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SPECIAL REPORT

The Role of the GP in Reducing Pancreatic Cancer Mortality

Pancreatic Cancer: The Not-So-Silent, Silent Killer The Hidden Killer Causes and Effects of Pancreatic Cancer Sponsored by

Diagnosis, Prognosis and Treatment Living with Pancreatic Cancer

Published by Global Business Media


Refresh your knowledge of pancreatic cancer with our FREE e-learning module.

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SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

SPECIAL REPORT

The Role of the GP in Reducing Pancreatic Cancer Mortality

Contents Foreword

2

John Hancock, Editor

Pancreatic Cancer: The Not-So-Silent, Silent Killer Pancreatic Cancer: The Not-So-Silent, Silent Killer The Hidden Killer Causes and Effects of Pancreatic Cancer

3

Ali Stunt, Founder & Chief Executive, Pancreatic Cancer Action (7 year+ pancreatic cancer survivor)

Diagnosis, Prognosis and Treatment

Sponsored by

Living with Pancreatic Cancer

Published by Global Business Media

Published by Global Business Media Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom Switchboard: +44 (0)1737 850 939 Fax: +44 (0)1737 851 952 Email: info@globalbusinessmedia.org Website: www.globalbusinessmedia.org Publisher Kevin Bell Business Development Director Marie-Anne Brooks Editor John Hancock Senior Project Manager Steve Banks Advertising Executives Michael McCarthy Abigail Coombes Production Manager Paul Davies For further information visit: www.globalbusinessmedia.org The opinions and views expressed in the editorial content in this publication are those of the authors alone and do not necessarily represent the views of any organisation with which they may be associated. Material in advertisements and promotional features may be considered to represent the views of the advertisers and promoters. The views and opinions expressed in this publication do not necessarily express the views of the Publishers or the Editor. While every care has been taken in the preparation of this publication, neither the Publishers nor the Editor are responsible for such opinions and views or for any inaccuracies in the articles.

Š 2014. The entire contents of this publication are protected by copyright. Full details are available from the Publishers. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical photocopying, recording or otherwise, without the prior permission of the copyright owner.

Survival Delays in Diagnosis Clinical Causes for Delays in Diagnoses Recognising the Symptoms Clinical Features of Pancreatic Cancer Investigations Who is at Risk? Conclusion

The Hidden Killer

9

John Hancock, Editor

What is the Pancreas? What is Pancreatic Cancer? A Poor Outlook Symptoms

Causes and Effects of Pancreatic Cancer

11

Camilla Slade, Staff Writer

Age and Dietary Factors Lifestyle and Workplace Factors Associations and Predispositions Diabetes and Treatments Racial Factors The Future Outlook

Diagnosis, Prognosis and Treatment

13

Peter Dunwell, Medical Correspondent

Diagnosis Stages of Pancreatic Cancer Prognosis Types of Surgery Other Treatments That Might Be Applied

Living with Pancreatic Cancer

15

John Hancock, Editor

Prevention is Better than Cure Managing the Condition Not Well Understood Research to Improve the Outlook

References 17

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SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

Foreword A

DIAGNOSIS of cancer is never going to be

diagnosis of the disease and identifies how to

welcomed but, for many cancers today, that

recognise the symptoms. It stresses, in particular, the

diagnosis at least carries with it the possibility of

importance of concentrating on the early features of

treatment, management and even, in a growing

the disease and details who is at risk.

number of cases, cure. Unfortunately that is not the case as far as some cancers are concerned and high on that list is pancreatic cancer. Hard to detect in the early stages and, currently, impossible to cure in the later stages, this condition is justifiably referred to as a silent or hidden assassin. That said, it is still the clinicians on the front line, GPs, who will most often be the first to encounter pancreatic cancer in a patient and so it is their watchfulness, diagnosis and prognosis that will be the first line of defence for those with a predisposition to the condition or whose lifestyle leaves them vulnerable to one of the swiftest and most deadly killers among cancers. This Special Report opens with an article that looks at the diagnosis, treatment and survival rates of pancreatic cancer by Ali Stunt, Founder and Chief Executive of Pancreatic Cancer Action. Pancreatic cancer has become the UK’s fifth largest cause

The second piece examines in greater detail the current diagnoses and survival rates as well as the dismal prognosis usually attendant on diagnosis and whether that has to be the case. Camilla Slade then takes up the baton with an overview of the causes of pancreatic cancer or, to be more accurate, the factors which seem to correlate with the condition and other possible factors, as well as their effects. In the next article, Peter Dunwell looks at prognosis, what treatments are available, how they are used and how the appropriate treatment can be determined for each patient. Finally, we look at the reality that, for the time being, most people with pancreatic cancer will have to live with it and not for a very long time. We consider how people can cope and, briefly, what is being done to improve treatment or even to find a cure or stop mechanism.

of cancer deaths and could pass breast cancer to become the fourth largest by 2030. The article examines a number of reasons for the delay in

John Hancock Editor

John Hancock has been Editor of Primary Care Reports since its launch. A journalist for 25 years, John has written and edited articles, papers and books on a range of medical and management topics. Subjects have included management of long-term conditions, elective and non-elective surgery, schizophrenia, health risks of travel, local health management and NHS management and reforms.

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SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

Pancreatic Cancer: The Not-So-Silent, Silent Killer Ali Stunt, Founder & Chief Executive, Pancreatic Cancer Action (7 year+ pancreatic cancer survivor)

Produced with the Royal College of GPs

E

VERY PRIMARY care doctor should recognise the scenario: jaundice, epigastric pain and significant and unexplained weight loss: all typical presentations of pancreatic cancer (PC) which require an urgent investigation. Even if the patient has this classic presentation, their disease is likely to be in the later stages. Unfortunately, this is the norm and the majority of patients will experience a delay in diagnosis. Currently only 11% of PC cases are diagnosed through the 2-week route, with 50% presenting as emergencies through our A&E system.1 Pancreatic cancer has a dismal prognosis. During 2011, doctors diagnosed 8,773 PC cases in the UK and 8,320 people died from the malignancy2. Between 2005 and 2009, only 3.7% of adults with PC in England survived for at least five years3 and this survival rate has sadly seen no improvement over the past 40 years despite significant improvement in survival for other forms of the disease. PC is the UK’s 5th largest cause of cancer death and could pass breast cancer to become the 4th biggest by 20304. “Pancreatic cancer is notoriously difficult to detect in its early stages” says Ali Stunt, Founder of Pancreatic Cancer Action, “so in order to get more diagnosed in time for surgery, we need to assist GPs in recognising those patients who will present in an a-typical manner.” Public health campaigns, which elucidate the risks and symptoms of the disease, also need to reach ordinary people. “We need to communicate with all sectors of society so they know when they should be going to their doctor.” Says Ali, “Many people and men in particular, put off going to their doctors often until their situation becomes an emergency. We need people to understand that if they have persistent symptoms that are not normal for them, they can bother their doctor.” Although there is ongoing research into the development of a screening tool for PC, it could be a decade or more before this translates to the clinical environment for the benefit of patients. “Whilst significant progress is being made within

Free the research environment, this will take some time to translate into improved results,” said Ross Carter, Consultant Surgeon, Glasgow Royal Infirmary, “the way to make an immediate impact is through the application of today’s technology and treatment at an earlier stage, and this will only be possible through earlier diagnosis.” This, coupled with limited efficacy in current treatments for pancreatic cancer, puts the onus for improving outcomes in the near future on earlier recognition of the disease by using the clinical acumen of the general practitioner and through a better informed public.

Survival While PC is less common, it is by no means a rare disease and the average-size GP practice is likely to see at least one case every year6,7. The median survival from the time of diagnosis to death ranges from 3 to 6 months after conventional therapy for locally advanced and metastatic disease8. Relative survival in the UK is 3% to 5 years and less than 17% to 1 year9. European 1-yr survival rates average at ~21% with the highest at 28.3%10,11. Poor 1-yr survival rates are generally taken to be an indicator of more advanced disease at diagnosis, and if the UK matched up to the best in Europe, there is the potential for many more lives to be saved. Saving those lives involves getting patients to surgery and the outlook is considerably improved if they do. After complete surgical resection and with the addition of adjuvant chemotherapy, in excess of 30% of eligible patients can expect to survive 5 years or more12. Unfortunately surgery,

Open access

CPD accredited Pancreatic cancer GP e-learning module

pancreaticcanceraction.org

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SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

PC is the UK’s 5th largest cause of cancer death and could pass breast cancer to become the 4th biggest by 2030

1. AGE STANDARDISED TEN-YEAR NET SURVIVAL TRENDS, ADULTS (AGED 15-99), SELECTED CANCERS, ENGLAND AND WALES, 1971-20115

about while two thirds admitted to dismissing their own symptoms initially. The reasons for delays in diagnosis can include complex presentations, especially in the presence of co-morbidities; patient delay such as prolonged time to re-visit or simply choosing not to visit their GP and system delays within primary and secondary care and health inequalities.

the only potentially curative option, is available to only 10% of all PC patients13.

Delays in Diagnosis There are many who label pancreatic cancer as a ‘silent killer’, but most patients experience symptoms many months before a referral is made. In a recent Pancreatic Cancer Action online survey14, 40% of patients had to wait four months or more from first reporting symptoms to a referral to a specialist with one in 10 waiting over 18 months. 50 per cent said that their GP initially dismissed their symptoms as nothing to worry 4 | WWW.PRIMARYCAREREPORTS.CO.UK

Clinical Causes for Delays in Diagnoses These may include: •D  iagnosis of Irritable Bowel Syndrome (IBS) in mature patients; • Investigation of weight-loss and steatorrhoea as a colorectal condition • Over-reliance on ultrasound tests •N  ot realising the patient has a family history of PC •L  ack of adequate follow-up in patients where symptoms are persisting •N  ot associating new-onset diabetes with possible PC


SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

Recognising the Symptoms Traditionally, the main symptoms of pancreatic cancer are stated as abdominal pain, substantial weight loss and obstructive jaundice. However, these are generally late symptoms and are only common at diagnosis because the majority of patients are diagnosed at a late stage. In order to increase the chances of an earlier diagnosis, it is more useful to concentrate on early features of the disease. In addition, combinations of symptoms and progressive symptoms are suggestive of pancreatic cancer rather than any symptom on its own. The following symptoms may occur in any combination or not at all15,16:

Clinical Features of Pancreatic Cancer Non-specific upper abdominal pain or discomfort New onset, non-specific upper abdominal or back pain or discomfort is usually one of the first symptoms of pancreatic cancer and may be overlooked by patients and doctors. Upper abdominal pain may sometimes be postprandial due to duct obstruction. Presence of risk factors Risk factors for pancreatic cancer have been discussed in detail above. Key risk factors include tobacco use, body weight, family history, and other hereditary cancer syndromes. Dyspepsia and reflux resistant to simple acid suppression Both heartburn and indigestion are independently associated with risk of pancreatic cancer.17 Nausea and vomiting Nausea and vomiting are reasonably common in patients with pancreatic cancer. Pancreatic cancer should be excluded in patients with

an unexplained episode of acute pancreatitis characterised by nausea, vomiting, anorexia, and mid-epigastric pain16. Change in bowel habit A change in bowel habit is common in patients with pancreatic cancer. Extensive infiltration of the pancreas or obstruction of the major pancreatic ducts will also cause exocrine dysfunction, resulting in malabsorption and steatorrhoea. However, actual steatorrhoea is rare. There is anecdotal information supplied by patients that many are given a diagnosis for irritable bowel syndrome (IBS). The majority of these patients are over the age of 50; however it is known that new-onset IBS rarely occurs in the mature patient18 and doctors need to beware of making a diagnosis for IBS in those over 50. New onset diabetes Endocrine dysfunction, resulting in new onset diabetes presenting with thirst, polyuria, nocturia, and weight loss, is present in 20% to 47% of patients with pancreatic cancer19. New onset diabetes (either diagnosed concomitantly with the cancer or within 2 years of diagnosis) has recently been identified to occur in up to 30% of patients and is something that can be detected in the presymptomatic phase20. It is estimated that approx. 1% of diabetics over the age of 50 will be diagnosed with pancreatic cancer within 3 years of “first meeting the criteria for diabetes.”21 Particular attention should be made to a new-onset diabetic who doesn’t conform to that of a patient with a typical metabolic syndrome (i.e. weight gain). Weight loss and anorexia Weight loss and anorexia are also signs of pancreatic cancer. Weight loss can occur at early and late stages of disease, and diabetes can result in rapid weight loss.

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SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

In order to increase the chances of an earlier diagnosis, it is more useful to concentrate on early features of the disease

Jaundice Jaundice suggests biliary obstruction or, very rarely, hepatic or hilar nodal metastases. Jaundice draws attention to tumours of the head of the pancreas (near the ampulla of Vater) at a relatively early stage. This means that these tumours tend to be more amenable to surgical resection. Patients with tumours of the body or tail of the pancreas tend not to experience jaundice until a fairly late stage of disease. At this point, the jaundice is caused by metastases and the cancer is often inoperable. At an early stage, jaundice may be difficult to see. Liver function tests may be abnormal for several months before diagnosis. Persistency of Symptoms Also key is the persistency of symptoms – symptoms such as unexplained dyspepsia, epigastric or back pain which are persistent even with the absence of alarm symptoms should be considered important and PC should be investigated remembering that previous normal investigations (such as blood tests) can provide both the clinician and the patient with false reassurance. Attention also needs to be paid to the rareattender who suddenly appears at the surgery, often in multiple visits, with unexplained weight loss, epigastric pain and alteration to their bowel habit.

Investigations Ultrasound scans are routinely used. H o w e v e r, i t i s important to be aware that a normal ultrasound will often produce a false negative, which will not necessarily rule out PC. Sensitivity is compromised due to the location of the gland, in a larger patient and/or in the presence of gas and falls to about 30% for tumours <2cm in diameter. Multi-slice contrast enhanced CT scans, which have a sensitivity of 97%22 are therefore the most useful investigation to diagnose and stage pancreatic tumours and, where specific symptoms exist, referral for a CT scan should be the first action.

Who is at Risk? Age While the aetiology of pancreatic cancer is poorly understood, there is a strong correlation with age with just under 2/3 of cases occurring in those over 70. Correspondingly, over a third of patients are age 65 or under and these 6 | WWW.PRIMARYCAREREPORTS.CO.UK

patients have the potential to be overlooked by diagnosing practitioners. Cigarette smoking Cigarette smoking is a confirmed environmental risk factor for PC. It is currently estimated that smoking contributes to 29%23 of all cases and recent research has identified that smokers have a risk of developing pancreatic cancer 2.2 times higher in comparison to never smokers24. The risk increases with an increasing number of cigarettes smoked per day (OR = 3.4 for ≥35 cigarettes per day, P for trend <0.0001). The risk increases in relation to duration of cigarette smoking up to 40 years of smoking (OR=2.4). Obesity High BMI has also been considered as an additional risk factor for PC with 12% of all cases being linked to obesity23. A meta-analysis has shown that risk of pancreatic cancer increases25: •B  y 10% per 5-unit body mass index (BMI) increase •B  y 11% per 10 cm waist circumference increase •B  y 19% per 0.1 increase in waist-to-hip ratio. Diabetes The association of diabetes mellitus and PC is complex because the diabetes mellitus may be the cause of PC or often the precursor to the onset of its symptoms and signs. PC induced diabetes, especially in the absence of obesity and family history, is often characterised by a short duration of course (months to years)26. A large number of epidemiological data support the hypothesis that diabetes mellitus is positively associated with increased risk of PC27. Alcohol Compared with people who consume less than one alcoholic drink per day, risk of pancreatic cancer has been found to be28,29 •2  2% higher in people who consume 3 or more alcoholic drinks per day •6  0% higher in people who consume 5 or more alcoholic drinks per day.


SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

Hereditary Pancreatic Cancer Most cases of pancreatic cancer are sporadic, but 5-10% are due to hereditary factors and some rare medical syndromes such as the BRCA2 gene, hereditary pancreatitis, hereditary colon cancer, familial melanoma, Peutz-Jeghers syndrome, and ataxia telangiectasia30. Pancreatic cancer by itself (not part of a known syndrome) runs in some families – Familial Pancreatic Cancer. People with at least two firstdegree relatives (mother, father, brother, sister) diagnosed with pancreatic cancer have almost double the risk of people without pancreatic cancer in their family31.

Conclusion There is a great deal that is not publicly known about PC and much is misunderstood and/or misrepresented. Virtually every statistic used to measure PC is dismal, but there is one that just sticks in the throat: 5 year relative survival is 3%, and this number has not changed in over 40 years. This pure and simply is due to the low levels of both investment and attention given to PC. Even if the medical breakthrough was found in a laboratory today, it could take at least 15-20 years before this reaches the clinical environment – and patients. Our increased knowledge of the temporal development of PC32 could increase further opportunities for research into an early diagnostic tool to catch the disease before it progresses too far. While we wait for this to happen, more focus must be made on the early diagnosis of PC. Currently the only potentially curative option lies with surgical resection and if eligible, outcomes for these patients are considerably improved. “The diversity of presentation in general practice creates great challenges,” said Mr Ross Carter, “however with 13% of patients presenting through planned cancer referral and nearly half presenting as a medical emergency, the stereotypical clinical presentation of jaundice and weight loss evidently are late phenomena. The majority [of patients] will in retrospect have unrecognised prodromal symptoms.”

To assist in the recognition of these symptoms, Pancreatic Cancer Action has developed a free, CPD credited online interactive training module for GPs alongside the Royal College of GPs: http:// elearning.rcgp.org.uk/course/info.php?id=103 and one for hospital doctors alongside BMJ Learning: http://learning.bmj.com/learning/ module-intro/.html?moduleId=10051332 If readers haven’t yet taken either one of these modules, we urge you to do so to refresh your knowledge of the disease in the hope that by spotting the signs of pancreatic cancer earlier and referring sooner you will help save lives and change the poor statistics for this grim disease. Ali Stunt is the Founder and Chief Executive of UK charity, Pancreatic Cancer Action. Ali was diagnosed with ductal adenocarcinoma in August 2007. Pancreatic Cancer Action works to improve survival through earlier diagnosis. They focus on raising awareness of the signs and symptoms of pancreatic cancer to the general public and medical profession; provide medical education and training, comprehensive patient information and funds research specifically for the early diagnosis of pancreatic cancer.

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SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

References: 1

NCIN (2012) Routes to Diagnosis 2006-2008, England Information Supplement

2

CRUK http://www.cancerresearchuk.org/cancer-info/cancerstats/types/pancreas/incidence/

3

Office for National Statistics Cancer Survival in England for patients diagnosed between 2007-2011 (and followed up to 2012) Published October 2013

4

Mistry M, Parkin D, Ahmad A, Sasieni P. Cancer incidence in the UK: Projections to the year 2030 British Journal of Cancer Vol 105 page 1795–1803

5

http://www.cancerresearchuk.org/cancer-info/cancerstats/survival/common-cancers/#Trends

6

NICE (2005) Referral for Suspected Cancer. A Clinical Practice Guideline.

7

The Kings Fund (2009) General Practice in England: An overview

8

Ghaneh et al., (2008) Biology and management of pancreatic cancer. Postgrad. Med. J 84 pp 478-497

9

Office for National Statistics Statistical Bulletin: Cancer Survival in England patients diagnosed 2007-2011 followed up to 2012 accessed 10/06/2014

10

Møller et al., (2009) A visual summary of the EUROCARE-4 results: a UK perspective. British Journal of Cancer 101 S110-S114

11

Cancer survival in England and the influence of early diagnosis: what can we learn from recent EUROCARE results? British Journal of Cancer (2009) 101, S102–S109.

12

Ghaneh et al., (2008) Biology and management of pancreatic cancer. Postgrad. Med. J 84 pp 478-497

13

Richter et al., (2003) Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience. World J Surgery 27(3) pp 324-9

14

Pancreatic Cancer Patient Survey October 2013 (data available on request)

15

BMJ Best Practice monograph on pancreatic cancer: http://bestpractice.bmj.com/best-practice/monograph/265.html

16

Pancreatic Section of the British Society of Gastroenterology, the Pancreatic Society of Great Britain & Ireland, The Association of Upper Gastrointestinal Surgeons of Great Britain & Ireland (2005) Guidelines for the management of patients with pancreatic cancer, periampullary and ampullary carcinomas. Gut 54 (Suppl 5) V1-16.

17

Hippisley-Cox J, Coupland C. Predictive effect of heartburn and indigestion and risk of upper gastro-intestinal malignancy. Br J Gen Pract. 2012 Mar;62(596):124-6.

18

Gunnarsson J, Simrén M. (2008) Efficient diagnosis of suspected functional bowel disorders Nat Clin Pract Gastroenterol Hepatol. 5(9):498-507.

19

Pannala R, Basu A, Petersen GM, et al. New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 2009;10:88-95

20

Bin Bao et al., (2011) The complexities of obesity and diabetes with the development and progression of pancreatic cancer. Biochimia et Biophysica Acta 1815 pp 135-146

21

Chari et al., (2005) Probability of pancreatic cancer following diabetes: a population based study. Gastroenterology 129: 504-511

22

GP Online – Pancreatic Cancer http://www.gponline.com/Clinical/article/772932/Pancreatic-cancer/

23

Parkin, D.M., Boyd, L., Walker, L.C. The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010. Summary and conclusions. Br J Cancer, 6 Dec 2011; 105 (S2):S77-S81; doi: 10.1038/bjc.2011.489

24

Bosetti C, Lucenteforte E, Silverman DT, Petersen G, Bracci PM, Ji BT, Negri E, Li D, Risch HA, Olson SH, Gallinger S, Miller AB, Bueno-de-Mesquita HB, Talamini R, Polesel J, Ghadirian P, Baghurst PA, Zatonski W, Fontham E, Bamlet WR, Holly EA, Bertuccio P, Gao YT, Hassan M, Yu H, Kurtz RC, Cotterchio M, Su J, Maisonneuve P, Duell EJ, Boffetta P, La Vecchia C. Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4). Ann Oncol. 2012 Jul;23(7):1880-8. doi: 10.1093/annonc/mdr541. Epub 2011 Nov 21. Erratum in: Ann Oncol. 2012 Oct;23(10):2773.

25

Aune D, Greenwood DC, Chan DS, Vieira R, Vieira AR, Navarro Rosenblatt DA, Cade JE, Burley VJ, Norat T. Body mass index, abdominal fatness and pancreatic cancer risk: a systematic review and non-linear dose-response meta-analysis of prospective studies. Ann Oncol. 2012 Apr;23(4):843-52. doi: 10.1093/annonc/mdr398. Epub 2011 Sep 2. Review

26

Czyzyk & Szczepanik (2000) Diabetes Mellitus and cancer. Eur. J. Intern. Med 11 pp245-252

27

Huxley et al., (2005) Type II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br. J. Cancer 92 pp 2076-2083

28

Lucenteforte E, La Vecchia C, Silverman D, Petersen GM, Bracci PM, Ji BT, Bosetti C, Li D, Gallinger S, Miller AB, Bueno-de-Mesquita HB, Talamini R, Polesel J, Ghadirian P, Baghurst PA, Zatonski W, Fontham E, Bamlet WR, Holly EA, ao YT, Negri E, Hassan M, Cotterchio M, Su J, Maisonneuve P, Boffetta P, Duell EJ. Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann Oncol. 2012 Feb;23(2):374-82. doi: 10.1093/annonc/mdr120. Epub 2011 May 2.

29

Tramacere I, Scotti L, Jenab M, Bagnardi V, Bellocco R, Rota M, Corrao G, Bravi F, Boffetta P, La Vecchia C. Alcohol drinking and pancreatic cancer risk: a meta-analysis of the dose-risk relation. Int J Cancer. 2010 Mar 15;126(6):1474-86

30

Klein AP. Identifying people at a high risk of developing pancreatic cancer. Nat Rev Cancer. 2013 Jan;13(1):66-74. doi: 10.1038/nrc3420. Epub 2012 Dec 6. Review

31

Greer JB, Whitcomb DC, Brand RE (2007) Genetic predisposition to pancreatic cancer: a brief review. Am J. Gastroenterol 102: 2564-25

32

Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467:1114-1117. 8 | WWW.PRIMARYCAREREPORTS.CO.UK


SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

The Hidden Killer John Hancock, Editor Although treatable if caught in time, pancreatic cancer is too often not identified until it has passed any possibility of curative action

A

S INCREASING numbers of cancers are better understood and the means to treat or manage them become ever more effective, it’s disappointing that, in some cases, very little progress seems to be made in diagnosis or treatment. One such is pancreatic cancer.

What is the Pancreas? “The Pancreas,” according to NHS Choices1, “is a large gland that’s part of the digestive system. It’s about 15cm (six inches) long, and is located high in the abdomen, behind the stomach, where the ribs meet at the bottom of the breastbone.” Its role is to produce the digestive enzymes that our body uses to break down food for absorption into the body and to produce a number of hormones, including insulin [and glucagon], to regulate blood sugars. Within the pancreas, groups of cells called Langerhans make the hormones. “The part of the pancreas which produces the digestive juices is called the exocrine pancreas: the part which produces hormones, including insulin, is called the endocrine pancreas. Cancers that develop from these two different parts of the pancreas can behave differently and can cause different symptoms.”2 The pancreas is often considered in three parts: the head, a large rounded section right next to the duodenum or small bowel; the middle part of the pancreas, known as the body; and the narrow section on the left of the abdomen, called the tail. “Pancreatic juices travel through small tubes (ducts) in the pancreas into a larger duct called the pancreatic duct. This joins with the bile duct, which carries bile from the liver and gall bladder, before opening into the duodenum. The pancreatic juices flow along the pancreatic duct into the duodenum where they help to digest food.“3

What is Pancreatic Cancer? Pancreatic Cancer can occur in any part of the pancreas but 70% to 80% of pancreatic cancers occur in the head of the gland. Most pancreatic cancers are exocrine cancers originating in the cells that line the ducts within the gland and known as ductal adenocarcinomas. There are

other types of exocrine cancers but treatment for all of them is similar. Notwithstanding the above, pancreatic cancer is the tenth most common cancer in the UK with 8,773 cases diagnosed in 2011. In the UK, prevalence varies between men, among whom it is the thirteenth most common cancer, and women, where it is the ninth most common. In the context of Europe, UK incidence of the condition is the eighth lowest for men and the twentieth highest for women. According to Cancer Research UK4, about 338,000 people worldwide were diagnosed with pancreatic cancer in 2012. It is mainly among those over age 60 that pancreatic cancer occurs but the incidence among younger age groups is not insignificant. Like most cancers, if it is diagnosed early, an operation to remove the cancer and the pancreas can offer hope of a cure; however, a later diagnosis, with the cancer having advanced and spread (metastasised) will reduce the chance of achieving a cure, although there are treatments that can slow the progress of the condition. Poor diagnosis rates mean that later diagnosis is more common with the result that, while it is the tenth most commonly occurring cancer, pancreatic cancer is the fourth to sixth (depending on where in the world) most prevalent cause of cancer death. Often, by the time a patient presents to their GP and a diagnosis has been made, palliative care and slowing the condition’s progress are the only options available.

A Poor Outlook It is a shameful fact that the 8,773 UK diagnoses in 2011, compare with 8,662 UK deaths from the condition in 2012. Only 3.7% of adult pancreatic sufferers survived for five years or more during 2005-2009. Equally sobering is that, following a decline in rates from the 1970s-1980s until the late 1990s (for women) and the early 2000s (for men), there has been a slight but definite increase in pancreatic cancer rates since those periods and up to date. Those statistics might well correlate to smoking trends, more of which later in this paper. However, pancreatic cancer remains relatively uncommon, developing in about 1 in 10,000 people annually in the UK. WWW.PRIMARYCAREREPORTS.CO.UK | 9


SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

Jaundice without pain is a common symptom among more than half of pancreatic cancer patients. This can manifest as yellowing of the skin and the whites of the eyes, itching, darker than usual urine and pale bowel motions

So GPs might not see it too often and therefore should be the more alert for it. Pancreatic cancer is more prevalent in developed countries with the USA, Japan and Western Europe leading the world statistics. That leads on to the possibility of lifestyle, dietary and environmental factors playing their part but, as yet, none of that has been closely researched â&#x20AC;&#x201C; except a link with smoking.

Symptoms Symptoms that might point to the presence of pancreatic cancer include consistent or variable pain and discomfort in the upper abdomen spreading, in some cases, to the back: there can also be weight loss in patients who have not changed the amounts of food they consume. Jaundice can be another symptom when the cancer blocks the bile duct but jaundice can also

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be a symptom of other conditions. Other dietary conditions such as appetite loss, nausea and/or indigestion, a sense of bloating after meals and diarrhoea can point to pancreatic cancer as can tiredness and depression. While these symptoms are not exclusive to the condition, they should merit further investigation, especially in patients over 60 or with a family history of the condition. Unfortunately, the symptoms are often vague but jaundice without pain is a common symptom among more than half of pancreatic cancer patients. This can manifest as yellowing of the skin and the whites of the eyes, itching, darker than usual urine and pale bowel motions. In some cases, the condition can cause fevers or shivering. Doctors should be alert to all of these possibilities. Only in this way will the diagnosis improve and more patients have a reasonable chance of a cure or a lengthened life.


SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

Causes and Effects of Pancreatic Cancer Camilla Slade, Staff Writer There’s always a cause but it isn’t always understood which increases the onus on diagnosing GPs

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HERE IS not always an obvious reason why somebody would develop pancreatic cancer but then that might be said for many cancers. However, some risk factors have been identified that have been associated with the condition – not the same as being proven to cause it but worth taking into account.

Age and Dietary Factors As John Hancock explained in the previous article, pancreatic cancer is more common in people over the age of 60 (in fact, more than half of new diagnoses are in people over age 75) and uncommon in those below 40; aging might well be a contributory factor but the condition does still occur at younger ages. Similarly, people whose diets are high in fat and with high meat content (especially processed meat) seem to be more at risk and obesity is definitely a contributory factor. That is the case for men and for women who carry most of their excess weight around the stomach who, research suggests, are 70% more likely to develop pancreatic cancer. The link, although demonstrable, is not fully understood: some researchers believe that it might be to do with increased level of insulin associated with a higher proportion of abdominal fat.

Lifestyle and Workplace Factors As with many cancers, smoking is a positively identifiable factor in many diagnoses. ‘Epidemiology and Prevention of Pancreatic Cancer’5 from Oxford Journals Medicine & Health states: “Smoking is the strongest environmental risk factor known to cause pancreatic cancer. Carcinogens derived from tobacco smoke probably reach the pancreas via the bloodstream after being absorbed from the lungs or from the upper aero-digestive tract. In addition, there is a possibility that ingested tobacco products reach the pancreas directly after reflux into the pancreatic ductal system from the duodenum. If this mode of exposure is correct, it could partly explain the large number of pancreatic cancers

that occur in the head of the pancreas. Nearly all published reports show that exposure to tobacco products increases the risk of pancreatic cancer, usually with about a 2-fold increased risk, compared to non-smokers.” As well as smoking it, chewing tobacco has also been linked and working with some chemicals might also be a factor applicable to sufferers – working in a job with little or no physical activity might also contribute to the condition.

Associations and Predispositions Other conditions have been associated with or might predispose people to pancreatic cancer; chronic pancreatitis has been linked to pancreatic cancer but it might be as much the cause of pancreatitis (excessive alcohol consumption) as the condition itself that is the problem. Nevertheless, the presence of both alcoholic and non-alcoholic chronic pancreatitis has been associated with a ten to twenty times increased risk of pancreatic cancer. Hereditary pancreatitis is also associated with a higher risk for pancreatic cancer. Stomach ulcers and other stomach infections are sometimes linked to the condition and a link has even been made with family history. Around 5% to 10% of pancreatic cancer cases might reflect a genetic predisposition. People with significant incidence of pancreatic cancer in their family should be offered a three yearly CT scan with other tests to spot changes in genes found in the pancreas.

Diabetes and Treatments Finally, diabetes is a seemingly obvious link but the vast majority of diabetics do not develop pancreatic cancers just as the vast majority in the population at large do not. Type 2 diabetes, in particular, has been shown to be linked with pancreatic cancer but researchers have yet to determine which one is the cause and which the effect. Researchers from the University of Melbourne6 have shown an association between WWW.PRIMARYCAREREPORTS.CO.UK | 11


SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

Chronic pancreatitis has been linked to pancreatic cancer but it might be as much the cause of pancreatitis (excessive alcohol consumption) as the condition itself that is the problem

the two which seems to be time related, i.e. diagnosis of diabetes seems to be the time of highest risk for pancreatic cancer developing although some risk remains throughout a diabetic’s life. Therefore, a sensible precaution would be to screen all new onset diabetes patients for risk factors associated with pancreatic cancer. There has also been speculation around the adverse effects on the pancreas and possible association with pancreatic cancer of some drugs used in the treatment of type 2 diabetes. However, the drugs in question (glucagon-like peptide-1 such as exenatide and dipeptidylpeptidase-4 inhibitors such as sitagliptin) are not first choice medication for most type 2 diabetes cases.

Racial Factors Research suggests that there might well be racial factors at play7 in pancreatic cancer rates and diagnoses. For instance, one study identified that black Americans had an unexplained 42% increased risk of pancreatic cancer mortality rates over white Americans, and neither differences in smoking or obesity rates explained this disparity. While there is no certainty, speculation has centred on the possibility that this also relates to

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lower levels of vitamin D intake but, again, that theory is complicated by other factors. Going back to the Oxford Journals (see above) we can read that; “In several publications, racial differences in survival have been recorded after treatment of pancreatic cancer. In particular, Asian patients appear to have a better survival rate than non-Asian patients [and] Asian patients tended to have less aggressive [tumours] than either white or black patients. The explanation for this unexpected finding is unclear… but there could be race-related genetic factors or differences in environmental exposure that determine survival.”

The Future Outlook Given the currently very low survival rate, it is pertinent to wonder whether pancreatic cancer is likely to increase or decline in the future. An aging population is likely to create a higher base line diagnosis rate for the condition as with most cancers whose incidence is known to increase with age: but trends, especially in smoking but also in eating, could either increase or mitigate that overall risk rate. It would certainly benefit from greater research into possible causes.


SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

Diagnosis, Prognosis and Treatment Peter Dunwell, Medical Correspondent What treatment options are available for pancreatic cancer depends on a number of factors which have to be determined first

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HILE EVERY case of pancreatic cancer is different, in the UK8, “[each patient’s] treatment will be planned by a team of specialist doctors and other healthcare professionals. This is known as a multidisciplinary team (MDT), and may include: •A  surgeon who specialises in treating pancreatic cancer; •O  ncologists – doctors who treat cancer with chemotherapy and radiotherapy; •A  pathologist – a doctor who specialises in analysing tissue samples (biopsies) for signs of diseases; •A  radiologist – a doctor who analyses x-rays and scans; •A  specialist nurse who specialises in caring for people with pancreatic cancer and who can give information and support.

present, the next step is to refer the patient to a hospital for further tests and/or to a specialist. Even if the tests show a lump on the pancreas, that lump might be benign or a cyst so further investigation could be necessary to confirm one way or the other. That further investigation will often entail a biopsy to obtain a sample of the tissue in the lump. At every stage, there are other conditions that are as or more likely than pancreatic cancer to cause whatever is found – notwithstanding the poor survival rates, it is still not a common cancer. Jaundice, for instance, can be caused by a range of disorders including a blocked gallstone or hepatitis (inflamed liver) but it might also be the result of a blockage from the head of the pancreas that could be caused by cancer.

The MDT may also include other healthcare professionals, such as: • A dietitian; • A physiotherapist; • An occupational therapist; • A psychologist or counsellor.

Because the pancreas is located in an inaccessible area of the abdomen, until recently, investigation has been difficult. Newer scanning and sampling methods will help here but it remains the case that, because in its early growing stages, pancreatic cancer does not generate significant symptoms, by the time that patients present to their doctor, the condition is often more advanced than would be ideal for a high probability of successful treatment. Consequently, if pancreatic cancer is diagnosed, the next stage will be to determine whether it has spread and, if so, how far. There are generally three stages at which a tumour might be found9: •O  perable cancer, which means a tumour is able to be surgically removed [resectable] primarily, or following chemotherapy with or without radiation therapy… These tumours are often treated with chemotherapy with or without radiation prior to surgery to try to shrink the tumour away from… important structures. •L  ocally advanced cancer, which means the tumour is found only in the pancreas with

Depending on the stage at which pancreatic cancer has been diagnosed, there are several treatments that might be discussed and considered. But it all has to start with a diagnosis. Unfortunately, a pancreas tumour, in the early stages, will not usually cause any symptoms so diagnosis is not easy.

Diagnosis Consultation will usually commence with a check of the patient’s general health, medical history and any symptoms that might present before progressing to look at skin and eyes for signs of any jaundice, to examine the abdomen looking for tenderness, swellings or lumps and then taking blood and urine samples. If, following a GP consultation and examination, there is any suspicion that pancreatic cancer might be

Stages of Pancreatic Cancer

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SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

Because in its early growing stages, pancreatic cancer does not generate significant symptoms, by the time that patients present to their doctor, the condition is often more advanced than would be ideal for a high probability of successful treatment

no evidence of spread to other organs, but is involving structures which cannot be safely removed (tumours at this stage are unresectable). •M  etastatic disease, which means that the cancer has spread to other parts of the body, for example, the liver (tumours at this stage are also unresectable).

Prognosis It is depending on which of these stages the cancer has reached that a prognosis can be made as to what would be appropriate treatment (or combination of treatments) for the patient. Pancreatic Cancer UK10 explains this stage to patients; “The treatment options for pancreatic cancer fall into three main types: •S  urgery – can be used to completely remove the cancer or surgical or other interventional procedures may be used to help relieve symptoms. •C  hemotherapy – can be used after surgery to reduce the chances of the cancer coming back or without surgery to relieve your symptoms and to try to shrink or slow down the growth of the cancer. •R  adiotherapy – can be used to try to slow down the growth of the cancer or to control and relieve pain.”

Types of Surgery Early stage pancreatic cancer is best treated with surgery to remove all or part of the pancreas in order to remove the tumour. There are four types of surgery available11: • A pylorus-preserving pancreatoduodenectomy (PPPD), also called a modified Whipple’s operation. This involves removing the head of the pancreas, most of the duodenum, the common bile duct, gall bladder and the surrounding lymph nodes. It is most commonly used for people with cancer in the head of the pancreas. •A  pancreatoduodenectomy or Whipple’s operation – this is similar to the PPPD operation, but the lower part of the stomach is also removed. •R  emoval of the whole pancreas (a pancreatectomy). •R  emoval of the lower end (body and tail) of the pancreas (a distal pancreatectomy). Any of these is a major operation and so will only be suitable for those whose tumour is small and

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who are otherwise fit and healthy. Also, recovery after surgery can be a lengthy process including, often, a six month course of chemotherapy. Chemotherapy following the operation will help to reduce the chances of the cancer returning. Also following surgery, the patient will almost certainly need insulin either while the remaining pancreas recovers to be able to produce insulin again or, where a total removal has been done, for life. Even where the cancer is too far advanced to be removed or has spread, surgery might be used to relieve the symptoms as the condition progresses. That could mean bypass surgery to address a blocked bowel or surgery to insert a stent into a blocked bile duct.

Other Treatments That Might Be Applied As well as being used after surgery, chemotherapy might be used before surgery to reduce the size of a tumour and improve the chances of a successful operation. It also might be used as a treatment in its own right, not to cure but to relieve the symptoms and slow down the growth. In a similar way, radiotherapy can be used as a post-operative therapy and/or to reduce a tumour but, again, it is not likely, on its own, to effect a full cure. Doctors are now looking at whether a combination of chemotherapy and radiotherapy could be more effective in preparing a tumour for surgery by shrinking it and making successful surgery more likely as well as reducing the chances that the condition will return. Whatever surgical procedure is employed, the patient will need fairly strong pain management in the immediate post-operative period. And pain is common with pancreatic cancer so that pain management is a key matter to accompany any treatment. The patient’s comfort (mental and physical) is paramount.


SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

Living with Pancreatic Cancer John Hancock, Editor How people cope, what they have to cope with and what hope is there for the future?

Prevention is Better than Cure As with any disease, the best approach to cancer is prevention to try and avoid the need for cure. This is especially true with pancreatic cancer where early diagnosis is not often possible and where the prognosis is, as a consequence, often poor. However, because the causes of pancreatic cancer are not known with any certainty, prevention has to focus more on the areas where links have been found likely between lifestyle and environmental factors and the condition. “Treatment has not improved substantially over the past few decades and has little effect on prolonging survival time. Therefore, prevention could play an important role in reducing pancreatic cancer mortality. International variations in rates and time trends suggest that environmental factors are likely to play a role in the etiology of pancreatic cancer.”12 Right at the top of the list is smoking. Stopping smoking will bring about improvements in so many areas of health and well-being and pancreatic cancer is no exception. The fact that both pancreatic cancer rates and smoking are declining for men in Western societies while both are increasing for women is indicative. With correlations also apparent between over-eating and, in particular, eating too much fat, meat and processed food, any reductions in these factors should also make a positive contribution to health overall and is very likely to reduce the risk of pancreatic cancer. Certainly managed weight loss away from obesity is likely to help prevention. Reduction in alcohol consumption will similarly address another factor whose rate has been found to correlate to pancreatic cancer rates although the link might be more complicated; possibly working through pancreatitis. Of course, that is all very well for those whose cancer might be caused by environmental and lifestyle factors; however, for those whose propensity is as much a function of genetics (family history or race) (see ‘Causes and effects’ above) such measures, while unlikely to be harmful, cannot make a complete prevention

strategy. So for some people, more frequent and targeted checks will help to identify where any signs of pancreatic cancer have manifested.

Produced with the Royal College of GPs

Managing the Condition Centres such as the University of Michigan are developing improved methods for managing pancreatic cancer and its effects but, notwithstanding the above, too many people do present with pancreatic cancer and have to live with it… or cope with it. Cancer Research UK explains13: “It can be very difficult coping with a diagnosis of cancer, both practically and emotionally. [The patient] may feel very upset and confused at first. As well as coping with the fear and anxiety that a diagnosis of cancer brings, [they] have to work out how to manage practically. There may be money matters to sort out. Who do [they] tell [they] have cancer? There may be children or grandchildren to consider.” It is important to be honest and open with a patient for whom their advanced pancreatic cancer will mean that no cure is currently available. They should have the opportunity to consider therapies to slow the progress of the disease (see ‘Diagnosis, prognosis and treatment’ above). They will also, almost certainly, need guidance and support on a range of matters, not least, the emotional impact of being diagnosed. Pancreatic cancer will also have an effect of their daily lives… on their digestive system and, if they opt for chemotherapy or radiotherapy, a whole raft of the usual side-effects of those therapies. Then there might well be other conditions as a result of the cancer having metastasised. The therapy most often appropriate for those with pancreatic cancer falls under the heading of palliative care; i.e. control of symptoms and quality of life.

Free Open access

CPD accredited Pancreatic cancer GP e-learning module

Not Well Understood While the most common form of the disease is ductal adenocarcinoma which originates in the pancreatic ducts, there are other less common cancers that can affect the pancreas. These

pancreaticcanceraction.org

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SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

While the most common form of the disease is ductal adenocarcinoma which originates in the pancreatic ducts, there are other less common cancers that can affect the pancreas

include cystic tumours (fluid-filled sacs in the pancreas, some of which are cancerous), acinar cell carcinomas (which start from the cells that make pancreatic juice), neuroendocrine tumours (which begin in the endocrine cells where insulin and other hormones are made) and lymphoma (a cancer of the lymphatic tissue in the pancreas). One of the more worrying aspects of the condition is that half of the people who suffer from pancreatic cancer had never heard of the disease before their diagnosis. That includes a number of well-known people who have lost their lives to it: actors, Patrick Swayze, Michael Landon, Rex Harrison; comedian, Jack Benny; actress, Joan Crawford; opera singer, Luciano Pavarotti; musicians, Henry Mancini, Dizzy Gilespie, Count Basie; entrepreneur, Steve Jobs and Formula One Driver and team manager, Ken Tyrel… to name but a few.

Research to Improve the Outlook So, with such a poor outlook, what is being done to tackle this silent and hidden killer? Even assessing the efficacy of treatment is difficult.

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“Pathologists need to be aware that some histologic features of treatment effect overlap with histologic features seen in untreated pancreatic cancer...” is how ‘Assessing treatment effect in pancreatic cancer’14 puts it. Research is progressing on two fronts. First there are many clinical trials underway to try to find new and better treatments for all cancers, including pancreatic. But, of course, all treatments have to be thoroughly researched before they can be used on the public. Very recently, pancreatic cancer patients in Wales became the first in the UK to be offered Abraxane, a new drug that can slow pancreatic cancer growth. And UK scientists are currently researching chokeberries from North America whose effect seems to improve the effectiveness of other conventional drugs in killing cancer cells in pancreatic cancer. At the same time, research is progressing into the causes of pancreatic cancer and, from that, effective screening methods. So, it is to be hoped that the present situation with the condition can only improve.


SPECIAL REPORT: THE ROLE OF THE GP IN REDUCING PANCREATIC CANCER MORTALITY

References: 1

NHS Choices, Pancreatic Cancer http://www.nhs.uk/conditions/Cancer-of-the-pancreas/Pages/Introduction.aspx

Cancer Research UK, About Pancreatic Cancer http://www.cancerresearchuk.org/prod_consump/groups/cr_common/@cah/@gen/documents/generalcontent/about-pancreatic-cancer.pdf

2

3

Macmillan Cancer Support, the pancreas http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Pancreas/Aboutpancreaticcancer/Thepancreas.aspx

4

Cancer Research UK http://www.cancerresearchuk.org/cancer-info/cancerstats/keyfacts/pancreatic-cancer/

5

Oxford Journals, Epidemiology and Prevention of Pancreatic Cancer http://jjco.oxfordjournals.org/content/34/5/238.full

6

Science Daily http://www.sciencedaily.com/releases/2014/03/140314111523.htm

7

American Association for Cancer Research http://cebp.aacrjournals.org/content/19/3/888.1.full.pdf

Macmillan Cancer Support, treatment overview for pancreatic cancer http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Pancreas/Treatingpancreaticcancer/Treatmentoverview.aspx

8

9

University of Michigan, Pancreatic Cancer http://www.mcancer.org/pancreatic-cancer scroll down for specific aspects

10

Pancreatic Cancer UK http://www.pancreaticcancer.org.uk/information-and-support/treatments-for-pancreatic-cancer/overview-of-treatment-options/

Macmillan Cancer Support, surgery for pancreatic cancer http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Pancreas/Treatingpancreaticcancer/Surgery.aspx

11

12

US National Library of Medicine, Epidemiology of pancreatic cancer http://www.ncbi.nlm.nih.gov/pubmed/15238885

Cancer Research UK, Living with Pancreatic Cancer http://www.cancerresearchuk.org/prod_consump/groups/cr_common/@cah/@gen/documents/generalcontent/living-with-pancreatic-cancer.pdf

13

14

US National Library of Medicine http://www.ncbi.nlm.nih.gov/pubmed/22208494

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Primary Care Reports – The Role of the GP in Reducing Pancreatic Cancer Mortality  

Primary Care – Special Report on the Role of the GP in Reducing Pancreatic Cancer Mortality

Primary Care Reports – The Role of the GP in Reducing Pancreatic Cancer Mortality  

Primary Care – Special Report on the Role of the GP in Reducing Pancreatic Cancer Mortality