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 5-year survival rate remains less than 5%.¹

The pancreas has dual exocrine and endocrine function. Most pancreatic malignancies are exocrine. 90% of these are ductal adenocarcinomas. 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. This subgroup carry better prognoses as they present with obstructive jaundice at an earlier stage. Rarer tumours (including intraductal papillary mucinous tumours and mucinous cystic tumours) also have a better prognosis.² Metastases occur most commonly to the liver, peritoneum and lungs.

Epidemiology

Incidence

• Exocrine pancreatic tumours are the sixth most common cause of cancer deaths in the UK and there were 7,684 new cases in 2007. There is a 1 in 86 lifetime risk of developing the disease.³
• Due to poor survival rates, incidence and mortality rates are similar at approximately 9 per 100,000 population per annum.³

Risk factors^4,5

Increased risk associated with:

• Age - rare <40 years, median age at presentation is 70-75 years. Three quarters of new cases occur in patients aged over 65 years.
• Smoking - in the past, there has been a male excess of pancreatic cancer but this has been declining, reflecting falling rates of smoking among men.
• Increased body mass index (BMI) - association shown in postmenopausal women, particularly with central obesity.⁶
• 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 - familial pancreatic cancer syndrome is rare (approximately 2%) with a positive family history (at least 2 other family members) of pancreatic cancer and reflects a heterogeneous assortment of genetic risk.⁷ Risk is also increased in other cancer syndromes including hereditary nonpolyposis colorectal carcinoma, familial adenomatous polyposis (strongly associated with periampullary tumours), familial breast-ovarian cancer syndromes, Peutz-Jeghers syndrome and familial melanoma syndromes.⁸

Dietary factors including fat intake, coffee consumption and alcohol have not been proven to increase risk.

Genetics:⁵

• High-frequency genetic changes associated with pancreatic adenocarcinoma include: mutations of K-ras oncogene, inactivation of p53, p16 and smad4/transforming growth factor β (TGF-β) tumour suppressor genes.
• The underlying genetic defects for hereditary syndromes with a predisposition for pancreatic cancer are being identified and may offer targets for future diagnostic and therapeutic interventions.
• 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.⁴

Presentation^2,9

General points:

• Early symptoms are often vague and nonspecific (frequently epigastric discomfort or dull backache) and their significance is frequently overlooked.
• Symptoms are generally related to mass effect rather than disruption of exocrine or endocrine activity and exact clinical features will depend on the size and location of the tumour as well as its metastases.
• More than two thirds occur in the head of the pancreas and classically present with painless, progressive, obstructive jaundice.
• Patients with tumours in the body and tail of the pancreas generally present with nonspecific pain and weight loss and are much less likely to cause obstructive signs and symptoms.
• Presentation may be due to paraneoplastic processes, e.g. thromboembolic disease.

Differential diagnosis

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

• Gallstone disease.
• Peptic ulceration.
• Gastric 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

These are generally nonspecific and findings may include:

1. FBC - anaemia.
2. LFTs - to confirm jaundice (raised bilirubin, usually with predominantly raised alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT) or hepatocellular involvement.
3. Serum glucose - hyperglycaemia.

There are no specific tumour markers - elevated carbohydrate antigen (CA) 19-9 is usual but has low sensitivity (50-75%) and specificity (83%) and normal levels do not exclude diagnosis, though it may be useful to help predict prognosis and recurrent disease post-resection.⁹ Other candidate markers include beta human chorionic gonadotrophin (beta hCG) and CA 72-4.

Radiology^4,10

All methods can miss small tumours.

1. 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.
2. Abdominal CT - this is the imaging method of choice where suspicion of pancreatic cancer or pancreatitis is high. Helical and multidetector CT with contrast improve rates of tumour detection.

Staging procedures^10,11

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:

1. 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.
2. Positron-emission tomography (PET) can be useful if the CT findings are equivocal and it is significantly more sensitive in detecting metastatic disease.¹²
3. 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.
4. Endoscopic ultrasonography (EUS) through gastric or duodenal wall (gastroscopy), if available, 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.¹³
5. 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.
6. 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.

Staging⁹

• 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

• 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.⁵

Management^4,5,14

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 10-15% of tumours are suitable for resection due to tumour size and spread at diagnosis. 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.¹⁵ Methods include:

• Proximal pancreaticoduodenectomy with antrectomy (Whipple's procedure):
  • This is the classic operation for a tumour in the head of the pancreas and removes the head of the pancreas, the gallbladder, the distal common bile duct, the duodenum and proximal jejunum, the regional lymph nodes and 40-50% stomach.
  • It is a major operation and patients must be physically fit to undertake such radical surgery.
  • Median postoperative survival is 11-20 months, between 1.4 and 24% survive to 5 years but 40-50% of these ultimately die of recurrence and only 8% of those operated on remain tumour-free.
  • Markers for long-term survival are: well-differentiated tumour, small tumour (<3 cm in diameter), clear resection margins and no lymph node involvement.
• 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 in terms of efficacy and survival - but the modified Whipple's procedure has tended to be the preferred option in the UK due to shorter operating time, and reduced blood loss, hospital stay, mortality and morbidity and complication rates, although these assumptions have been challenged.¹⁶
• Total pancreaticoduodenectomy and distal pancreatectomy.

Extended radical resections increase morbidity without improving survival or quality of life and are not part of routine practice.⁵

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:
Now recommended following the European Study Group for Pancreatic Cancer 1 (ESPAC-1) trial¹⁷ which showed chemotherapy to improve survival (21% vs 8% at 5 years). Regimens commonly use either 5-fluorouracil (5-FU) or gemcitabine.

Adjuvant radiotherapy or chemoradiotherapy:
The role of radiochemotherapy in adjuvant treatment of pancreatic cancer remains a topic of debate: early studies failed to show any survival benefit (ESPAC-1).¹⁷

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:⁴
Pancreatic ductal adenocarcinoma is very resistant to conventional chemotherapy. However, increased duration of survival with palliative chemotherapy has been demonstrated in some trials:

• Single-agent chemotherapy with gemcitabine (nucleoside analogue, inhibiting DNA synthesis) in advanced and metastatic tumours achieved modest but significant improvements in survival and symptom relief. Symptom improvement was found in more patients with gemcitabine compared with 5-fluorouracil, the traditional agent.¹⁸
• 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.¹⁹
• Results from studies looking at combination gemcitabine chemotherapy have not shown great benefit, but meta-analyses suggest that combinations with capecitabine or platinum-based agents carry some survival benefits, but with greater risk of toxicity and side-effects.²⁰
• Erlotinib, a tyrosine kinase inhibitor, has been shown to improve survival (in combination with gemcitabine), but the benefit is very modest - a median increased survival of 10 days.²¹

• 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, e.g. the use of growth factor inhibitors and monoclonal antibodies.²²
• Vaccine-based therapy, to induce an immunological response against the cancer.²³

Whilst our molecular understanding of pancreatic cancer has increased, it is clear that it is a heterogeneous cancer genetically and individualised therapy will be required.¹

Palliative measures:^4,24

• 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% 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.^5,25Stents 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% and are often due to slowed gastric emptying and 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 1-year and 5-year survival rates are 12% and 3% respectively.⁵ See staging table (above) for median survival times.

Prevention⁴

• 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 drugs²⁶ 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.

Document references

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3. Pancreatic cancer UK incidence, Cancer Research UK, last updated June 2010
4. No authors listed; Guidelines for the management of patients with pancreatic cancer periampullary and ampullary carcinomas.; Gut. 2005 Jun;54 Suppl 5:v1-16.
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19. Pancreatic cancer - gemcitabine, NICE Technology Appraisal (2001); The use of gemcitabine for the treatment of pancreatic cancer
20. Sultana A, Tudur Smith C, Cunningham D, et al; Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer: results of secondary end points analyses. Br J Cancer. 2008 Jul 8;99(1):6-13. Epub 2008 Jun 24. [abstract]
21. Moore MJ, Goldstein D, Hamm J, et al; Erlotinib plus gemcitabine compared with gemcitabine alone in patients with J Clin Oncol. 2007 May 20;25(15):1960-6. Epub 2007 Apr 23. [abstract]
22. Cardenes HR, Chiorean EG, Dewitt J, et al; Locally advanced pancreatic cancer: current therapeutic approach. Oncologist. 2006 Jun;11(6):612-23. [abstract]
23. Miyazawa M, Ohsawa R, Tsunoda T, et al; Phase I clinical trial using peptide vaccine for human vascular endothelial Cancer Sci. 2010 Feb;101(2):433-9. Epub 2009 Oct 27. [abstract]
24. No authors listed; Management of pancreatic cancer.; Drug Ther Bull. 2003 May;41(5):36-40. [abstract]
25. Moss AC, Morris E, Mac Mathuna P; Palliative biliary stents for obstructing pancreatic carcinoma.; Cochrane Database Syst Rev. 2006 Apr 19;(2):CD004200. [abstract]
26. Sarkar FH, Adsule S, Li Y, et al; Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem. 2007 Jun;7(6):599-608. [abstract]

Acknowledgements