Pancreatic cancer

Abstract

Pancreatic cancer is the eleventh most common cancer in the UK, yet it is the fifth most common cause of cancer death. In the UK, the age-standardised incidence has risen by 11% over the last decade. The symptoms are often vague, and as a result, it rarely presents at an early stage. Prognosis is determined by stage at presentation, therefore prompt recognition and referral of suspicious symptoms is vital. Survival rates remain poor, with just a 3% rate of 5-year survival. GPs therefore have an important role in both the early recognition and palliative care of patients with pancreatic cancer.

The GP curriculum and pancreatic cancer

Clinical module 3.13: Digestive health lists the learning objectives required for a GP to manage pancreatic cancer in the community. In particular, GPs are expected to be able to:

Take a central role in the diagnosis and management of digestive problems in primary care

Understand the risks associated with various symptoms which may indicate gastrointestinal cancer, and refer with appropriate levels of urgency

Be able to manage primary contact with patients who have a digestive problem

Demonstrate a systematic approach to investigating common digestive symptoms, taking into account the prevalence of these symptoms in primary care and the likelihood of conditions such as peptic ulcer, oesophageal varices, hepatitis, gastrointestinal cancers and post-operative complications

Understand the indication for urgent referral for suspected gastrointestinal cancer

Understand the epidemiology of gastrointestinal symptoms and disorders in primary care, and the evidence on the risks for cancer and other serious diseases associated with various symptoms and symptom complexes

Epidemiology

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, remains one of the most common causes of cancer-related death in the world. Cancer Research UK have reported that every year within the UK, 9–10 000 people are newly diagnosed with PDAC, with only a slightly smaller number of patient’s dying from the disease. Without curative surgery, the median survival following the diagnosis of pancreatic cancer is 6–12 months. Even for those who undergo ‘curative’ surgery, median survival is only 20–24 months. Overall 5-year survival is just 3% in the UK, with only a marginal improvement in survival in the last four decades. This is in contrast with the majority of other common cancers.

Risk factors

Multiple risk factors for PDAC have been identified (see Box 1). Like many cancers, advancing age has been linked with development of PDAC. The majority of cases occur over the age of 60 years, and incidence is equal between men and women. Smoking is another important risk factor, and a meta-analysis has shown current smokers to have a 1.74 increased risk of developing PDAC compared with non-smokers (Iodice et al., 2008). This increased risk has been shown to persist for up to 20 years following smoking cessation. A study by the Mayo Clinic in 2008 revealed more than 40% of patients with PDAC had a diagnosis of diabetes mellitus (DM) (Bosetti et al., 2014). It is not an uncommon on review of a patient’s history to find a recent diagnosis of DM or worsening diabetic control prior to the new diagnosis of PDAC. However, it may be difficult to determine whether the cancer has caused DM or DM has caused the cancer.

Box 1.

Risk factors for pancreatic cancer.

• Age

• Smoking

• Obesity

• Diabetes mellitus

• Chronic pancreatitis

• Genetic factors

Chronic pancreatitis has been established as a risk factor for the development of PDAC. Patients with hereditary pancreatitis have a 40% life-time risk of developing PDAC. Therefore, close follow up of these patients is part of the EUROPAC study in the UK.

One of the strongest risk factors for PDAC is a positive family history, although this does not necessarily represent a specific genetic mutation. There are, however, a few genetic conditions that are known to be associated with PDAC including BRCA 2, Peutz–Jeghers, and Lynch syndrome.

Several premalignant lesions have been found to arise in the pancreas, including intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, each with different malignant potential. These are often picked up as incidental findings, and should be followed up by a centre specialising in pancreatic disease.

Anatomy and pathophysiology

The pancreas is a fatty, retroperitoneal organ that lies in the transpyloric plane. The pancreas lies within the C of the duodenum (see Fig. 1). Anatomically it is divided into several parts with relatively indistinct borders between the parts. The uncinate process develops from the ventral pancreatic bud, which rotates in utero to lie behind the superior mesenteric vein (SMV) and superior mesenteric artery (SMA). The rest of the pancreas develops from the dorsal pancreatic bud. The dorsal pancreas is divided into the head, lying to the right of the SMV, and the neck, overlying the SMV and SMA. The body and tail lie to the left of the SMA with no clear boundary dividing them. Up to 80% of PDACs are found within the head or uncinate process. The pancreas lies close to several major blood vessels, which can become involved early in the disease process, rendering the tumour inoperable.

Figure 1.

Coronal section of pancreas and duodenum. The uncinate process is seen to lie behind the superior mesenteric vessels. The head lies to the right of the SMV, the neck over lies the superior mesenteric vessels and body and tail lie to the left of the SMA.

PDAC arises from the cells lining the pancreatic ducts; however, other cell types within the pancreas can also develop tumours. In particular, neuroendocrine tumours, which arise from the islets of Langerhan cells, and also the rarer acinar cell carcinoma that arises from exocrine acinar cells.

Presentation

The presenting symptoms and associated signs of pancreatic cancer will depend predominantly on the anatomical location of the tumour. Tumours within the uncinate process or head of the pancreas may typically present with painless jaundice, due to biliary obstruction, giving the classic Courvoisier’s sign (palpable distended gallbladder in the presence of jaundice). In tumours originating within the neck, body or tail, symptoms may not arise until there is infiltration of the tumour into the local splanchnic nerves, leading to vague upper abdominal and back pain. Weight loss, lethargy and early satiety are common. Unfortunately, due to the ambiguity of symptoms, only 15–20% of patients will have curable disease at the time of diagnosis. Curable disease is more likely in tumours of the head compared with those of the tail. As mentioned above, a new diagnosis of DM or recent worsening of glycaemic control should raise suspicion of pancreatic cancer. A palpable epigastric mass and new supraclavicular lymphadenopathy (Virchow’s node), should alert to the possibility of pancreatic cancer. Box 2 lists the symptoms and signs that may be associated with pancreatic cancer.

Box 2.

Signs and symptoms of pancreatic cancer.

• Weight loss

• Back pain

• Lethargy

• Steatorrhoea

• Jaundice

• Migratory thombophlebitis

• Courvoisier’s sign

• Palpable mass

Diagnosis

Pancreatic cancer is an elusive disease, with very few pathognomonic symptoms or signs to signal its presence to the clinician. It is therefore imperative for the GP to have a high index of suspicion for this fatal disease. In 2015, the National Institute for Health and Care Excellence (NICE) updated its guidelines for urgent suspected cancer referral criteria for pancreatic cancer. These are summarised in Box 3.

Box 3.

NICE (2015) guidelines of the referral of patients with suspected pancreatic cancer.

• Refer people using urgent suspected cancer pathway in those over 40 years with new onset jaundice

• Consider urgent direct access computed tomography (CT) scan (within 2 weeks) or urgent ultrasound scan if CT not available, in patients over 60 years with weight loss and any of the following:

° Diarrhoea

° Back pain

° Abdominal pain

° Nausea

° Vomiting

° Constipation

° New onset diabetes

Investigations

Primary care

Basic blood tests including full blood count, urea and electrolytes, liver function tests and coagulation profile should be obtained. Tumour marker estimation as a blind diagnostic tool should be used with caution. A Ca19-9 level may be falsely elevated in the presence of biliary obstruction; also, up to 10% of the population has a germline mutation for the production of Lewis antibodies, and will therefore not express Ca19-9 even in the presence of pancreatic cancer.

The initial radiological investigation should be a contrast computed tomography (CT) scan of the abdomen and pelvis. A transabdominal ultrasound scan (USS) can be requested if access to CT scanning is not possible from primary care. Referral to an upper gastrointestinal or pancreatic specialist should be made according to the guidelines in Box 3. If USS shows an obvious mass within the pancreas, then a staging CT of the chest, abdomen and pelvis should be obtained while awaiting specialist review.

Secondary care

Patients with significant jaundice may undergo endoscopic retrograde cholangiopancreatography (ERCP) with insertion of a stent to obtain biliary drainage as well as brushings for histology. Some centres are trialling fast track surgery and resection without biliary drainage, assuming definitive surgery can be undertaken within 2 weeks. All patients should have a CT of the chest, abdomen and pelvis to rule out metastatic disease.

Further evaluation of pancreatic lesions can be organised in secondary care with magnetic resonance imaging of the pancreas or magnetic resonance cholangiopancreatogram. Endoscopic ultrasound (EUS) and biopsy may be undertaken to obtain tissue and assess local tumour invasion and any lymphadenopathy. Increasingly, positron emission tomography CT is undertaken to rule out occult metastatic disease not seen on standard CT, or to further assess indeterminate lesions picked up with other imaging modalities. If no contraindications to resection are identified on imaging (metastatic disease or locally advanced disease), then the patient will be put forward for resection after being deemed fit to withstand the procedure. If imaging is equivocal or there is a high pre-operative Ca19-9, staging laparoscopy may be undertaken prior to resection to avoid non-therapeutic laparotomy.

Management

Surgical

Surgery offers the only chance of cure in PDAC, but just 15–20% of patients will be suitable for curative surgery. Contra-indications to resection include metastatic disease, lymph node involvement outside of the field of resection, and arterial encasement (superior mesenteric artery/coeliac axis).

A patient deemed likely to have resectable disease after full staging investigations will have an anaesthetic assessment before proceeding to surgical exploration. Surgery usually involves a pylorus- preserving pancreatoduodenectomy (PPPD) for tumours affecting the head or neck of the pancreas. The resection removes the entire duodenum (except for a 1-cm cuff distal to the pylorus), the head of the pancreas, the distal bile duct (this is divided just above the confluence of the cystic duct and the common hepatic duct) and the surrounding lymphatic tissue. Afterwards, a loop of jejunum is anastomosed to the distal pancreas, the divided end of the bile duct and the pylorus to reinstate continuity of the gastrointestinal tract. The distal stomach may be resected en bloc in a traditional ‘Whipple’s procedure’.

Tumours of the body and tail of the pancreas are treated with radical left pancreatectomy, which involves removing the pancreas to the left of the portal vein with the spleen and surrounding lymph nodes. Left pancreatectomies are predominantly carried out laparoscopically at present, and in some centres surgeons are gaining increasing experience at performing laparoscopic PPPDs and Whipple’s procedure.

Both a traditional Whipple’s procedure and PPPD are major operations, with significant morbidity and mortality. It will often take months for patients to function at pre-operative levels following such surgery.

Oncological

It is now standard practice in the UK to consider all patients undergoing surgical resection for adjuvant chemotherapy if their performance status allows it. The European Society for Pancreatic Cancer (ESPAC)’s trials formed the basis for the role of adjuvant oncological treatment in patients with resectable disease in the UK. Although ESPAC-1 showed clear survival benefit for patients undergoing adjuvant chemotherapy with 5-Fluorouracil compared with those not receiving chemotherapy, it also revealed that adjuvant radiotherapy actually had a negative impact on survival. The current treatment standard is to offer 6-months of gemcitabine and capecitabine (as per ESPAC-4); however, there is emerging evidence that modified FOLFIRINOX (5FU, folinic acid, irinotecan and oxaloplatin) can increase median survival further. However, this regimen is more toxic to the patient. It is now accepted that it is more important to commence chemotherapy regimens when the patient is fit enough to receive the full course rather than to start prematurely before prior fitness is regained, even if this means waiting several weeks before beginning chemotherapy. Currently the role neo-adjuvant therapy for borderline resectable pancreatic cancer (those patients with a high chance of having an involved surgical margin) is being explored in the ESPAC-5 trial.

Palliative

Managing the symptoms of pancreatic cancer in those not suitable for resection or in those who have tumour recurrence can be challenging. More often than not these patients are managed in the community, with primary care playing an important role in co-ordination of care. The most common symptoms encountered are those related to malignant biliary obstruction (pruritis, cholangitis), poor nutrition (gastric outlet obstruction, pancreatic exocrine failure) and pain.

Patients found to have non-resectable disease at the time of surgical exploration will often undergo pre-emptive biliary and gastric bypass, in anticipation of future obstruction with tumour growth. This is often in the form of a roux-en-y hepaticojejunostomy with a gastrojejunostomy. If the patient has a metal biliary stent in-situ at the time of exploration, then biliary bypass may be deemed unnecessary. An intra-operative coeliac nerve block (neurolysis) may be undertaken at this time to improve pain control.

In patients who develop biliary obstruction with inoperable PDAC or who present with jaundice and are then found on imaging to be inoperable, long-term biliary drainage can be achieved with the placement of a metal stent. This is usually achieved at ERCP, although sometimes a percutaneous approach or combined ERCP/percutaneous (rendezvous) procedure is required to obtain satisfactory biliary drainage.

Gastric outlet obstruction (GOO) often presents more of a challenge for management. The development of endoscopically placed duodenal stents has improved the palliation in patients with GOO. However, some patients will undergo surgical bypass if stenting is not deemed appropriate or possible. All patients with pancreatic cancer (operable or not) should be prescribed pancreatic enzyme supplementation (e.g. Creon) and a proton pump inhibitor to improve nutrition. Short courses of low-dose dexamethasone can be considered to try and improve poor appetite, however, if the desired effect is not obtained, steroids should be discontinued.

Pain management should initially conform to the WHO analgesic ladder. However, some patients will require more advanced forms of pain relief. Anti-inflammatories can be considered if there are no contra-indications. If oral opiates are failing to achieve satisfactory pain control, then consideration can be given to a EUS-guided coeliac plexus block.

As well as the physical issues associated with the diagnosis of pancreatic cancer, it is important to consider the psychological burden that the poor prognosis of this disease carries. Encouraging patients to engage in support groups can be beneficial, and there are several charities that can provide emotional support to patients.

It is important for GPs to recognise the symptoms of disease progression and to know how to manage these patients, or when to refer if management in the community is not possible. Close liaison with palliative care services contributes to comprehensive care and end of life planning for these patients.

KEY POINTS

Pancreatic cancer still has a poor prognosis, with only a minority of patients being suitable for curative surgery

Symptoms are often vague, and therefore, a high index of suspicion is required for early stage diagnosis of pancreatic cancer

A new diagnosis of DM or recent worsening of glycaemic control should raise suspicion of pancreatic cancer; suspicious symptoms also include weight loss, lethargy, early satiety and painless jaundice

Referral based on the criteria and guidelines for urgent suspected pancreatic cancer is essential

Nutritional support with creon is important, and should be started in all patients with pancreatic cancer

Primary care plays a key role in symptom control and palliation of symptoms for patients with advanced disease

References

Bosetti

Lucenteforte

Silverman

, et al. (2012) Cigarette smoking and pancreatic cancer: An analysis from the International Pancreatic Case Control Consortium (Panc4). Annals of Oncology 23(7): 1880–1888. DOI: 10.1093/annonc/mdr541.

Boseeti

Rosato

, et al. (2014) Diabetes, antidiabetic medication and pancreatic cancer risk: An analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4). Annals of Oncology 25(10): 2065–2072. DOI: 10.1093/annonc/mdu276.

Cancer Research UK. Pancreatic cancer statistics. Available at: www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer#heading-One (accessed 26 October 2018).

Cancer Research UK. Pancreatic cancer survival. Available at: www.cancerresearchuk.org/about-cancer/pancreatic-cancer/survival (accessed 26 October 2018).

Ahuja

Makary

, et al. (2014) 2564 resected periampullary adenocarcinomas as a single institution: Trends over three decades. HPB: The Official Journal of the International Hepato Pancreato Biliary Association 16(1): 83–90. DOI: 10.1111/hpb.12078.

Iodice

Gandini

Maisonneuve

(2008) Tobacco and the risk of pancreatic cancer: A review and meta-analysis. Langenbeck's Archives of Surgery 393(4): 535–545. DOI: 10.1007/s00423-007-0266-2.

Kastrinos

Mukherjee

Tayob

, et al. (2009) Risk of pancreatic cancer in families with Lynch Syndrome. Journal of the American Medical Society 302(16): 1790–1795. DOI: 10.1001/jama.2009.1529.

NICE (2015) Suspected cancer: Recognition and referral. Available at: www.nice.org.uk/guidance/ng12/chapter/1-Recommendations-organised-by-site-of-cancer#upper-gastrointestinal-tract-cancers (accessed 26 October 2018).

Noë

Brosens

Offerhaus

(2018) Pancreatic cancer: Precancerous lesions. In: Beger

Warshaw

Hruban

, et al. (eds) The Pancreas: An Integrated Textbook of Basic Science, Medicine and Surgery, Third Edition, Oxford: Wiley Blackwell, pp. 705–716.

10.

RCGP. Clinical module 3.13: Digestive health. Available at: www.rcgp.org.uk/training-exams/training/gp-curriculum-overview/online-curriculum/applying-clinical-knowledge-section-1/3-13-digestive-health.aspx (accessed 12 February 2019).

11.

Roberts

Prasad

Steele

, et al. (2017) A reduced time to surgery within a “fast track” pathway for periampullary malignancy is associated with an increased rate of pancreatoduodenectomy. HPB: The Official Journal of the International Hepato Pancreato Biliary Association 19(8): 713–720. DOI: 10.1016/j.hpb.2017..04.011.