Pancreatic enzyme replacement therapy for steatorrhoea in pancreatic cancer (2024)

PMCID: PMC6491113

Yazan H Nofal, Yaser Abu Dail, Yazan Assaf, Hayan Abo Samra, Fatima Abbas, Ammar Hamzeh, and Nahla Alhaj Hasan

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Types of studies

We will include all RCTs or quasi‐RCTs (“a trial in which randomisation is attempted but subject to potential manipulation, such as allocating participants by day of the week, date or birth, or sequence of entry into trial”) (CCCRG 2016).

We will include studies reported as full text, those published in abstract form only, and unpublished data, with no restrictions on blinding, publication status, or language.

Types of participants

We will include people with pancreatic cancer, diagnosed using any validated criteria, irrespective of gender, age, or ethnicity.

We will use the following inclusion criteria:

1. clinical presentation (medical history, physical examination, and information from imaging, chemical, histological, and cellular studies) compatible with pancreatic cancer;

2. steatorrhoea (see Background for definition).

We will include studies conducted in any healthcare setting.

We will exclude studies involving combined populations (i.e. people with pancreatic cancer along with those with chronic pancreatitis, cystic fibrosis, or any other people suffering from other diseases causing PEI) if they do not report results for individuals with pancreatic cancer separately.

Types of interventions

We will include the following types of study.

1. Studies comparing PERT (single‐ or multi‐enzyme preparations, various coating methods (e.g. enteric or non‐enteric coatings) different pharmacological forms) versus placebo or no treatment.

2. Studies comparing PERT versus fat restriction.

We will include studies investigating opiate usage as a cointervention provided that this is not a part of the randomised treatment, keeping in mind that it may hide the effects of exocrine insufficiency, which could complicate the detection and treatment of malabsorption (Imrie 2010); however, when opiates are used in one or more of the groups and not in others (treatment or control groups) we will exclude the study.

As mentioned above, we will include studies comparing PERT with fat restriction, which is a treatment for steatorrhoea. We will include trials that do not compare PERT with fat restriction, but which include the use of fat restriction in all groups; however, when fat restriction is used in one or more of the groups and not in others (treatment or control groups), we will exclude the study.

Types of outcome measures

Electronic searches

We will conduct a literature search to identify all published and unpublished RCTs.We will construct the search strategies by using a combination of subject headings and text words relating to pancreatic cancer, steatorrhoea, and PERT. A preliminary search testing suggests that only a very small number of studies has been published that mention terms related to pancreatic cancer, steatorrhoea, and PERT (< 50 hits in MEDLINE). As we want to review all identified references including reviews, we will not apply a RCT filter on this search combination. To further increase the literature search sensitivity, we will also search any RCT that used terms related to pancreatic cancer and PERT in the abstract even if these studies do not mention terms relating to steatorrhoea in the abstract. We will apply the standard Cochrane search strategy filter for identifying RCTs to this supplemental search because a large of number of hits are found (> 1000 in MEDLINE). Hence, the final search strategy will combine terms related to: (pancreatic cancer AND steatorrhoea AND pancreatic enzyme therapy) OR (pancreatic cancer AND pancreatic enzyme therapy AND RCT filter). Will will not use an RCT filter for the search in the Cochrane Library (pancreatic cancer AND pancreatic enzyme therapy). We will apply no language restrictions. We will translate non‐English language papers and fully assess them for potential inclusion in the review, as necessary.

We will search the following electronic databases for identifying potential studies:

• Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 2);

• MEDLINE (1966 to present) (Appendix 3);

• Embase (1988 to present) (Appendix 4); and

• CINAHL (Cumulative Index to Nursing and Allied Health Literature; 1982 to present) (Appendix 5).

We will also conduct a search of ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp/en/).

Searching other resources

We will handsearch the published abstracts from the conference proceedings published in Digestive Disease Week and United European Gastroenterology Week from 2011 to 2018. We will handsearch the references cited in studies found by the above search to identify further relevant studies. We will check the reference lists of all primary studies and review articles for additional references. We will contact authors of identified studies and ask them to identify other published and unpublished studies. We will also contact manufacturers and experts in the field.

We will search for errata or retractions for any eligible studies and for studies that are not indexed by MEDLINE in PubMed (www.ncbi.nlm.nih.gov/pubmed) prior to publication of the review and report the date this was done within the review.

Selection of studies

Four review authors (YHN, YA, YAD, and FA) will independently screen the titles and abstracts of all the potential studies we identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full‐text study reports/publications and four review authors (YHN, YA, YAD, and FA) will independently screen the full text and identify studies for inclusion, and identify and record reasons for exclusion of any ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult another review author (NAH). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and a 'Characteristics of excluded studies' table.

Data extraction and management

We will use a standard data collection form for study characteristics and outcome data, adapted from the Cochrane Upper Gastrointestinal and Pancreatic Diseases website (Resources for Authors), which we will pilot on at least one study in the review. Four review authors (YHN, YA, YAD, and HAS) will extract study characteristics from included studies. We will extract the following study characteristics.

1. Methods: study design, total duration study and run in, number of study centres and location, study setting, withdrawals, and date of study.

2. Participants: number, age range, mean age, gender, severity of condition, diagnostic criteria, inclusion criteria, and exclusion criteria.

3. Interventions: intervention (routes of delivery (e.g. oral or intravenous delivery), doses (e.g. amount or intensity of each treatment, frequency of delivery), timing (e.g. before, during, or after a meal), pharmacological form, length of treatment, comparisons, concomitant medications (antacids, etc.), excluded medications (when opiates are used in one or more of the groups and not in others (treatment or control groups)), excluded treatment (when fat restriction is used in one or more of the groups and not in others (treatment or control groups)).

4. Outcomes: primary and secondary prespecified and collected outcomes at different time points.

5. Notes: funding source of the study and potential conflicts of interest of the study authors.

Four review authors (YHN, YAD, YA, FA) will independently extract outcome data from included studies. We will note in a 'Characteristics of included studies' table whether outcome data were reported in an unusable way. We will resolve disagreements by consensus or by involving another review author (NAH). One review author (YA) will copy across the data from the data collection form into Review Manager 5 (RevMan 5) (RevMan 2014). Each review author (YHN, YAD, YA, FA) will double check that the data are entered correctly by comparing the study reports with the data presented in the systematic review. A review author (NAH) will spot‐check study characteristics for accuracy against the study report.

Assessment of risk of bias in included studies

Four review authors (YHN, YA, YAD, and HAS)will independently assess the risk of bias for each study using the criteria outlined in theCochrane Handbook for Systematic Reviews of Interventions(Higgins 2011). Any disagreement will be resolved by discussion or by involving afifthreview author (NAH). For individually randomised studies we will assess the risk of bias according to the following domains.

Measures of treatment effect

We will analyse dichotomous variables (e.g. improvement in steatorrhoea, reductions in symptoms and improvements in fat‐soluble vitamin deficiency‐related diseases) using risk ratios with 95% confidence intervals. For continuous variables (e.g. measuring weight change, malabsorption, abdominal pain and costs) we will calculate mean differences with 95% confidence intervals. We will use standardised mean differences with 95% confidence intervals for quality of life or any other continuous variable if studies used different scales. We will ensure that higher scores for continuous outcomes have the same meaning for each particular outcome, explain the direction to the reader, and report where the directions were reversed, if this was necessary. For count outcomes, such as the number of adverse events, we will calculate the rate ratios with 95% confidence intervals.

We will undertake meta‐analyses only where this is meaningful (i.e. if the treatments, participants, and the underlying clinical question are sufficiently similar for pooling to make sense).

A common way that trialists indicate the presence of skewed data is the reporting of medians and interquartile ranges. When we encounter this we will note that the data are skewed and consider the implications of this.

Unit of analysis issues

The unit of analysis will be the individual participant with pancreatic cancer suffering from steatorrhoea.

We will consider special issues in the analysis of studies with non‐standard designs as follows.

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is published in abstract form only).

For dichotomous variables we will perform an intention‐to‐treat analysis whenever possible, which will include all participants randomised to a study irrespective of what happened subsequently (Higgins 2011; Lewis 1993; Newell 1992). This will involve imputing outcomes for the missing participants and we will assume that all missing participants did not experience the desired outcome (reduction in steatorrhoea and related symptoms). If this is not possible, we will conduct a per‐protocol analysis (an analysis of the results of only those participants who completed the study and who complied with (or received some of) their allocated intervention (in this review, PERT)) (Higgins 2011); we will, however, assess the impact of the worst‐ and best‐case scenarios on the results in the sensitivity analysis. For continuous outcomes, we will perform an available‐case analysis. If we are unable to obtain the necessary information from the investigators or study sponsors, we will impute the mean from the median (i.e. consider the median as the mean) and the standard deviation from the standard error, interquartile range, or P values, according to guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011); we will, however, assess the impact of including such studies using a sensitivity analysis. If we are unable to calculate the standard deviation from the standard error, interquartile range, or P values, we will impute the standard deviation as the highest standard deviation in the remaining studies included in the outcome, being fully aware that this method of imputation will decrease the weight of a study in a meta‐analysis of mean differences and will shift the effect estimate towards no effect for standardised mean differences. We will assess the impact of including such studies using a sensitivity analysis.

Assessment of heterogeneity

We will test heterogeneity using:

1. the Chi² test, with significance set at P < 0.1;

2. the I² statistic (Higgins 2003), which can be interpreted as the percentage of variation observed between the studies that is attributable to between‐study differences rather than sampling error (chance) (Higgins 2011); we will consider an I² statistic greater than 50% as indicative of high‐level heterogeneity. We will recognise that there is uncertainty in the I² statistic when there are few studies in a meta‐analysis;

3. Tau², which represents an estimate of the between‐study variance in a random‐effects meta‐analysis (Higgins 2011). If Tau² is similar to the treatment effect we will conclude that the heterogeneity is very high.

If we find high levels of heterogeneity (I² > 50%, or Tau² is similar to the treatment effect) for our primary outcomes, we will explore possible sources of heterogeneity using the sensitivity and subgroup analyses described below.

Assessment of reporting biases

We will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results using a sensitivity analysis.

If we are able to pool more than 10 studies, we will create and examine a funnel plot to explore possible publication biases.

We will consider reporting biases (publication, time lag, duplicate publication, location, citation, language, and outcome reporting) at all points of both the data analysis and the interpretation. If sufficient numbers of RCTs are found in a particular field, attempts will be made to analyse the studies for publication bias using funnel plots, bearing in mind that publication bias does not necessarily cause asymmetry (Egger 1997; Macaskill 2001). We will consider a P value of less than 0.05 statistically significant for reporting bias.

Data synthesis

We will perform the analysis using RevMan 2014. We will use both a fixed‐effect model and a random‐effects model for the analysis. For subgroup analyses, if the studies are found to be hom*ogeneous (in terms of age, diagnostic subtype, intervention type, intervention duration) we will use a fixed‐effect model; if they are found to be heterogeneous we will perform a random‐effects model. In case of discrepancies between the two models, we will report both results.

• We will summarize dichotomous (binary) variables (e.g. proportion of participants who develop side effects) using risk ratios.

• We will summarize continuous data using the mean difference when studies use the same scale. We will use the standardised mean difference to measure the difference between groups in studies that use different scales

• We will summarize ordinal outcomes data and scales as dichotomous data for short scales and continuous data for long scales

• When studies have a multifactorial design comparing multiple intervention groups, we will extract data and assign them to the relevant intervention group. We will treat each intervention group independently within our analysis

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses.

• PERT in participants with unresectable or resectable cancers prior to the Whipple procedure as one group versus participants after the Whipple procedure as another group. This is because the procedure is greatly invasive and its malabsorption consequences could be a result of many factors other than the loss of pancreatic enzymes.

• Coadministration of antacids and various PERT preparations versus various PERT preparations alone, to allow for the change in pH level in the stomach associated with antacids that could affect PERT efficacy (Vecht 2006).

• Different administration schedules (before, with, or after meals), to allow for their effect on the therapeutic efficacy of PERT, considering that the change in the timing of the arrival of PERT with chymus in the duodenum could affect PERT efficacy (Dominguez‐Munoz 2005).

• Doses of 25,000 or lower lipase units per main meal versus doses of more than 25,000 lipase units per main meal (Struyvenberg 2017).

We will use steatorrhoea as the outcome in subgroup analyses.

We will use the formal statistical test for heterogeneity across subgroups based on the random‐effects model to test for subgroup interactions (Borenstein 2008) and we will use caution in the interpretation of subgroup analyses, as advised in Section 9.6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will compare the magnitude of the effects between the subgroups by assessing the overlap of the confidence intervals of the summary estimate (non‐overlap of the confidence intervals indicates statistical significance).

Sensitivity analysis

We will perform sensitivity analyses defined a priori to assess the robustness of our conclusions. These will involve:

• excluding studies at unclear or high risk of bias (one or more of the 'Risk of bias' domains classified as unclear or high, including: methods used for randomisation, allocation to interventions, blinding or missing data);

• excluding those at unclear or high risk of bias for sequence generation (e.g. quasi‐RCTs);

• making different hypotheses on any imputed data (e.g. excluding studies in which either means or standard deviations, or both are imputed);

• excluding cluster RCTs in which the adjusted effect estimates are not reported;

• excluding studies published in abstract form only;

• excluding studies of low statistical power;

• excluding unpublished studies;

• excluding studies funded by industry;

• comparing summary statistics (risk ratios versus odds ratios) by calculating a risk ratio for the desired outcome (no steatorrhoea and malabsorption after PERT therapy); if the risk ratio is close to one, we will compare this with the odds ratio to analyse sensitivity;

• comparing meta‐analysis modelling (fixed‐effect versus random‐effects);

• evaluating the influence of missing data on the results (intention‐to‐treat analysis versus per‐protocol analysis);

• performing a best‐case, worst‐case type analysis in which all missing participants in one arm are assumed to have had the outcome of interest and all missing participants in the other arm are assumed to have not had the outcome, and vice‐versa.

We will report the results from the sensitivity analyses in a summary table and produce a summary table detailing decisions made during the process of conducting the review and the potential impact of these decisions on the findings. We will address significant decisions in the 'Discussion' section of the review.

Appendix 1. Glossary of terms

Alkaline phosphatase: any of the phosphatases (as phosphom*onoesterase from blood plasma or milk) optimally active in an alkaline medium and occurring in especially high concentrations in bone, liver, kidneys, or placenta

Amylase: any of a group of enzymes (as amylopsin) that catalyse (mediate) the hydrolysis (chemical process of decomposition involving the splitting of a bond and the addition of the hydrogen cation and the hydroxide anion of water) of starch and glycogen (a white amorphous tasteless polysaccharide (C₆H₁₀O₅)_x that constitutes the principal form in which glucose is stored in animal tissues) or their intermediate hydrolysis products

Anastomosed: connected or joined by anastomosis (the surgical union of parts and especially hollow tubular parts)

Bilirubin: a reddish yellow pigment (C₃₃H₃₆N₄O₆) that occurs especially in bile and blood, and causes jaundice if accumulated in excess

BMI: body mass index, a measure of body fat that is the ratio of the weight of the body in kilograms to the square of its height in meters

Body of the pancreas: the largest part of the pancreas, located between the neck and tail of the pancreas

BRCA2: a tumour suppressor gene that in mutated form tends to be associated with an increased risk of certain cancers and especially breast and ovarian cancers

Cachexia: loss of skeletal muscle mass with or without the loss of fat mass

Chemotherapy: the use of chemical agents in the treatment or control of disease or mental disorder

Common bile duct: the duct formed by the union of the hepatic and cystic ducts, and opening into the duodenum

Common hepatic duct: the duct formed by the convergence of the right hepatic duct (which drains bile from the right functional lobe of the liver) and the left hepatic duct (which drains bile from the left functional lobe of the liver). The common hepatic duct then joins the cystic duct coming from the gallbladder to form the common bile duct

Concomitant: accompanying or associated with

Diabetes mellitus: a variable disorder of carbohydrate metabolism caused by a combination of hereditary and environmental factors, and usually characterised by the inadequate secretion or utilisation of insulin, excessive urine production, excessive amounts of sugar in the blood and urine, and by thirst, hunger, and loss of weight

Distal: refers to parts of the body further away from the centre

Duodenum: the first, shortest, and widest part of the small intestine, which in humans is about 25 cm long, and which extends from the pylorus (the opening from the vertebrate stomach into the intestine) to the undersurface of the liver, where it descends for a variable distance, receives the bile and pancreatic ducts, and then bends to the left and finally upward to join the jejunum

Endocrine: secreting internally and specifically producing secretions that are distributed in the body by way of the bloodstream

Exocrine: producing, being, or relating to a secretion that is released outside its source

FAMMM: familial atypical multiple mole melanoma (a type of skin cancer) syndrome

Gall bladder: a membranous muscular sac in which bile from the liver is stored

Gastric: relating to the stomach

Head of the pancreas: the portion of the pancreas that is lodged within the curve of the duodenum and is flattened anteriorly (from before)

Histological: related to microscopic tissue structure or organisation

HNPCC: hereditary non‐polyposis (characterised by the absence of polyps) colorectal cancer

Incidence: act of occurring

Invasive: tending to spread and especially tending to invade healthy tissue

Jaundice: a yellowish pigmentation of the skin, tissues, and certain body fluids caused by the deposition of bile pigments that follows interference with the normal production and discharge of bile (as in certain liver diseases) or the excessive breakdown of red blood cells (as after internal haemorrhage (bleeding) or in various haemolytic states (related to the lysis of red blood cells))

Jejunum: the section of the small intestine that comprises the first two‐fifths beyond the duodenum and that is larger, thicker‐walled, and more vascular, and has more circular folds and fewer Peyer's patches (numerous large oval patches of closely aggregated nodules of lymphoid tissue in the walls of the small intestine especially in the ileum) than the ileum

Lipase: any enzyme (secreted by the pancreas) that catalyses (mediates) the breakdown of fats and lipoproteins (conjugated proteins composed of a complex of protein and lipid) usually into fatty acids and glycerol (a sweet syrupy hygroscopic trihydroxy alcohol C₃H₈O₃ usually obtained by the saponification of fats)

Luminal: relating to a lumen, the cavity of a tubular organ or part

Malabsorption: faulty absorption of nutrient materials from the alimentary canal (digestive tract)

Maldigestion: imperfect or impaired digestion

Malignant: tending to infiltrate, metastasize, and terminate fatally

Malnutrition: faulty nutrition due to inadequate or unbalanced intake of nutrients or their impaired assimilation or utilisation

Metabolism: chemical changes in living cells by which energy is provided for vital processes and activities, and new material is assimilated

Metastasised: spread by metastasis, the spread of a disease‐producing agent (e.g. cancer cells or bacteria) from the initial or primary site of disease to another part of the body

Morbidity: a diseased state or symptom

Mortality: death or the quality or state of being subject to death

Mutation: a relatively permanent change in hereditary material involving either a physical change in a chromosome (linear body of the cell nucleus of eukaryotic organisms that takes up basophilic stains and contains most or all of the genes of the organism) or a biochemical change in the codons (specific sequences of three consecutive nucleotides that are part of the genetic code and that specify a particular amino acid in a protein or start or stop protein synthesis) that make up genes and also the process of producing a mutation

Non‐enteric coated: not containing a coating to prevent breakdown in the stomach

Obstructive jaundice: jaundice due to obstruction of the biliary passages (as by gallstones or tumours)

Oncogene: a gene having the potential to cause a normal cell to become cancerous

Osteomalacia: a disease of adults that is characterised by softening of the bones; analogous to rickets in the young

Pancreatic duct: a duct connecting the pancreas with the intestine

Pancreatic exocrine insufficiency (PEI): a condition characterised by deficiency of the exocrine pancreatic enzymes, resulting in the inability to digest food properly

Pancreatitis: inflammation of the pancreas

PERT: pancreatic enzyme replacement therapy

Peutz‐Jeghers: a familial polyposis condition characterised by the presence of numerous polyps (projecting masses) in the stomach, small intestine, and colon, and by melanin‐containing spots on the skin and mucous membranes, especially the lips and gums. Melanin is any various black, dark brown, reddish brown, or yellow pigment of animal or plant structures

Physiology: the organic processes and phenomena of an organism or any of its parts, or of a particular bodily process

Precancerous: tending to become cancerous

Prognosis: the prospect of survival and recovery from a disease as anticipated from the usual course of that disease or indicated by special features of the case

Protease: any of numerous enzymes that hydrolyse (cause the chemical process of decomposition involving the splitting of a bond and the addition of the hydrogen cation and the hydroxide anion of water) proteins and are classified according to the most prominent functional group (a serine or cysteine) at the active site

Quality of life: the standard of health, comfort, and happiness experienced by an individual or group

Radiotherapy: the treatment of disease by means of radiation (as X‐rays)

Ras: any of a family of genes that undergo mutation to oncogenes (genes having the potential to cause a normal cell to become cancerous) and especially to some commonly linked to human cancers (e.g. the colon, lung, and pancreas)

Resection: the surgical removal of part of an organ or structure

Risk factor: something that increases risk or susceptibility

Sarcopenia: loss in skeletal muscle mass

Serum: the clear yellowish fluid that remains from blood plasma (liquid portion of blood in which red and white blood cells and platelets are suspended) after clotting proteins have been removed

Skeletal muscle: striated muscle that is usually attached to the skeleton and is usually under voluntary control

Steatorrhoea: an excess of fat in the stool

Survival rate: a part of survival analysis, indicating the percentage of people in a study or treatment group who are alive for a given period of time after diagnosis

Tail of the pancreas: the part of the pancreas located anatomically left near the hilum of the spleen

Tumour marker: a biomarker (a distinctive biological or biologically derived indicator of a process, event, or condition) found in the blood, urine, or body tissues that can be elevated in cancer, among other tissue types

Tumour‐suppressor gene: any of a class of genes (such as p53) that act in normal cells to inhibit unrestrained cell division and that when inactivated (as by mutation) place the cell at increased risk of malignant proliferation

Whipple’s procedure: a major surgical operation involving the pancreas, duodenum, and other organs

Appendix 2. CENTRAL search strategy

#1 MeSH descriptor: [Pancreatic Neoplasms] explode all trees

#2 Pancrea* near/5 (cancer* or carcin* or malig* or tumor* or tumour* or neoplas*) (Word variations have been searched)

#3 #1 or #2

#4 MeSH descriptor: [Amylases] explode all trees

#5 Pancrea* near/5 (enzyme* or amylase* or lipase* or protease or phospholipase* or trypsin* or chymotrypsin*) (Word variations have been searched)

#6 enzyme replacement or enzyme supplement* or "PERT" or "PEPs" (Word variations have been searched)

#7 pancrelipase or pancreatin or Creon or Pancreaze or Zenpep or Pancrecarb or TheraCLEC‐Total or Panokase or plaretase or Lipram or Pangestyme or Ku‐Zyme or Palcaps or Pangestyme or Panocaps or Pancrease MT (Word variations have been searched)

#8 pancrinase or nutrizym 22 or Cotazym or Dygase or Kutrase or Lapase or Pertzye or ultracaps or viokace or Viokase or ultresa or Ultrase (Word variations have been searched)

#9 #4 or #5 or #6 or #7 or #8

#10 #3 and #9

Appendix 3. MEDLINE search strategy

1 exp Pancreatic Neoplasms/

2 (Pancrea* adj5 (cancer* or carcin* or malig* or tumor* or tumour* or neoplas*)).tw,kw.

3 1 or 2

4 exp steatorrhea/

5 (steatorrhea or steatorrhoea).tw,kw.

6 ((fat or fatty or oily) adj5 (feces or faeces or fecal or faecal or stool or stools)).tw,kw.

7 4 or 5 or 6

8 3 and 7

9 exp Amylases/

10 (Pancrea* adj5 (enzyme* or amylase* or lipase* or protease or phospholipase* or trypsin* or chymotrypsin*)).tw,kw.

11 (enzyme replacement or enzyme supplement* or "PERT" or "PEPs").tw,kw.

12 (pancrelipase or pancreatin or Creon or Pancreaze or Zenpep or Pancrecarb or TheraCLEC‐Total or Panokase or plaretase or Lipram or Pangestyme or Ku‐Zyme or Palcaps or Pangestyme or Panocaps or Pancrease MT).tw,kw.

13 (pancrinase or nutrizym 22 or Cotazym or Dygase or Kutrase or Lapase or Pertzye or ultracaps or viokace or Viokase or ultresa or Ultrase).tw,kw.

14 or/9‐13

15 8 and 14

16 3 and 14

17 randomized controlled trial.pt.

18 controlled clinical trial.pt.

19 random*.ab.

20 placebo.ab.

21 drug therapy.fs.

22 trial.ab.

23 groups.ab.

24 or/17‐23

25 exp animals/ not humans.sh.

26 24 not 25

27 16 and 26

28 15 or 27

Appendix 4. Embase search strategy

1 exp pancreas cancer/

2 (Pancrea* adj5 (cancer* or carcin* or malig* or tumor* or tumour* or neoplas*)).tw,kw.

3 1 or 2

4 exp steatorrhea/

5 (steatorrhea or steatorrhoea).tw,kw.

6 ((fat or fatty or oily) adj5 (feces or faeces or fecal or faecal or stool or stools)).tw,kw.

7 4 or 5 or 6

8 3 and 7

9 exp pancreas enzyme/

10 (Pancrea* adj5 (enzyme* or amylase* or lipase* or protease or phospholipase* or trypsin* or chymotrypsin*)).tw,kw.

11 (enzyme replacement or enzyme supplement* or "PERT" or "PEPs").tw,kw.

12 (pancrelipase or pancreatin or Creon or Pancreaze or Zenpep or Pancrecarb or TheraCLEC‐Total or Panokase or plaretase or Lipram or Pangestyme or Ku‐Zyme or Palcaps or Pangestyme or Panocaps or Pancrease MT).tw,kw.

13 (pancrinase or nutrizym 22 or Cotazym or Dygase or Kutrase or Lapase or Pertzye or ultracaps or viokace or Viokase or ultresa or Ultrase).tw,kw.

14 or/9‐13

15 8 and 14

16 3 and 14

17 random:.tw.

18 clinical trial:.mp.

19 exp health care quality/

20 placebo:.mp.

21 double‐blind:.tw.

22 or/17‐21

23 exp animal/ not human.sh.

24 22 not 23

25 16 and 24

26 15 or 25

Appendix 5. CINAHL search strategy

S19 S14 OR S18

S18 S10 AND S17

S17 S15 OR S16

S16 TX ((fat or fatty or oily) and (feces or faeces or fecal or faecal or stool or stools))

S15 TX steatorrhea or steatorrhoea

S14 S10 AND S13

S13 S11 OR S12

S12 (MH "Randomized Controlled Trials")

S11 TX random*

S10 S3 AND S9

S9 S4 OR S5 OR S6 OR S7 OR S8

S8 TX pancrinase or nutrizym 22 or Cotazym or Dygase or Kutrase or Lapase or Pertzye or ultracaps or viokace or Viokase or ultresa or Ultrase

S7 TX ancrelipase or pancreatin or Creon or Pancreaze or Zenpep or Pancrecarb or TheraCLEC‐Total or Panokase or plaretase or Lipram or Pangestyme or Ku‐Zyme or Palcaps or Pangestyme or Panocaps or Pancrease MT

S6 TX enzyme replacement or enzyme supplement* or "PERT" or "PEPs"

S5 TX Pancrea* and (enzyme* or amylase* or lipase* or protease or phospholipase* or trypsin* or chymotrypsin*)

S4 (MH "Amylases")

S3 S1 OR S2

S2 TX Pancrea* and (cancer* or carcin* or malig* or tumor* or tumour* or neoplas*)

S1 (MH "Pancreatic Neoplasms+")