PANCREATIC DISEASE DECISION SUPPORT TOOL · strongest risk factor for pancreatic cancer was a history of chronic pancreatitis (RR 2.7-5.1). Tobacco smoking (RR 1.5 -2.2), diabetes

Pancreatic diseases decision support tool – summary of the evidence V1.0 5/11/2019

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PANCREATIC DISEASE DECISION SUPPORT TOOL

Summary of the evidence

Contents Forward ......................................................................................................................................................... 3

Pancreatic cancer.......................................................................................................................................... 3

Symptoms ................................................................................................................................................. 3

Positive predictive values ..................................................................................................................... 3

Proportion of patients with symptoms ................................................................................................ 3

Risk factors ................................................................................................................................................ 3

Table 1: Positive predictive values for prodromal symptoms of pancreatic cancer ................................ 4

Table 2: Summary of pooled proportions of prodromal symptoms for pancreatic cancer ..................... 5

Table 3: Relative risk of pancreatic cancer by risk factors: pooled analysis from Maisonneuve et al1 .... 5

Chronic pancreatitis ...................................................................................................................................... 6

Proportion of patients with symptoms .................................................................................................... 6

Risk factors ................................................................................................................................................ 6

Table 4: Summary of pooled proportions of prodromal symptoms for chronic pancreatitis .................. 7

Table 5: Effect measure for association between risk factors of chronic pancreatitis ............................ 7

Pancreatic enzyme insufficiency (PEI) .......................................................................................................... 8

Proportion of patients with symptoms .................................................................................................... 8

Risk factors ................................................................................................................................................ 8

Table 6: Summary of pooled proportions for prodromal symptoms of pancreatic enzyme insufficiency .................................................................................................................................................................. 8

References .................................................................................................................................................... 9

Appendix 1: Systematic review of the literature - methods ...................................................................... 10

Appendix 2: Forest plots from meta-analyises of prodromal symptoms of pancreatic cancer ................ 13

Pooled Odds Ratios ............................................................................................................................... 13

Abdominal pain, indigestion, nausea/vomiting and weight loss ........................................................ 13

Abdominal distension, anorexia, bloating and dysphagia .................................................................. 14

Back pain, changed bowel habits, and malaise .................................................................................. 14

Pooled proportions ................................................................................................................................ 15

Abdominal pain ................................................................................................................................... 15

Nausea/vomiting ................................................................................................................................ 15

Weight loss ......................................................................................................................................... 16


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Anorexia .............................................................................................................................................. 16

Back pain ............................................................................................................................................. 17

Changed bowel habits ........................................................................................................................ 17

Malaise/tired ...................................................................................................................................... 18

Diarrhoea ............................................................................................................................................ 18

Other pain ........................................................................................................................................... 19

Fever and malabsorption .................................................................................................................... 19

Indigestion, bloating, dysphagia and abdominal distension .............................................................. 20

Appendix 3: Forest plots from meta-analyises of prodromal symptoms of chronic pancreatitis ............. 21


Steatorrhoea ....................................................................................................................................... 21

Abdominal pain ................................................................................................................................... 22

Jaundice and diabetes ........................................................................................................................ 22

Weight loss, nausea/vomiting, indigestion and abdominal distension .............................................. 23

Diarrhoea, anorexia and fever ............................................................................................................ 24

Anaemia, acute pancreatitis, ascited and GI bleed ............................................................................ 25

Risk factors: overweight, smoker, alcohol intake ............................................................................... 25

Appendix 4: Forest plots from meta-analyises of prodromal symptoms of pancreatic enzyme insufficiency .................................................................................................................................................................... 26


Diarrhoea, steatorrhoea, abdominal pain, bloating, nausea and weight loss ................................... 26


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Forward This document provides a summary of the peer-reviewed evidence on the symptoms experienced by patients before a diagnosis, and risk factors for pancreatic cancer, chronic pancreatitis or pancreatic enzyme insufficiency. Details about how the systematic review was performed are included in Appendix 1.

The written summary does not include abdominal pain, jaundice or symptoms of steattorhoea, as these are identified as “red flag” symptoms. All symptoms, including “red flag” symptoms, are included in tables and Appendices 2, 3 and 4.

Pancreatic cancer Symptoms Positive predictive values Only a small number of population-based studies have calculated positive predictive values for symptoms of pancreatic cancer. These are small, ranging from 0.6/1000 patients with back pain to 6.5/1000 patients with weight loss. That is, for every 1000 patients who present with weight loss, 6.5 will be diagnosed with pancreatic cancer. Refer to Table 1 for the full results.

Proportion of patients with symptoms We pooled data from across multiple studies to generate the proportion of patients who present with each symptom. Note that there was very high heterogeneity for almost all symptoms; the one exception was dysphagia but this occurred uncommonly.

Weight loss was the most frequently occurring symptom (39%). Other common symptoms were anorexia (30%), malaise (26%), nausea and/or vomiting (22%) and indigestion (21%). Refer to Table 2 for full results. Forest plots including details of the included studies and the pooled analyses are included in Appendix 2.

Odds ratios Odds ratios were pooled from case control studies. Weight loss was associated with the largest odds ratio (OR 11.7) and back pain was associated with the smallest odds ratio (OR 1.4). Full results included in Appendix 2.

Risk factors For risk factors associated with pancreatic cancer, we refer to the study by Maisonneuve et al, which provides estimates of risk based on the combined results from 117 meta-analytical or pooled reports.1 Full text of the article is available at https://academic.oup.com/ije/article/44/1/186/655734. The strongest risk factor for pancreatic cancer was a history of chronic pancreatitis (RR 2.7-5.1). Tobacco smoking (RR 1.5-2.2), diabetes mellitus (1.4-2.2) and having a family history (1.7-1.8) almost doubled risk. Helicobacter pylori infection (1.2-1.7), reducing adiopectin level (RR 1.6) and a history of gastrectomy (RR 1.5) were associated with about a 50% increased risk of pancreatic cancer.1 Refer to Table 3 for full results.

https://academic.oup.com/ije/article/44/1/186/655734

https://academic.oup.com/ije/article/44/1/186/655734


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Table 1: Positive predictive values for prodromal symptoms of pancreatic cancer Symptom and Study PPV (per 1000 people) (95% CI) Abdominal pain

Hippisley-Cox, et al. 3.3 (3, 4) Collins, et al. 1.4 (1, 2) Stapely, et al. 2.0 (1.9, 2.2)

Weight loss Hippisley-Cox, et al. 6.5 (5.0, 8.3) Collins, et al. 2.8 (2.2, 3.5) Stapely, et al. 4.4 (3.6, 5.5)

Nausea/vomiting Stapely, et al. 1.9 (1.7, 2.1)

Jaundice Stapely, et al. 129 (79, 271)

Anorexia Collins, et al. 3.9 (2.5, 5.8)

Diarrhoea Stapely, et al. 0.9 (0.8, 1.1)

Back pain Stapely, et al. 0.6 (0.5, 0.7)

Abdominal distension Hippisley-Cox, et al. 2.6 (1.1, 4.9) Collins, et al. 1.1 (0.7, 1.9)

Malaise Stapely, et al. 1.2 (1, 1.5)

Dysphagia Hippisley-Cox, et al. 2.0 (1, 3.6) Collins, et al. 1.0 (0.7, 1.9)

Changed bowel habit Stapely, et al. 1.0 (0.9, 1.1)

Diabetes Stapely, et al. 0.9 (0.8, 1)


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Table 2: Summary of pooled proportions of prodromal symptoms for pancreatic cancer Symptom Pooled Proportion I2 % (Heterogeneity) No. of studies Abdominal pain 0.54 (0.47, 0.60 ) 97.83 24 Weight loss 0.39 (0.27, 0.51) 99.34 25 Other pain 0.30 (0.10, 0.56) 99.43 6 Anorexia 0.29 (0.14, 0.46) 99.12 11 Malaise 0.26 (0.14, 0.40) 99.27 9 Malabsorption 0.23 (0.10, 0.41) - 3 Nausea/vomiting 0.22 (0.16, 0.29) 97.49 12 Indigestion 0.21 (0.18, 0.25) - 3 Back pain 0.21 (0.15, 0.28) 97.92 13 Diarrhoea 0.19 (0.06, 0.36) 99.22 7 Changed bowel habits 0.16 (0.09, 0.23) 98.11 11 Bloating 0.14 (0.02, 0.33) 98.5 4 Fever 0.08 (0.03, 0.16) - 3 Abdominal distension 0.02 (0.01, 0.03) 66.25 4 Dysphagia 0.02 (0.01, 0.02) 0 4

Table 3: Relative risk of pancreatic cancer by risk factors: pooled analysis from Maisonneuve et al1

Risk factor Relative Risk Tobacco smoking 1.5 – 2.2 Helicobacter pylori infection 1.2 – 1.7 Non-O blood group 1.3 – 1.4 Diabetes Mellitus 1.4 – 2.2 Obesity 1.5 – 1.5 Reducing adiponectin level 1.6 Increasing red or processed meat 1.1 – 1.5 Heavy alcohol intake 1.1 – 1.5 Family history 1.7 – 1.8 History of chronic pancreatitis 2.7 – 5.1 Hepatitis B infection 1.2 – 1.4 History of gastrectomy 1.5 History of cholecystectomy 1.2


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Chronic pancreatitis Proportion of patients with symptoms There are no studies reporting positive predictive values. Pooled estimates of the proportion of patients with sumptoms are shown in Table 4. Note that the heterogeneity was high where calculated (only when the symptom was reported by 3 or more studies).

Apart from abdominal pain, the most commonly occurring symptoms prior to a diagnosis of chronic pancreatitis were a history of acute pancreatitis (66%), anorexia (49%), diabetes (36%) and weight loss (25%). Forest plots including details of the included studies and the pooled analyses are included in Appendix 3.

Risk factors Few studies report on the relative risk of chronic pancreatitis by exposure to risk factors. A recent metaanalysis of the risk of smoking on chronic pancreatitis report that compared with never smokers, increased risk exists among current smokers (RR 1.93), former smokers (RR 1.3) and ever smokers (RR 1.6).2 The risk associated with smoking is independent of alcohol drinking.3 Alcohol drinking is associated with a increased hazard ratio of about 10% for each additional drink per day (HR 1.09).3 Similarly, very heavy drinkers have a 3-fold risk of chronic pancreatitis compared with abstainers or light drinkers (OR 3.1).4 Patients diagnosed between ages 35 and 65 are most likely to have alcoholic aetiology compared with those younger than 35 (OR 2.4) or after 65 years (OR 4.6).5 Refer to Table 5 for full results.


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Table 4: Summary of pooled proportions of prodromal symptoms for chronic pancreatitis

Symptom Pooled proportion

Proportion I2 % (Heterogeneity) No. of studies

Abdominal pain 0.79 (0.72, 0.84) 98.61 27

Acute pancreatitis 0.66 (0.56, 0.75) 91.66 3

Alcohol intake 0.50 (0.41, 0.60) 95.69 4

Smoker 0.49 (0.34, 0.64) 98.26 4

Anorexia 0.49 (0.32, 0.65) - 2

Diabetes 0.36 (0.30, 0.42) 97.87 25

Indigestion 0.31 (0.28, 0.34) - 2

Anaemia 0.29 (0.21, 0.38) - 1

Overweight 0.28 (0.25, 0.30) - 1

Weight loss 0.25 (0.17, 0.33) 96.27 10

Steatorrhoea 0.19 (0.13, 0.25) 98.32 23

Ascites 0.13 (0.08, 0.20) - 1

Jaundice 0.13 (0.08, 0.19) 91.84 8

Nausea/vomiting 0.08 (0.05, 0.11) - 2

Diarrhoea 0.05 (0.02, 0.07) - 2

Fever 0.04 (0.02, 0.09) - 1

GI Bleed 0.03 (0.01, 0.05) - 2

Abdominal distension 0.01 (0.0, 0.05) - 1 Table 5: Effect measure for association between risk factors of chronic pancreatitis

Risk factor Effect size (95% CI) Age (vs < 35 years)5

35 – 65 years OR 2.4 (1.6, 3.6) < 35 year OR 4.6 (2.3, 9.5)

Smoking status (vs never smoker)2 Pooled Relative Risk Current smoker RR 1.9 (1.6, 2.3) Former smoker RR 1.3 (1.1, 1.6) Ever smoker RR 1.6 (1.4, 1.8)

Additional alcoholic drink per day3 HR 1.1 (1.0, 1.1) Heavy drinkers vs abstainers/light drinkers4 OR 3.1 (1.9, 5.1)


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Pancreatic enzyme insufficiency (PEI) Proportion of patients with symptoms We identified only 3 studies that reported on symptoms of PEI independently of an existing diagnosis of pancreatic disease or other chronic illnesses. Diarrhoea was very common, occurring in 70% of patients. Weight loss was reported in about 10% of patients, and bloating and nausea were extremely uncommon. Refer to Table 6 for full results. Forest plots including details of the included studies and the pooled analyses are included in Appendix 3.

Risk factors People with chronic pancreatitis, cystic fibrosis, stomach ulcers, coeliac disease, and those have undergone undergone surgery of the stomach, pancreas or gall bladder are at risk of PEI. PEI often occurs at the time of, and following, acute pancreatitis. The risk of PEI following acute pancreatitis increases with the severity of the pancreatitis (RR 1.5) and with alcoholic aetiology compared with biliary (RR 1.6).6

Table 6: Summary of pooled proportions for prodromal symptoms of pancreatic enzyme insufficiency

Symptom Proportion (95% CI) No. of studies

Diarrhoea 0.70 (0.64, 0.75) 2

Steatorrhoea 0.18 (0, 0.51) 3

Abdominal pain 0.16 (0.12, 0.21) 1

Weight loss 0.10 (0.06, 0.14) 2

Bloating 0.03 (0.01, 0.05) 1

Nausea 0 (0, 0.02) 2


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References 1. Maisonneuve P, Lowenfels AB. Risk factors for pancreatic cancer: a summary review of metaanalytical studies. Int J Epidemiol. 2015;44(1):186-98. 2. Aune D, Yahya, M., Norat, T., Riboli, E. Tobacco smoking and the risk of pancreatitis: A systematic review and meta-analysis of prospective studies. Pancreatology. 2019;In Press. 3. Tolstrup JS, Kristiansen L, Becker U, Grønbæk M. Smoking and risk of acute and chronic pancreatitis among women and men. Archives of Internal Medicine. 2009;169(6):603-9. 4. Yadav D, Hawes RH, Brand RE, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med. 2009;169(11):1035-45. 5. Conwell DL, Banks PA, Sandhu BS, et al. Validation of Demographics, Etiology, and Risk Factors for Chronic Pancreatitis in the USA: A Report of the North American Pancreas Study (NAPS) Group. Dig Dis Sci. 2017;62(8):2133-40. 6. Huang W, de la Iglesia-Garcia D, Baston-Rey I, et al. Exocrine Pancreatic Insufficiency Following Acute Pancreatitis: Systematic Review and Meta-Analysis. Dig Dis Sci. 2019;64(7):1985-2005.


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Appendix 1: Systematic review of the literature - methods Review Question:

Aims:

The primary aim of this study is to systematically review the literature to identify symptoms that may indicate a diagnosis of pancreatic cancer, chronic pancreatitis and pancreatic enzyme

insufficiency (PEI). Review questions:

1. What proportion of cases present with specific symptoms, or what is the size of the association (e.g. odds or risk ratio) between the exposure and each disease outcome5? Searches:

A comprehensive literature search was carried out in PubMed and Embase. Population Exposure Comparison (control) Outcome People with disease diagnosed

Symptom

People without the disease diagnosis

Prevalence within the population (%). Effect of exposure (OR or RR)


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PANCREATIC CANCER Outcome Exposure Limits Outcome measures

Free text terms / natural language terms

Pancreatic neoplasm Pancreatic cancer PDAC

Symptoms

Symptoms identified from test results. Post-diagnosis therapies Gestational diabetes

Prevalence in population Estimate of size of association (OR/RR)

Controlled vocabulary terms / Subject terms

MeSH terms

"Pancreatic Neoplasms/diagnosis"[Majr] “Pancreatic Neoplasms/prevention & control”[Majr] "Pancreatic Intraductal Neoplasms/diagnosis"[Majr] "Carcinoma, Pancreatic Ductal/diagnosis"[Majr] "Carcinoma, Pancreatic Ductal/prevention and control"[Majr]

“early detection of cancer”[MeSH] “Predict”[All Fields] “prodromal symptoms”[MeSH] “Signs and Symptoms”[MeSH] "risk assessment" “Predict”[All Fields]

NOT neoplasm proteins, biomarkers, genetic techniques or diagnostic techniques NOT assessment of therapeutic modalities: chemotherapy/adjuvant therapy Restricted to: Humans, adults, full text, English language, not gestational diabetes

Incidence Odds ratio Relative risk Risk ratio


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CHRONIC PANCREATITIS AND PANCRATIC ENZYME INSUFFICIENCY

Outcome Exposure Limits Outcome measures

Free text terms / natural language terms

Pancreatic neoplasm Pancreatic cancer PDAC

Symptoms

Excluded from search: Symptoms identified from test results. Post-diagnosis therapies

Prevalence in population Estimate of size of association (OR/RR)

“Pancreatitis, chronic”[MeSH] "Exocrine pancreatic insufficiency"[Majr]

“early diagnosis”[MeSH] “Predict”[All Fields] “prodromal symptoms”[MeSH] “Signs and Symptoms”[MeSH] "risk assessment" “risk factors”[MeSH]

NOT proteins or biomarkers, treatment or diagnostic investigations Restricted to: Humans, adults, full text, English language

11 Summary of evidence – Pancreatic diseases decision support tool V1.0 31/10/2019

Pancreatic diseases decision support tool – summary of the evidence V1 5/11/2019

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Appendix 2: Forest plots from meta-analyises of prodromal symptoms of pancreatic cancer Pooled Odds Ratios Abdominal pain, indigestion, nausea/vomiting and weight loss


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Abdominal distension, anorexia, bloating and dysphagia

Back pain, changed bowel habits, and malaise


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Pooled proportions Abdominal pain

Nausea/vomiting


16

Weight loss

Anorexia


17

Back pain

Changed bowel habits


18

Malaise/tired

Diarrhoea


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Other pain

Fever and malabsorption

Heterogeneity between groups: p = 0.000

Overall (I^2 = 99.43%, p = 0.00);

OTHER PAIN

Mizuno, et al.

Gobbi, et al.

Study

Ruckert, et al.

Keane, et al.

Walter, et al.

Kalser, et al.

2013

2013

Year

2013

2014

2016

1985

195

38

Events

37

335

3

307

540

170

Total

79

2790

119

393

0.30 (0.10, 0.56)

0.36 (0.32, 0.40)

0.22 (0.17, 0.29)

ES (95% CI)

0.47 (0.36, 0.58)

0.12 (0.11, 0.13)

0.03 (0.01, 0.07)

0.78 (0.74, 0.82)

100.00

16.80

16.64

Weight

16.38

16.86

16.54

%

16.77

0 .5 1

FEVER Al-Majed, et al. Gambill, et al. Maringhini, et al. Subtotal (I^2 = .%, p = .)

MALABSORPTION Gambill, et al. Porta, et al. Mannell, et al. Subtotal (I^2 = .%, p = .)

Study

2013 1970 1993

1970 2005 1986

Year

8 23 12

25 46 31

Events

251 239 80

239 185 79

Total

0.03 (0.02, 0.06) 0.10 (0.06, 0.14) 0.15 (0.09, 0.24) 0.08 (0.03, 0.16)

0.10 (0.07, 0.15) 0.25 (0.19, 0.32) 0.39 (0.29, 0.50) 0.23 (0.10, 0.41)

ES (95% CI)

35.36 35.19 29.45 100.00

34.30 33.91 31.79 100.00

Weight %

0 .5 1


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Indigestion, bloating, dysphagia and abdominal distension


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Appendix 3: Forest plots from meta-analyises of prodromal symptoms of chronic pancreatitis Pooled proportions Steatorrhoea


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Abdominal pain

Jaundice and diabetes


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Weight loss, nausea/vomiting, indigestion and abdominal distension


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Diarrhoea, anorexia and fever

DIARRHOEA Jha, et al. Bhasin, et al. Subtotal (I^2 = .%, p = .)

ANOREXIA Wakabayashi, et al. Sheel, et al. Subtotal (I^2 = .%, p = .)

FEVER Jha, et al.

Study

2017 2009

2018 2018

2017

Year

5 7

14 4

6

Events

139 123

25 12

139

Total

0.04 (0.02, 0.08) 0.06 (0.03, 0.11) 0.05 (0.02, 0.07)

0.56 (0.37, 0.73) 0.33 (0.14, 0.61) 0.49 (0.32, 0.65)

0.04 (0.02, 0.09)

ES (95% CI)

53.04 46.96 100.00

67.11 32.89 100.00

100.00

Weight %

0 .5 1


25

Anaemia, acute pancreatitis, ascited and GI bleed

Risk factors: overweight, smoker, alcohol intake

ANAEMIA Chen, et al.

ACUTE PANCREATITIS Schwarzenberg, et al. Machicado, et al. Issa, et al. Subtotal (I^2 = .%, p = .)

ASCITES Bhasin, et al.

GI BLEED Jha, et al. Bhasin, et al. Subtotal (I^2 = .%, p = .)

Study

2006

2019 2018 2017

2009

2017 2009

Year

30

662 37 38

16

3 4

Events

104

930 89 46

123

139 123

Total

0.29 (0.21, 0.38)

0.71 (0.68, 0.74) 0.42 (0.32, 0.52) 0.83 (0.69, 0.91) 0.66 (0.44, 0.84)

0.13 (0.08, 0.20)

0.02 (0.01, 0.06) 0.03 (0.01, 0.08) 0.03 (0.01, 0.05)

ES (95% CI)

100.00

35.78 33.24 30.98 100.00

100.00

53.04 46.96 100.00

Weight %

0 .5 1

OVERWEIGHT Schwarzenberg, et al.

SMOKER Olesen, et al. Schwarzenberg, et al. Balakrishnan, et al. Sheel, et al. Subtotal (I^2 = 98.26%, p = 0.00)

ALCOHOL INTAKE Olesen, et al. Schwarzenberg, et al. Balakrishnan, et al. Sheel, et al. Subtotal (I^2 = 95.69%, p = 0.00)

Study

2019

2019 2019 2008 2018

2019 2019 2008 2018

Year

289

568 536 292 10

593 562 400 8

Events

1050

1071 1063 1033 12

1071 1063 1033 12

Total

0.28 (0.25, 0.30)

0.53 (0.50, 0.56) 0.50 (0.47, 0.53) 0.28 (0.26, 0.31) 0.83 (0.55, 0.95) 0.49 (0.34, 0.64)

0.55 (0.52, 0.58) 0.53 (0.50, 0.56) 0.39 (0.36, 0.42) 0.67 (0.39, 0.86) 0.50 (0.41, 0.60)

ES (95% CI)

100.00

28.54 28.54 28.53 14.39 100.00

30.41 30.41 30.38 8.80 100.00

Weight %

0 .5 1


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Appendix 4: Forest plots from meta-analyises of prodromal symptoms of pancreatic enzyme insufficiency Pooled proportions Diarrhoea, steatorrhoea, abdominal pain, bloating, nausea and weight loss

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PANCREATIC DISEASE DECISION SUPPORT TOOL · strongest risk factor for pancreatic cancer was a history of chronic pancreatitis (RR 2.7-5.1). Tobacco smoking (RR 1.5 -2.2), diabetes