Pancreatic cancer

Contributed by Mr Sherif Awad, specialist registrar, and Mr Ian Beckingham, consultant general surgeon at the Wolfson Digestive Diseases Centre, Queen's Medical Centre, Nottingham.

1. Aetiology and epidemiology

Pancreatic cancer kills over 6,000 people annually in the UK and it is the sixth most common cause of cancer death.

The annual incidence is 100 per million population and 80 per cent of cases occur between 60 and 80 years of age. Worldwide it is a cancer of affluent countries and the incidence is highest in Japan, Israel, Canada, Sweden, the UK and USA.

Risk factors include smoking, diets high in fat, exposure to chemicals such as napthylamine, benzidine and ethylene dichloride, and previous partial gastrectomy.

Patients are statistically more likely to have a family history of the disease, leading to familial clustering, although most cases occur sporadically.

Ductal adenocarcinoma of the pancreas accounts for more than 90 per cent of all malignant exocrine tumours and two thirds of cases arise in the head of pancreas.

The most common extra-lymphatic sites of spread are liver, peritoneum and lung.

Immunohistochemical staining with CA 19-9 and carcinoembryonic antigen characterises the tumour. It is staged using TNM classification (see box), which correlates with survival.

Ductal adenocarcinomas need to be differentiated from other peri-ampullary tumours (carcinomas of the ampulla, distal third of bile duct and duodenum), which present similarly but carry a better prognosis.

These diagnoses are usually not possible until examination of the resected specimen.

The rest of this review will focus on adenocarcinoma of the pancreas.

TNM staging

Primary tumour (T)

T0 - No evidence of primary tumour

T1 - Tumour limited to pancreas (1a [s39]2cm size, 1b >2cm)

T2 - Tumour extends directly to any of following: duodenum, bile duct, peripancreatic tissues

T3 - Tumour extends directly to any of following: stomach, spleen, colon, adjacent large vessels

Regional lymph nodes (N)

N0 - No regional lymph node metastases

N1 - Regional lymph node metastases

Distant metastases (M)

M0 - No distant metastases

M1 - Distant metastases

2. Diagnosis

Presentation varies according to the site of the primary tumour. In carcinoma of the head of pancreas, obstructive jaundice, abdominal pain and weight loss are common symptoms.

Nausea and vomiting are present in 30-50 per cent of patients but actual duodenal obstruction only occurs in 5 per cent.

Jaundice is progressive and results from obstruction of the common bile duct. Pain is usually epigastric and radiation to the back occurs in 25 per cent. This is an ominous symptom as it may indicate posterior capsular invasion and unresectability.

Carcinomas of the body or tail are more advanced at presentation because of the absence of jaundice, which if present in this group indicates advanced disease.

Investigations

Investigation aims to confirm the diagnosis, accurately stage the disease and assess resectability.

The initial investigation of the jaundiced patient should be trans-abdominal ultrasound, which will confirm biliary dilation and the presence or absence of gallstones.

It may detect pancreatic masses, extrapancreatic spread, ascites and liver metastases. Overall diagnostic sensitivity is up to 70 per cent but this falls to below 30 per cent for tumours <2cm in diameter. An ultrasound-guided biopsy of metastatic lesions may be the only investigation required in patients in advanced stages.

Multi-slice contrast enhanced CT is the most useful to diagnose and stage pancreatic tumours and has an overall sensitivity of 97 per cent.

False positives occur in 10 per cent, and this underlies the importance of obtaining histological confirmation in patients with unresectable tumours.

Features of an irresectable tumour include contiguous organ or vascular invasion and distant metastases.

MRCP and ERCP

Gadolinium-enhanced MRI and magnetic resonance cholangiopancreatography (MRCP) are effective at identifying subtle changes in pancreatic contour and avoid the morbidity associated with endoscopic retrograde cholangiopancreatography (ERCP), which should only be used selectively when other investigations are equivocal.

Endoscopic ultrasound (EUS) is superior to CT and ERCP in detecting tumours <3cm in size and is useful in detecting vascular invasion and nodal deposits.

The best tumour marker is CA 19-9; the level corresponds to the tumour volume. It has a sensitivity of up to 90 per cent. Specificity is only 75 per cent as it is raised in other conditions, such as pancreatitis and other GI cancers. Its principal role is in the follow-up of treated patients.

3. Management

Only 10-20 per cent of patients are amenable to pancreatic resection, reflecting the advanced stage of disease at presentation.

Nearly half of all patients have distant spread of tumour and a third have locally advanced disease.

Surgical resection

Complete macroscopic resection offers the only hope for prolonging survival. Proximal pancreatoduodenectomy remains the standard operation for tumours of the head of pancreas. Some centres have adopted the pylorus-preserving proximal pancreatoduodenectomy, which retains the entire stomach.

Distal pancreatectomy and splenectomy is indicated for lesions located in the body and tail of the pancreas.

Median survival for patients undergoing resection with curative intent is 11-15 months and the five year survival rate is around 10 per cent.

Adjuvant therapy

Adjuvant chemotherapy in resected patients improves survival and should be offered to all patients undergoing resection. Gemcitabine-based therapies are currently being trialled.

Palliation

Given that 80-90 per cent of patients with pancreatic cancer have advanced disease precluding surgery, treatment in most patients is palliative chemotherapy and symptomatic relief.

Gemcitabine remains the chemotherapeutic agent of choice in patients with advanced pancreatic cancer.

The aims of symptomatic treatment are the relief of jaundice and associated pruritus, relieving or preventing duodenal obstruction.

Relief of obstructive jaundice normalises liver function and prevents the development of liver failure, reverses coagulopathy, corrects metabolic derangements and improves nutritional status and overall wellbeing. This may be achieved by endoscopic, percutaneous or surgical biliary drainage.

Endoscopic biliary stenting has a success rate of around 90 per cent. Complications relate to ERCP and include acute pancreatitis and perforation of the bile duct or duodenum.

Percutaneous biliary stenting is an alternative when endoscopic stent placement fails.

Operative drainage may be achieved by choledochojejunostomy and studies have shown this to be as effective as stenting in short-term relief of jaundice. Gastric outlet obstruction may be palliated surgically or endoscopically by placement of expandable metal stents in the duodenum.

Pain control

Appropriate analgesia should be used. Other proven methods for pain control include coeliac nerve plexus blockade, thoracoscopic division of the splanchnic nerves and external beam radiotherapy.

Developmental therapies include gene therapy, immunotherapy and anti-angiogenic therapy.

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