi? N, Mili?evi? M. Viscum album extract therapy in patients with locally advanced or metastatic pancreatic cancer: a randomised clinical trial on overall survival. Eur J Cancer. 2013;49(18):3788-3797. 
  53. Friess H, Beger HG, Kunz J, Funk N, Schilling M, Büchler MW. Treatment of advanced pancreatic cancer with mistletoe: results of a pilot trial. Anticancer Res. 1996;16(2):915-920.
  54. Springett GM, Husain K, Neuger A, et al. A Phase I safety, pharmacokinetic, and pharmacodynamic presurgical trial of vitamin E ?-tocotrienol in patients with pancreatic ductal neoplasia. EBioMedicine. 2015;2(12):1987-1995. 
  55. Kraft M, Kraft K, Gärtner S, et al. L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN)--a randomized multicentre trial. Nutr J. 2012;11:52. 
  56. Frass M, Friehs H, Thallinger C, et al. Influence of adjunctive classical homeopathy on global health status and subjective wellbeing in cancer patients - a pragmatic randomized controlled trial. Complement Ther Med. 2015;23(3):309-317. 
  57. Gaertner K, Müllner M, Friehs H, et al. Additive homeopathy in cancer patients: retrospective survival data from a homeopathic outpatient unit at the Medical University of Vienna. Complement Ther Med. 2014;22(2):320-332. 
  58. Chatterjee A, Biswas J, Chatterjee AK, Bhattacharya S, Mukhopadhyay B, Mandal S. Psorinum therapy in treating stomach, gall bladder, pancreatic, and liver cancers: a prospective clinical study. Evid Based Complement Alternat Med. 2011;2011:724743.
  59. Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage. 2010;39(2):167-179. 
  60. Kramer JL. Medical marijuana for cancer. CA Cancer J Clin. 2015;65(2):109–122.
  61. Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207-218. 
  62. Portenoy RK, Ganae-Motan ED, Allende S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438–449.
  63. Panagiotarakou M, Gupta A, Syrigos K, Saif M. Use of supportive care for symptom management in pancreatic cancer: application of clinical research to patient care. Journal of the Pancreas. 2012;13(4):342-344.
  64. Dibase J, Islam R. Bile Acids: An unrecognized and underappreciated cause of chronic diarrhea. Practical Gastroenterology. 2012;32-44.
  65. Vahouny G, Tombes R, Cassidy M, Kritchevsky D, Gallo L. Dietary fibers: Binding of bile salts, phsopholipids and cholesterol from mixed micelles by bile acid sequestrants and dietary fibers. Lipids. 1980;15(12):1012-1018.
  66. Hillman LC, Peters GS, Fisher CA, Pomare EW. Effects of the fibre components of pectin, cellulose and lignan on bile salt metabolism and biliary lipid composition in man. Gut. 1986;27(1):29-36.