Ali Stunt summarises the challenges presented by pancreatic cancer and possible new approaches in diagnosis and treatment

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Read this article to learn more about:

  • why pancreatic cancer has some of the lowest survival rates of any cancer
  • risk factors for pancreatic cancer and how to recognise early symptoms
  • why CT scans are more reliable than ultrasound for diagnosis and staging.

Key points

GP commissioning messages

 

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Disclaimer

This article has been developed in association with Pancreatic Cancer Action.

P ancreatic cancer has a dismal prognosis and the statistics make grim reading. In 2014, 9614 people were diagnosed with pancreatic cancer in the UK and 8834 died from the malignancy.1 Only about 4.5% of people diagnosed with pancreatic cancer in the UK survive beyond 5 years (see Figure 1, below, which shows trends to 2011).2

It is the fifth commonest cause of death from cancer in the UK and is set to overtake breast cancer as the fourth commonest cause by 2030.3–5

Late stage at diagnosis and chemoresistance of pancreatic tumours are key factors why pancreatic cancer has some of the lowest survival rates of any cancer, but so is the lack of awareness of the disease, along with decades of chronic underfunding. A survey of patients with pancreatic cancer in 2015 found that almost half had not heard of the disease before their own diagnosis.6

Despite having the fifth highest mortality rate of all cancers in the UK, pancreatic cancer receives only 1.6% of the National Cancer Research Institute's total spending portfolio.7

Aetiology and risk factors

The most common risk factors associated with pancreatic cancer are smoking, obesity, and age with the median age at diagnosis being 72 years8 (see Figure 2, below). While advising patients on how a healthy lifestyle can cut their risk of developing pancreatic cancer, it is important to note that, according to researchers at John's Hopkins University, pancreatic cancer is considered to be one of a number of 'bad luck' cancers with two-thirds of pancreatic cancer tumours attributable to the random mutations that occur in stem cell divisions throughout a person's lifetime.9

Figure 2: Risk factors for pancreatic cancer12
Risk factors for pancreatic cancer

Pancreatic Cancer Action. Causes of pancreatic cancer. Reproduced with permission.

Diagnosis

Pancreatic cancer is difficult to diagnose because the symptoms of pancreatic cancer are often mistaken for those of other illnesses, such as irritable bowel syndrome. Yet it is crucially important that patients are diagnosed as early as possible because early diagnosis can increase the chance of a patient having surgery to remove the tumour—currently the only potential cure. At present, only around 10% of cases are eligible for resectional surgery.10 See Box 1 (below) for some key facts for medical professionals about pancreatic cancer.

Box 1: Key messages for the medical community13

  • Pancreatic cancer affects men and women (almost) equally12
  • 40% of patients are under the age of 69 years14,15
  • The majority of patients with pancreatic cancer experience a delay in diagnosis with nearly one-half of them presenting as emergencies14
  • Only 12% of patients are diagnosed through the 2-week referral system14,15
  • Most patients with pancreatic cancer require a contrast-enhanced CT scan and/or endoscopic ultrasound for diagnosis.16

Symptoms to look out for

The traditional symptoms of pancreatic cancer are unexplained weight loss, abdominal pain, and obstructive jaundice. These, however, often appear in the advanced stages of the disease when cancer has spread. In order for patients to be diagnosed in time for surgery, it is important for medical professionals to spot the earliest symptoms. The frequency of specific symptoms is something that can be subject to interpretation, as the studies in Table 1 have shown (see below).

Table 1: Study comparisons of pancreatic cancer symptoms20
Symptom/signs/diseaseStapley et al (2012) (>= 40 years)Stapley et al (2012) (>= 60 years)Hippisley-Cox & Coupland (2012) (30–84 years)Collins and Altman (2013) (30–84 years)Keane et al (2014) (no age range)
Abdominal pain 42.4% 41.2% 39.8% 57.1% 43.9%
Jaundice 30.5% 32.3% Not reported Not reported 30.8%
New-onset diabetes 22.1% 23.6% Not reported Not reported 13.6%
Change in bowel habit 22.3% 23.5% Not reported 3.3%* 27.4%
Dyspepsia Not reported Not reported Not reported Not reported 20.0%
Nausea/vomiting 16.2% 16.7% Not reported Not reported 16.6%
Weight loss 9.7% 10.7% 7.8% 13.0% 10.5%
Malaise 5.1% 5.7% Not reported Not reported Not reported
Abdominal distention Not reported Not reported 1.2% 2.4% 4.1%
Non-cardiac chest pain Not reported Not reported Not reported Not reported 12.0%
Shoulder pain Not reported Not reported Not reported Not reported 4.9%
Dysphagia Not reported Not reported 1.4% 2.7% 1.8%
Appetite loss Not reported Not reported 3.5% 3.9% Not reported
* data reported for constipation only; †  data reported for women only; ‡  data reported for men only

The following symptoms may occur alone or in any combination11 (see also Box 2, below).

Box 2: Spotting pancreatic cancer11

  • Consider pancreatic cancer in the following:
    • new-onset IBS in patients over the age of 40 years
    • a patient aged over 40 years who has not attended the surgery for a considerable time, who presents with weight loss, abdominal pain, and alteration to bowel habit
    • new-onset diabetes not associated with weight gain
    • new-onset and persistent dyspepsia (not responding to PPI medication)
    • persistent epigastric or back pain
    • the rare-attender who suddenly appears at the surgery, often in multiple visits, with unexplained weight loss, epigastric pain, and alteration to their bowel habit.

NB Painless jaundice and/or new-onset dyspepsia demand an urgent diagnosis at any age.

IBS=irritable bowel syndrome; PPI=proton pump inhibitor

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 can often be overlooked by both patients and medical professionals. Upper abdominal pain may sometimes be postprandial due to duct obstruction.

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 the 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 detect but liver function tests may be abnormal for several months before diagnosis.

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 ducts will also cause exocrine dysfunction, resulting in malabsorption and steatorrhoea. However actual symptomatic steatorrhoea is rare.

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 people with pancreatic cancer.17

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 phase.10

Dyspepsia and reflux resistant to simple acid suppression

Both heartburn and indigestion are independently associated with the risk of pancreatic cancer.18 Suspicion should be raised when patients do not respond to a course of proton pump inhibitor (PPI) treatment.

Nausea and vomiting

Nausea and vomiting are reasonably common in patients with pancreatic cancer. It is important to investigate pancreatic cancer as a differential diagnosis in patients with an unexplained episode of acute pancreatitis characterised by nausea, vomiting, anorexia, and mid-epigastric pain.19

Weight loss and loss of appetite

A tumour in the pancreas can cause weight loss and a loss of appetite. Weight loss can occur at the early and late stages of the disease, and diabetes can result in rapid weight loss.

Persistence of symptoms

Also key is the persistence of symptoms—symptoms such as unexplained dyspepsia, epigastric or back pain that are persistent (even in the absence of alarm symptoms should be considered important and the patient should be investigated for pancreatic cancer; clinicians should be aware that previous investigations which showed no abnormality (e.g. blood tests and even ultrasound scans) can provide both the clinician and the patient with false reassurance.

Clinical guidelines

The NICE guideline on Suspected cancer: recognition and referral21 (NICE Guideline 12) was updated in June 2015 and, for the first time, pancreatic cancer has its own section and combinations of symptoms and new-onset diabetes have been added (see Box 3, below). NICE is also developing a clinical guideline specifically on pancreatic cancer, which is expected to be published in January 2018.

Box 3: NICE referral guidelines for cancer21

  • 1.2.4 Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) for pancreatic cancer if they are aged 40 and over and have jaundice. [new 2015]
  • 1.2.5 Consider an urgent direct access CT scan (to be performed within 2 weeks), or an urgent ultrasound scan if CT is not available, to assess for pancreatic cancer in people aged 60 and over with weight loss and any of the following:
    • diarrhoea
    • back pain
    • abdominal pain
    • nausea
    • vomiting
    • constipation
    • new onset diabetes. [new 2015]

CT=computerised tomography

National Institute for Health and Care Excellence (2015). Suspected cancer: recognition and referral. NICE Clinical Guideline 12. Available from: www.nice.org.uk/ng12
NICE has not checked the use of its content in this article to confirm that it accurately reflects the NICE publication from which it is taken.

Further investigations

If pancreatic cancer is suspected, further investigations will usually include a check of the patient's:

  • general health
  • medical history
  • symptoms that might be present
  • skin and eyes for any signs of jaundice
  • abdomen for any tenderness, swellings, or lumps
  • blood and urine.

Blood tests

There are two markers that some pancreatic cancers may produce and which might be revealed following a blood test; these are CEA and CA 19-9.

Serum CA 19-9 is more commonly used and is considered to be elevated when its value is greater than 37 U/mL (units per millilitre). CA 19-9 serum levels have a sensitivity and specificity of 79–81% and 82–90%, respectively, for the diagnosis of pancreatic cancer in symptomatic patients; but they are not useful as a screening marker because of low positive predictive value (0.5–0.9%).22 It is important to remember that not every patient with pancreatic cancer will have elevated CA 19-9, and some non-cancerous conditions can cause a high level of CA 19-9.

Scans

While an abdominal ultrasound scan and endoscopic ultrasound can be used to discover a mass on the pancreas, contrast-enhanced CT-scans are one of the most reliable ways to diagnose pancreatic cancer; however, GPs rarely have direct access to them and usually have to refer patients to a specialist who may then order the scan.

Primary care professionals may not fully appreciate the possibility of false negative results from ultrasound scans. Ultrasound scans are routinely used, however, so it is important to be aware that a normal ultrasound will often produce a false negative, which will not necessarily rule out pancreatic cancer. 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 <2 cm in diameter. Multi-slice contrast-enhanced CT scans, which have a sensitivity of 97%, are therefore the most useful investigation to diagnose and stage pancreatic tumours23 and, where specific symptoms exist, referral for a CT scan should be the first action.

Even if the tests show a mass on the pancreas, that mass might be benign or a cyst so further investigation could be needed to confirm the diagnosis one way or the other. That further investigation will often include a biopsy to obtain a sample of tissue.

Treatment

Treatments for pancreatic cancer vary and depend on the stage of the disease and fitness of the patient:

  • surgery to remove the pancreatic cancer tumour is the optimum treatment for patients but only 10–20% of patients present with pancreatic cancers that are operable24
  • for the rest, who do not have the option of curative surgery, chemotherapy can be an option depending on the stage of the cancer, fitness of the patient, and whether the patient wishes to have treatment.

Surgery

Research has shown that two-thirds of patients are underweight before surgery, but that survival improved significantly (164 to 259 days) when weight stabilisation was effectively managed.25 Identifying, advising, and managing this aspect of care can clearly make a huge difference to a patient's quality of life.

Chemotherapy

Both patients who are post-surgical and some who have advanced cancer may be offered chemotherapy. The choice of chemotherapy to be offered should depend on the patient’s situation. The chemotherapy drugs sometimes used to treat pancreatic cancer are:26

  • gemcitabine
  • fluorouracil
  • capecitabine
  • FOLFIRINOX (i.e. folinic acid, fluorouracil, irinotecan, oxaplatin).

In Scotland and Wales, nab-paclitaxel may be used in combination with gemcitabine for people with metastatic pancreatic cancer.

Radiotherapy

Radiotherapy is used less often than surgery or chemotherapy in the treatment of pancreatic cancer but may be given—more information.

Management of symptoms

Pancreatic exocrine insufficiency27

Patients, whether resectable or not, may experience pancreatic exocrine insufficiency (PEI) due to a reduction in the production of pancreatic enzymes needed to digest food. Such patients will need pancreatic enzyme replacement therapy (PERT); enzyme supplements such as pancreatin will be prescribed.28

Patients often need specialist help to determine dosage and nutritional advice to manage the symptoms of PEI. Once PEI symptoms are managed, patients are better able to maintain or gain weight.

Diabetes

Pancreatic cancer, and removal of all or part of the pancreas, which is responsible for the production of insulin, can lead to the development of diabetes, known as type 3c.29

Patients will often require support with managing this condition and signposting to specialist advice.

Role of GPs

In 2015, GPs agreed that earlier recognition of symptoms would lead to earlier diagnosis.30 It has been shown that early detection leads to more patients having curative surgery and, as a result, their chance of surviving 5 years or more increases 10-fold; so GPs and other primary care professionals play a vital role in improving outcomes for people with pancreatic cancer.

With just 3% of GPs feeling fully confident and informed about the symptoms of pancreatic cancer,30 empowering primary care teams to recognise the red-flag symptoms and respond proactively to patients experiencing unresolved and persistent symptoms is essential to achieving better outcomes for people with pancreatic cancer.

General practitioners can also encourage those patients who are at most risk of developing pancreatic cancer to maintain a healthy lifestyle to reduce their risk (e.g. by smoking cessation and maintaining a healthy weight), which could also make a real difference to improving survival rates.

It is also important to be aware of the ongoing issues faced by patients with pancreatic cancer, given the fact that the majority will have advanced disease. Patients can be extremely unwell with chronic pain, loss of appetite, rapid weight loss, and fatigue. Patients and their families may also suffer from the psychological impact of pancreatic cancer, particularly with the poor prognosis. It can be challenging for GPs to deal with all these components and to alleviate patients' fears.

General practitioners can also help by sharing their experiences (both positive and negative) in diagnosing pancreatic cancer with colleagues and CCGs, to inform best practice; 1-year survival rates can then perhaps begin to meet those of better performing regions and countries.

A joined-up approach is essential to ensure that survival rates finally start to improve, to match those of other cancers.

What is the future?

The future for people with pancreatic cancer is starting to look more positive, with groundbreaking research revealing that there is at least 15 years from the initial mutation to metastatic spread of the tumour.31 There is also evidence to support the use of neoadjuvant therapy (typically chemotherapy and radiation therapy) in patients with locally advanced pancreatic cancer that is borderline resectable, to shrink the main tumour before surgery.32

Research is also being developed into proteins in blood and urine.33 Unfortunately, a biomarker for use in clinic is a long way off and still needs significant research investment.

With the advances in science taking place every day, we could afford scientists the window needed for early intervention; however, in order for us to do this, there needs to be development of a reliable diagnostic biomarker, particularly one that distinguishes between pancreatic cancer and pancreatitis.

Sources of information

Some useful sources of information for practitioners and patients are shown in Box 4, below.

Box 4: Information and resources about pancreatic cancer for professionals and patients

Pancreatic Cancer Action

  • GP eLearning module:
    • in conjunction, with the Royal College of General Practitioners, Pancreatic Cancer Action produced a free online CPD accredited eLearning module on pancreatic cancer. The module, Pancreatic cancer: early diagnosis in general practice, has been designed and written by specialists in the field and overseen by practising GPs
  • Patient information booklets:
    • Pancreatic Cancer Action produces a number of publications on pancreatic cancer. These can be viewed online or sent to a UK address free of charge. These publications are produced under the Information Standard certified scheme.

Cancer Research UK

Macmillan Cancer Support

Conclusion

Pancreatic cancer is often referred to as the 'silent killer' because it is difficult to detect in the early stages and difficult to treat in the late stages. There is still more work to be done to improve awareness among patients and healthcare professionals to optimise early diagnosis.

Any advances, whether in diagnostics or treatments, made in the laboratory today could take up to 10 to 15 years to translate into the clinical environment and benefit patients. Therefore, GPs, who are most likely to be the first to encounter a person with pancreatic cancer, must make sure that they are aware of the risk factors and symptoms so that they can act quickly when a patient experiences these symptoms. This is especially important if the patient has a family history of the disease and/or if they are a rare attender now frequently visiting the practice.

While research continues into better ways to detect and treat pancreatic cancer, better awareness and more proactivity among healthcare professionals will contribute to saving lives through early diagnosis in the short term.

 

Key points

  • Less than 5% of patients diagnosed with pancreatic cancer in the UK survive beyond 5 years
  • Pancreatic cancer is set to overtake breast cancer as the fourth commonest cause of death from cancer by 2030
  • Almost half of patients with pancreatic cancer have not heard of the disease before their diagnosis
  • Development of a reliable diagnostic biomarker is needed
  • The commonest risk factors are smoking, obesity, and age
  • Median age for diagnosis is 72 years
  • Symptoms are often mistaken for those of other illnesses
  • Surgical removal of the tumour is currently the only possible cure:
  • only 10–20% of patients present with tumours that are operable
  • Early diagnosis can increase the chance of curative surgery
  • New-onset, non-specific upper abdominal or back pain or discomfort is usually one of the first symptoms
  • Jaundice may be difficult to detect but liver function tests may be abnormal for several months before diagnosis
  • New-onset diabetes can occur in up to 30% of people with pancreatic cancer and can be detected in the presymptomatic phase
  • Heartburn and indigestion are independently associated with a risk of pancreatic cancer
  • Pancreatic cancer should be excluded in patients with an unexplained episode of acute pancreatitis
  • Symptoms that are unexplained and persistent should be considered important
  • Ultrasound scans can produce false negative results; patients should instead be referred for a multi-slice, contrast-enhanced CT scan
  • Chemotherapy can be an option
  • Radiotherapy is used less often than surgery or chemotherapy
  • Managing the patient’s weight can help to improve outcomes:
  • when PEI symptoms are managed, patients are better able to maintain or gain weight
  • General practitioners can encourage patients at risk of developing pancreatic cancer to maintain a healthy lifestyle
  • Clinicians can share their experiences (both positive and negative) in diagnosing pancreatic cancer with colleagues, to inform best practice.

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GP commissioning messages

written by Dr David Jenner, GP, Cullompton, Devon

  • Commissioners should ensure that GPs are aware of NICE Guideline (NG) 12 on Suspected cancer: recognition and referral in relation to pancreatic cancer
  • Direct access to CT scanning (within 2 weeks) for suspected pancreatic cancer should be available to GPs in preference to ultrasound
  • People over the age of 60 years with a new diagnosis of diabetes who are experiencing weight loss and any of the symptoms listed in NICE NG12 should be referred for urgent CT scanning and this should be included in diabetes management pathways
  • Pancreatic cancer is currently the commissioning responsibility of NHS England, and it will need to define which centres will perform the complex surgery required for this condition
  • PbR tariff cost for CT scan, one area, pre and post contrast (RA10Z): tariff (including cost of reporting) £84, cost of report £20.a

awww.england.nhs.uk/resources/pay-syst/tariff-consultation-notice/

CT=computerised tomography; PbR=payment by results

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