Pancreatic cancer

What is pancreatic cancer?^{1 2}

Pancreatic cancer is a much feared disease due to its notoriously late presentation, early metastases and poor survival rates. Less than a fifth of patients present with localised, potentially curable tumours and the overall five-year survival rate is 7.3%. Pancreatic cancer survival has not shown much improvement in the last 40 years in the UK.

In the UK, pancreatic cancer is the 6th most common cause of cancer death, despite being the 10th most common cancer overall. 95% of pancreatic cancers are adenocarcinomas.

The pancreas has dual exocrine and endocrine function. Most pancreatic malignancies are exocrine tumours.There is a separate Pancreatic Endocrine Tumours article.

Infiltrating ductal adenocarcinomas account for 90% of pancreatic cancers. The majority arise in the head, neck or uncinate process. 90% of periampullary malignancies arise from the pancreas and the remaining 10% from the distal common bile duct, the ampulla of Vater and the duodenum. Pancreatic metastases occur most commonly to the liver, peritoneum and lungs.

Pancreatic cancers arising from the distal common bile duct, the ampulla of Vater and the duodenum carry a better prognosis as they present with obstructive jaundice at an earlier stage.

Pancreatic cancer epidemiology

Pancreatic cancer incidence³

• Incidence rates for pancreatic cancer in the UK are highest in people aged 85 to 89. Each year 47% of all new pancreatic cancer cases in the UK are diagnosed in people aged 75 and over.

• There is no significant difference in incidence between males and females.

• Since the early 1990s, incidence rates have increased by 17% in the UK. Rates in females have increased by 17%, and rates in males have increased by 14%.

• Pancreatic cancer incidence rates in England are higher in deprived areas.

• Pancreatic cancer is more common in White and Black people than in Asian people.

Pancreatic cancer risk factors³

• The main risk factors are smoking, diet (high BMI, red meat intake, low fruit and vegetables intake), diabetes and alcohol intake² .

• Chronic and hereditary pancreatitis: chronic pancreatitis is associated with a 5- to 15-fold increase in risk and hereditary pancreatitis with a 50- to 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. 5-10% of pancreatic cancers are due to genetic alteration² .

Pancreatic cancer symptoms⁴

Early pancreatic cancer 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 abuse³ .

• 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 fewer 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 pancreatic cancer.

Pancreatic cancer 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 colorectal 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 includes:

• Bile duct strictures (benign or malignant).

• Common duct stone.

• Pancreatitis.

• Cholangiocarcinoma.

Investigations

Initial blood tests

• FBC - normochromic anaemia, thrombocytosis or both³ .

• 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 markers² :

  • Are of limited diagnostic value but they are often taken as a baseline in order to guide treatment and follow-up.

  • Carbohydrate 19-9 (CA19-9) is the most useful tumour marker.

Diagnosis⁶

NICE recommends:

• People with obstructive jaundice:

  • For people with obstructive jaundice and suspected pancreatic cancer, offer a pancreatic protocol CT scan before draining the bile duct.

  • If the diagnosis is still unclear, offer fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) and/or endoscopic ultrasound (EUS) with EUS-guided tissue sampling.

  • Take a biliary brushing for cytology if endoscopic retrograde cholangiopancreatography (ERCP) is being used to relieve the biliary obstruction, and there is no tissue diagnosis.

• People without jaundice who have pancreatic abnormalities on imaging

  • Offer a pancreatic protocol CT scan to people with pancreatic abnormalities but no jaundice.

  • If the diagnosis is still unclear, offer FDG-PET/CT and/or EUS with EUS-guided tissue sampling.

  • If cytological or histological samples are needed, offer EUS with EUS-guided tissue sampling.

• People with pancreatic cysts

  • Offer a pancreatic protocol CT scan or magnetic resonance cholangiopancreatography (MRI/MRCP) to people with pancreatic cysts. If more information is needed after one of these tests, offer the other one.

• Refer people with any of these high-risk features for resection:

  • Obstructive jaundice with cystic lesions in the head of the pancreas

  • Enhancing solid component in the cyst

  • A main pancreatic duct that is 10 mm diameter or larger.

• Offer EUS after CT and MRI/MRCP if more information on the likelihood of malignancy is needed, or if it is not clear whether surgery is needed.

• Consider fine-needle aspiration during EUS if more information on the likelihood of malignancy is needed.

• When using fine-needle aspiration, perform carcinoembryonic antigen (CEA) assay in addition to cytology if there is sufficient sample.

• For people with cysts that are thought to be malignant, follow the recommendations on staging (see below).

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 cancer² . Helical and multidetector CT with contrast improve rates of tumour detection.

• Endoscopic ultrasound is increasingly used for diagnosing pancreatic cancer³ . Endoscopic ultrasound enables biopsy of the tumour² .

Pancreatic cancer staging procedures⁶

NICE recommends:

• For people with newly diagnosed pancreatic cancer who have not had a pancreatic protocol CT scan, offer a pancreatic protocol CT scan that includes the chest, abdomen and pelvis.

• Offer fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) to people with localised disease on CT who will be having cancer treatment (surgery, radiotherapy or systemic therapy).

• If more information is needed to decide the person's clinical management, consider one or more of the following:

  • MRI, for suspected liver metastases.

  • Endoscopic ultrasound, if more information is needed for tumour and node staging.

  • Laparoscopy with laparoscopic ultrasound, for suspected small-volume peritoneal and/or liver metastases if resectional surgery is a possibility.

Pancreatic cancer staging

Staging is based on the TNM system

• 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.

Pancreatic cancer 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.

Pancreatic cancer treatment and management⁶

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. Management will include not only treating the tumour but also psychological support, pain management and relief of biliary obstruction as required.

Resectable and borderline disease

NICE recommends:
Surgery

• For people having surgery for head of pancreas cancer, consider pylorus-preserving resection if the tumour can be adequately resected.

• Consider standard lymphadenectomy, rather than extended lymphadenectomy for people having head of pancreas resection.

Adjuvant treatment

• Give people time to recover from surgery before starting adjuvant therapy. Start adjuvant therapy as soon as they are well enough to tolerate all six cycles.

• Offer adjuvant gemcitabine plus capecitabine to people who have had sufficient time to recover after pancreatic cancer resection.

• Consider adjuvant gemcitabine for people who are not well enough to tolerate combination chemotherapy.

Follow-up for resected pancreatic cancer

• For people who have had resection, offer ongoing specialist assessment and care to identify and manage any problems resulting from surgery.

• For people who have new, unexplained or unresolved symptoms after treatment, provide access to specialist investigation and support services.

Unresectable disease

Locally advanced pancreatic cancer

• Offer systemic combination chemotherapy to people with locally advanced pancreatic cancer who are well enough to tolerate it.

• Consider gemcitabine for people with locally advanced pancreatic cancer who are not well enough to tolerate combination chemotherapy.

• When using chemoradiotherapy, consider capecitabine as the radiosensitiser.

Metastatic pancreatic cancer
First-line treatment

• Offer FOLFIRINOX to people with metastatic pancreatic cancer and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

• Consider gemcitabine combination therapy for people who are not well enough to tolerate FOLFIRINOX. For guidance on combination therapy with gemcitabine and nab-paclitaxel, see NICE's technology appraisal guidance on paclitaxel as albumin-bound nanoparticles with gemcitabine for untreated metastatic pancreatic cancer.

• Offer gemcitabine to people who are not well enough to tolerate combination chemotherapy.

Second-line treatment

• Consider oxaliplatin-based chemotherapy as second-line treatment for people who have not had first-line oxaliplatin.

• Consider gemcitabine-based chemotherapy as second-line treatment for people whose cancer has progressed after first-line FOLFIRINOX.

Venous thromboembolism prophylaxis
NICE recommends pharmacological VTE prophylaxis with LMWH for people with pancreatic cancer who are receiving chemotherapy⁹ .

Irreversible electroporation
This is a non-thermal cell-destruction technique, which is claimed to allow targeted destruction of cancerous cells with less damage to surrounding supporting tissue (including blood vessels and nerves) than other types of treatment. However, NICE recommends that the current evidence on the safety and efficacy of irreversible electroporation for treating pancreatic cancer is inadequate¹⁰ .

Pain management

As part of pain management, NICE recommends EUS-guided or image-guided percutaneous neurolytic coeliac plexus block to manage pain for people with pancreatic cancer who:

• Have uncontrolled pancreatic pain.

• Are experiencing unacceptable opioid adverse effects.

• Are receiving escalating doses of analgesics.

Nutritional management

NICE recommends:

• Offer enteric-coated pancreatin for people with unresectable pancreatic cancer.

• Consider enteric-coated pancreatin before and after pancreatic cancer resection.

• Do not use fish oils as a nutritional intervention to manage weight loss in people with unresectable pancreatic cancer.

• For people who have had pancreatoduodenectomy and who have a functioning gut, offer early enteral nutrition (including oral and tube feeding) rather than parenteral nutrition.

Biliary obstruction

• Offer resectional surgery rather than pre-operative biliary drainage to people who:

  • Have resectable pancreatic cancer and obstructive jaundice; and

  • Are well enough for the procedure; and

  • Are not enrolled in a clinical trial that requires pre-operative biliary drainage.

• During attempted resection for pancreatic cancer, consider surgical biliary bypass if the cancer is found to be unresectable.

• If biliary drainage is needed in a person who has resectable pancreatic cancer and obstructive jaundice and is not yet fit enough for resectional surgery, offer endoscopically placed self-expanding metal stents.

• For people with suspected pancreatic cancer who may need their stent removed later on, consider endoscopically placed self-expanding fully covered metal stents.

• Offer endoscopically placed self-expanding metal stents rather than surgical biliary bypass to people with unresectable pancreatic cancer.

Duodenal obstruction

• During attempted resection for head of pancreas cancer, consider prophylactic gastrojejunostomy if the cancer is found to be unresectable.

• If possible, relieve symptomatic duodenal obstruction caused by unresectable pancreatic cancer.

• When deciding between gastrojejunostomy and duodenal stent placement, consider gastrojejunostomy for people with a more favourable prognosis.

Palliative care

See also the separate Palliative Care article.

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.

• Coeliac plexus block (an injection of local anaesthetic into or around the coeliac plexus of nerves) is effective for the treatment of severe upper abdominal pain associated with pancreatic cancer¹¹ .

Malabsorption and weight loss

Quality of life and steatorrhoea can be improved by the use of pancreatin supplements, titrated to prevent diarrhoea. See also the separate Nutritional Support in Primary Care article.

Nausea and vomiting

Nausea and vomiting often occur. They are often due to slowed gastric emptying and are improved by prokinetic agents such as metoclopramide or domperidone. If due to duodenal obstruction, duodenal stenting or bypass may be required.

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.

• Deep vein thrombosis, pulmonary embolus.

• Intractable pain (due to parenchymal pressure secondary to ductal obstruction, neural infiltration, pancreatic inflammation and associated biliary stenosis).
  

Prognosis¹

• 25.4% of people diagnosed with pancreatic cancer in England survive their disease for one year or more.

• 7.3% of people diagnosed with pancreatic cancer in England survive their disease for five years or more.

• It is predicted that 5% of people diagnosed with pancreatic cancer in England survive their disease for ten years or more.

• Pancreatic cancer survival for females is higher than for males at one year and at five years.

• Pancreatic cancer survival in England is higher for people diagnosed aged under 50 years.

• More than 3 in 20 men and around a quarter of women in England who are diagnosed with pancreatic cancer and aged 15-49 survive their disease for five years or more, compared with only 2% of people diagnosed aged 80 and over.

• Pancreatic cancer survival has not shown much improvement in the last 40 years in the UK.

Prevention⁷

• 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 may also have a protective effect - although this is unproven and investigational¹² .

Pancreatic cancer surveillance⁶

Secondary screening has been recommended for high-risk patients (chronic pancreatitis, hereditary pancreatitis, familial pancreatic cancer, ovarian and breast cancer familial syndrome and familial multiple mole melanoma syndrome).

NICE recommends surveillance for pancreatic cancer to people with:

• Hereditary pancreatitis and a PRSS1 mutation.

• BRCA1, BRCA2, PALB2 or CDKN2A (p16) mutations, and one or more first-degree relatives with pancreatic cancer.

• Peutz-Jeghers syndrome.

Consider surveillance for pancreatic cancer for people with:

• Two or more first-degree relatives with pancreatic cancer, across two or more generations.

• Lynch syndrome (mismatch repair gene [MLH1, MSH2, MSH6 or PMS2] mutations) and any first-degree relatives with pancreatic cancer.

Consider an MRI/MRCP or endoscopic ultrasound (EUS) for pancreatic cancer surveillance in people without hereditary pancreatitis.

Consider a pancreatic protocol CT scan for pancreatic cancer surveillance in people with hereditary pancreatitis and a PRSS1 mutation.

Do not offer EUS to detect pancreatic cancer in people with hereditary pancreatitis.