Epidemiology

Incidence

• The peak incidence for pancreatic cancer is in the seventh and eighth decades of life. There is no difference in incidence between the sexes.^[2]
• Due to poor survival rates, incidence and mortality rates are similar at approximately 9 per 100,000 population per annum.^[5]

Risk factors^[2]

• Smoking.
• Alcohol.
• Increased body mass index.
• Diabetes mellitus: patients over the age of 50 years with late-onset diabetes have an eightfold increased risk of developing pancreatic cancer within three years of the diagnosis compared to the general population.
• Chronic and hereditary pancreatitis: chronic pancreatitis is associated with a 5-15-fold increase in risk and hereditary pancreatitis with a 50-70-fold increase.
• Family history of pancreatic cancer
• Familial cancer syndromes: BRCA1, BRCA2, familial adenomatous polyposis, Peutz-Jeghers syndrome, familial melanoma syndromes, Lynch syndrome, von Hippel-Lindau syndrome, multiple endocrine neoplasia type 1, Gardner's syndrome.
• Other medical conditions: inflammatory bowel disease, periodontal disease, peptic ulcer disease.

All patients at increased risk of inherited pancreatic cancer should be referred to a specialist centre for clinical advice and genetic counselling with appropriate genetic testing.

Presentation^[6]

Early symptoms are often vague and nonspecific (frequently epigastric discomfort or dull backache) and their significance is frequently overlooked. More than two thirds occur in the head of the pancreas and classically present with painless, progressive, obstructive jaundice. Tumours in the body and tail of the pancreas generally occur in patients presenting with nonspecific pain and weight loss and are much less likely to cause obstructive signs and symptoms. Presentation may be due to paraneoplastic processes, eg thromboembolic disease.

• Abdominal pain: typically located in the epigastric region, radiating through to the back. Can present as simple back pain. Back pain is typically dull and worse when supine and eased by sitting forward.
• Jaundice: obstructive jaundice causes dark urine, pale stools and pruritus.
• Acute pancreatitis: pancreatic cancer should be considered in the differential diagnosis of any elderly patient presenting for the first time with acute pancreatitis, particularly in the absence of known precipitating factors such as gallstones or alcohol abuse.^[2]
• Unexplained weight loss, anorexia.
• Steatorrhoea due to malabsorption.
• Epigastric mass (late).
• Palpable gallbladder: Courvoisier's sign (a palpable gallbladder in the presence of painless jaundice) occurs in less than 25% of patients.
• Compression of the duodenum or the stomach may cause gastric outlet obstruction or delayed gastric emptying, leading to nausea and vomiting.
• Haematemesis, melaena or iron-deficiency anaemia.

Patients presenting with rapid weight loss, persistent back pain, ascites, an epigastric mass or enlarged supraclavicular node (Virchow's node) are likely to have advanced disease.

Differential diagnosis

The differential diagnosis of upper right-sided or epigastric abdominal pain is wide and can include:

• Gallstone disease.
• Peptic ulceration.
• Gastric cancer or colon cancer.
• Oesophagitis.
• Hepatitis.
• Liver abscess.
• Primary or secondary liver tumours.
• Right-sided heart failure.
• Pneumonia.
• Pulmonary embolism.
• Aortic aneurysm.
• Pancreatitis.

Differential diagnosis of obstructive jaundice or extrahepatic cholestasis:

• Bile duct strictures (benign or malignant).
• Common duct stone.
• Cancer of the head of the pancreas.
• Tumour of the ampulla of Vater.
• Pancreatitis.
• Cancer of the gallbladder.

Investigations

Blood tests

• FBC - normochromic anaemia, thrombocytosis or both.^[2]
• LFTs - to confirm jaundice (raised bilirubin, usually with predominantly raised alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT) or hepatocellular involvement.
• Serum glucose - hyperglycaemia.
• Tumour markers are of limited diagnostic value but they are often taken as a baseline in order to guide treatment and follow-up.^[4] Carbohydrate 19-9 (CA19-9) is now one of the most widely used serum tumour markers, with a sensitivity of 80% and specificity of 73% for pancreatic cancer. CA19-9 can be used in assessing response to treatment and for surveillance following treatment.^[2]

Radiology^[7][8]

All methods can miss small tumours.

• Ultrasound - a scan of the liver, bile duct and pancreas is usually the primary investigation. It can show tumour mass, dilated bile ducts, and bulky lymph nodes as well as any liver metastases. Its sensitivity at detecting pancreatic cancer is reported as 76-85% - usually due to most pancreatic cancer being advanced at presentation, but overlying bowel gas or fat may hide part of the pancreas so that continuing symptoms post-ultrasound should prompt CT.
• Abdominal CT - CT scan is currently the preferred imaging modality used for the diagnosis and staging of pancreatic cancer.^[4] Helical and multidetector CT with contrast improve rates of tumour detection.
• Endoscopic ultrasound is increasingly used for diagnosing pancreatic cancer.^[2] For small tumours, endoscopic ultrasound has been reported to be superior to CT.^[4]

Staging procedures^[8]

These are usually undertaken to assess suitability for surgical resection. Whilst a tissue diagnosis is not necessary prior to surgery, it is important in establishing prognosis and suitability for chemotherapy and radiotherapy. Investigations include:

• Multiphase spiral or helical CT with intravenous contrast - uptake at different times can show the degree of invasion of arteries, veins and surrounding tissues and distant lymphatic spread. It can predict surgical resectability with 80-90% accuracy.
• Positron emission tomography (PET) can be useful if the CT findings are equivocal and it is significantly more sensitive in detecting metastatic disease.^[9]
• Dynamic contrast-enhanced MRI, including magnetic resonance cholangiopancreatography (MRCP) and occasionally magnetic resonance angiography (MRA), will accurately delineate tumour size, its relationship with the vascular system and metastatic spread in most cases.
• Endoscopic ultrasonography through gastric or duodenal wall can be used to assist fine needle aspiration (FNA) or guided biopsy and is the most sensitive method for detecting small tumours. Whilst not widely available in the UK, its use is being explored elsewhere in the world.^[10]
• Endoscopic retrograde cholangiopancreatography (ERCP) visualises the common bile duct and pancreatic duct, and cancer of the head of the pancreas tends to produce a characteristic malignant stricture of the lower end of the common bile duct. It also allows brushings to be taken for cytology, biopsies to be taken and stenting undertaken at the same time. It has fallen from favour as a primary diagnostic test, as small early cancers and those situated in the uncinate process may be missed, offers little guidance as to tumour size or spread and it carries the risk of inducing pancreatitis. It does allow for the insertion of a stent in those with obstructive jaundice.
• Transperitoneal biopsy can be used in patients selected for palliative treatment but should be avoided if the lesion is resectable, due to concerns regarding tumour cell seeding.

Staging^[6]

• TIS = in situ carcinoma; T1 = tumour limited to pancreas but <2 cm; T2 = tumour limited to pancreas but larger than 2 cm; T3 = tumour extends beyond the pancreas but not into the coeliac axis or superior mesenteric artery; T4 = tumour involves coeliac axis or superior mesenteric artery.
• N0 = no regional lymph node metastasis; N1 = regional lymph node metastasis.
• M0 = no distant metastasis; M1 = distant metastasis.

*Tumours with regional lymph node involvement are sometimes considered surgically resectable if nodes are within the resection area.

Histology

Primary solid non-endocrine epithelial tumours:

• Ductal adenocarcinoma (75-90%)
• Adenosquamous carcinoma
• Acinar cell carcinoma
• Giant cell carcinoma
• Pancreatoblastoma

Primary cystic non-endocrine epithelial tumours:

• Serous cystic neoplasms
• Mucinous cystic neoplasms
• Intraductal papillary-mucinous neoplasms
• Solid and cystic papillary neoplasms
• Acinar cell cystadenocarcinoma

Most non-inflammatory pancreatic cysts are malignant or pre-malignant - the main differential diagnosis is a pancreatic pseudocyst. Patients with pancreatic cysts are at an increased risk of developing other cancers of the pancreas but also extrapancreatic cancer. Serous cystadenomas are nearly always benign, and are usually managed conservatively under radiological surveillance.^[11]

Management^[11][12]

When pancreatic cancer is suspected on the basis of clinical and radiological findings, patients should be referred to designated pancreatic cancer centres for further assessment and treatment. Teams of experienced gastroenterologists, interventional radiologists, surgeons, pathologists, oncologists and palliative care specialists optimise the identification and survival of patients where surgery is appropriate and the best care for the majority with unresectable disease.

Resectable disease

Surgical resection of the tumour and neighbouring lymph nodes offers the only chance of cure but only 10-20% of tumours are suitable for resection, due to tumour size and spread at diagnosis.^[2] These should be performed in specialised centres, as there is evidence of lower mortality and morbidity where high volume of this type of surgery is undertaken.^[13] Methods include:

• Proximal pancreaticoduodenectomy with antrectomy (Whipple's procedure):
  • Proximal pancreaticoduodenectomy with pylorus preservation (modified Whipple's procedure):
    • Stomach, pylorus and first 3-4 cm of duodenum are left intact.
    • There is no evidence of superiority of Whipple's procedure versus modified Whipple's procedure.^[14]
  • Distal pancreatectomy: this is performed for tumours of the body and tail of the pancreas.
  • Total pancreaticoduodenectomy: extended radical resections increase morbidity without improving survival or quality of life and are not part of routine practice.^[11]

  Adjuvant treatment

  • Even where a tumour has been fully resected, the outcome in patients with early pancreatic cancer is disappointing. Large trials have established the role of postoperative adjuvant treatment in patients with resected pancreatic cancer:
  • Surgery plus systemic adjuvant chemotherapy is now recommended following the European Study Group for Pancreatic Cancer 1 (ESPAC-1) trial which showed chemotherapy improved survival (21% vs 8% at five years).^[15]
  • Regimens commonly use either 5-fluorouracil (5-FU) or gemcitabine. The ESPAC-4 trial is currently comparing gemcitabine alone against combination therapy of gemcitabine plus capecitabine.^[2]
  • The ESPAC-1 trial showed a clear advantage for adjuvant chemotherapy in patients with resected pancreatic cancer over chemoradiotherapy.^[2]

  Unresectable disease

  The majority of patients (85-90%) fall into this category, having locally advanced or metastatic disease. Many patients have a very limited survival expectancy and some do not wish to undergo anticancer therapy, concentrating on a palliative approach.
  
  Chemotherapy:^[7]
  • Pancreatic ductal adenocarcinoma is very resistant to conventional chemotherapy. However, increased duration of survival with palliative chemotherapy has been demonstrated in some trials.
  • The National Institute for Health and Clinical Excellence (NICE) guidelines suggest that gemcitabine be used as first-line palliative chemotherapy in pancreatic cancer provided there is reasonable performance status.^[16]
  Future directions for clinical management:^[17][18]
  • Preoperative neoadjuvant chemoradiation for resectable disease or allowing downstaging and surgical resection for borderline cases.
  • Gemcitabine as radiation sensitiser - use of chemoradiation regimens.
  • Gemcitabine as an adjuvant treatment.
  • Evolving gemcitabine-based combination therapies.
  • Targeted therapy at identified molecular targets, eg the use of growth factor inhibitors and monoclonal antibodies.^[19]
  • Vaccine-based therapy, to induce an immunological response against the cancer.^[20]

  Palliative measures:^[7]

  See also separate Palliative care article.
  • Obstructive jaundice and pruritus - obstruction of the common bile duct can be relieved by surgical bypass (choledochojejunostomy) or biliary stenting. Stenting relieves itch and reverses jaundice in about 85% of patients. Stents can be inserted during an endoscopic retrograde cholangiopancreatography (ERCP) or percutaneously in those with extensive disease or in those otherwise unsuitable for surgery. A polyethylene stent has an average patency of 3-4 months, potentially leading to recurrent jaundice in those who survive longer than this. Expanding metal stents have a functional life approximately twice this and should be used for patients with good performance status and a locally advanced primary tumour <3 cm.^[11][21] Stents do block - this does not necessarily mean terminal progression of the tumour, so patients with recurrence of jaundice should be referred back for reassessment.
  • Pain control - pain occurs in over 50% and may be severe and difficult to manage. Where opiates fail to control pain or are contra-indicated/poorly tolerated, early referral to a specialist palliative team is important - alternative analgesia, ablation of the coeliac ganglia, or external beam radiotherapy may provide significant improvement.
  • Malabsorption and weight loss - quality of life and steatorrhoea can be improved by the use of pancreatin supplements, titrated to prevent diarrhoea.
  • Nausea and vomiting - these develop in about 20%; they are often due to slowed gastric emptying and are improved by prokinetic agents such as metoclopramide or domperidone. If due to duodenal obstruction, it may require duodenal stenting or bypass.
  • Depression - there is a stronger association with pancreatic cancer compared with other malignancies so a low threshold for intervention and treatment may be appropriate.

  Complications

  • Obstructive jaundice.
  • Duodenal obstruction (15-20%).
  • Deep vein thrombosis or pulmonary embolus.
  • Intractable pain (due to parenchymal pressure secondary to ductal obstruction, neural infiltration, pancreatic inflammation and associated biliary stenosis).

  Prognosis

  • The majority of ductal carcinomas present when they are locally advanced and palliative treatments alone are possible. Overall one-year and five-year survival rates are 12% and 3% respectively.^[11]
  • The median survival for patients who undergo successful resection (only 20% of patients) is approximately 12-19 months, with a five-year survival rate of 15-20%.^[3]
  See 'Staging' table (above) for median survival times.

  Prevention^[7]

  • Reducing tobacco consumption is likely to reduce cases of pancreatic cancer.
  • Physical activity, high fruit and vegetable intake, and avoiding central obesity may have a protective effect.
  • The use of non-steroidal anti-inflammatory drugs^[22] may also have a protective effect - although this is unproven and investigational.
  • No simple screening test is currently available for use in the general population.
  • Secondary screening in high-risk cases (chronic pancreatitis, hereditary pancreatitis, familial pancreatic cancer, ovarian and breast cancer familial syndrome and familial multiple mole melanoma syndrome) may be carried out as part of an investigational programme through specialist centres only.