Metastatic pancreatic cancer

Summary points

* 6000 people die from pancreatic cancer each year in the United Kingdom

* Presentation is usually with painless insidious jaundice

* Median survival from diagnosis is less than six months

* Less than 15% of all pancreatic tumours are resectable, and five year survival after resection is 10-15%

* Endoscopic retrograde cholangiopancreatography and surgical biliary drainage offer good palliation of jaundice

* Cystic and endocrine pancreatic tumours are uncommon but have a better prognosis

Neoplasms of the pancreas may originate from both exocrine and endocrine cells, and they vary from benign to highly malignant. Clinically, 90% of pancreatic tumours are malignant ductal adenocarcinomas, and most of this article concentrates on this disease.

Ductal adenocarcinoma

Incidence and prognosis

Carcinoma of the pancreas has become more common in most Western countries over the past three decades, and although there is evidence of plateauing in some countries such as the United States, it still ranks as the sixth commonest cause of cancer death in the United Kingdom. Most patients are over the age of 60 years (80%) and many will have concurrent medical illnesses that complicate management decisions, particularly because the median survival from diagnosis is less than six months.

Clinical presentation

Two thirds of pancreatic cancers develop in the head of the pancreas, and most patients present with progressive, obstructive jaundice with dark urine and pale stools. Pruritus, occurring as a result of biliary obstruction, is often troublesome and rarely responds to antihistamines. Back pain is a poor prognostic sign, often being associated with local invasion of tumours. Severe cachexia, as a result of increased energy expenditure mediated by the turnout, is also a poor prognostic indicator. Cachexia is the usual presenting symptom in patients with tumours of the body or tail of the pancreas.

Examination

The commonest sign is jaundice, with yellowing of the sclera and, once the bilirubin concentration exceeds 35 [micro]mol/l, the skin. Many patients with high bilirubin concentrations will have skin scratches associated with pruritus. Patients with advanced disease have severe weight loss accompanied by muscle wasting and occasionally an enlarged supraclavicular lymph node. A palpable gall bladder suggests pancreatic malignancy, but it can be difficult to detect when displaced laterally or covered by an enlarged liver. The presence of ascites or a palpable epigastric mass usually indicates end stage disease. Full assessment of the patient's general fitness is essential to develop an individualised management plan.

Investigation

Because of the poor prognosis, care should be taken not to overinvestigate or embark on treatment strategies based on the unrealistic expectations of patients, their families, or the referring doctor. An increasing number of investigations are available, and the aim is to select patients who will not benefit from major resection by use of the fewest, least invasive, and least expensive means. The choice of investigation will vary according to local availability, particularly of newer investigations such as laparoscopic and endoscopic ultrasonography, and it remains to be seen if these techniques offer major advantages over the latest generation of computed tomography and magnetic resonance imaging scanners. Early cooperation between a gastroenterologist, radiologist, and surgeon should avoid inappropriate investigations and treatment that might interfere with patients' quality of life.

Endoscopic retrograde cholangiopancreatography is an important investigation in patients with obstructive jaundice. As well as showing biliary and pancreatic strictures, the pathology can be confirmed by taking brushings for cytology or biopsy specimens of the duct for histology. The technique can also be used to place a stent to relieve biliary obstruction. However, it is important not to use this approach before patients are properly selected for treatment.

The diagnosis can also be confirmed by fine needle aspiration guided by ultrasonography or computed tomography, but this investigation has a high rate of false negative results and is rarely necessary. Fine needle aspiration should be avoided in patients with potentially resectable tumours as it can cause seeding and spread of the tumour.

Treatment

Surgical resection does not improve survival in patients with locally advanced or metastatic disease. Turnout stage and the patient's fitness for major surgical resection are the main factors in determining optimal treatment.

Resectable tumours

Surgical resection, usually a pancreaticoduodenectomy (Whipple's procedure), is the only hope for cure. Less than 15% of tumours are suitable for resection. Very few tumours of the body and tail are resectable (3%) as patients usually present late with poorly defined symptoms.

The outcome of resection has been shown to be better in specialised pancreatobiliary centres that perform the procedure regularly than in small units. Mortality has fallen to 5-10% in dedicated units. The overall five year survival rate of 10-15% after resection remains disappointing, although survival is as high as 20-30% in some subgroups such as patients with small ([is less than] 2 cm), node negative tumours. Furthermore, the median survival of patients who have resection is 18 months compared with six months for patients without metastatic disease who do not have resection.

Preoperative biliary drainage remains controversial. The reduced complications from resolution of jaundice are offset by more inflammatory tissue at surgery and higher rates of biliary sepsis after stenting. Ideally patients with minimal jaundice should be operated on without stenting whereas those with higher bilirubin concentrations ([is less than] 100 [micro]mol/1) probably benefit from endoscopic stenting and reduction of bilirubin concentrations before surgery.

Locally advanced disease

Several options are available for the 65% of patients who have locally advanced disease. These depend on factors such as age, disease stage, and the patient's fitness. Endoscopic insertion of a plastic or metal wall stent relieves jaundice in most patients. Plastic stents are cheaper but have a median half life of three to four months compared with six months for metal stents. Blockage of a stent results in rigors and jaundice, and patients should be given antibiotics and have the stent replaced.

Surgical exploration and bypass should be used in patients who are predicted to survive longer than six months, in whom it is not certain that the tumour cannot be resected, in areas with limited access to endoscopic retrograde cholangiopancreatography, or with recurrent stent blockage or obstruction of the gastric outlet. Surgical bypass (open or laparoscopic) now has a low mortality and has the advantage of long term palliation of jaundice with a low risk of recurrence.

Metastatic disease

Patients with metastatic disease are often cachectic and rarely survive more than a few weeks. Treatment should focus on alleviation of pain and improving quality of life with input from palliative care teams. Patients with less advanced metastatic disease may require endoscopic stenting, especially if they have intractable pruritus.

Radiotherapy and chemotherapy

Despite numerous trials, radiotherapy with or without chemotherapy has not been shown to prolong survival. The search for new chemotherapeutic and immunotherapeutic drugs continues, but they currently have little role outside clinical trials.

Symptom control

A liberal policy of pain control with paracetamol, non-steroidal anti-inflammatory drugs, and opiate analgesics should be followed. In difficult cases and when increasingly large doses of opiates are required, patients should be referred to a specialist pain clinic for consideration of coeliac plexus block or thoracoscopic splanchnicectomy. Early referral to the palliative care team and Macmillan nurses, who can bridge the gap between hospital and community care, is beneficial.

Cachexia is an important cause of disability in many patients. Nutritional supplementation rarely combats weight loss, and pancreatic replacement therapy is also of doubtful benefit. Encouraging results have recently been reported with polyunsaturated fatty acids (fish oil) and non-steroidal anti-inflammatories, which seem to inhibit the inflammatory response provoked by the tumour and reduce the speed of weight loss with some survival benefit. Impaired gastric emptying is generally underdiagnosed and may be functional or mechanical in origin.

Cystic tumours