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Pancreas Cancer - The Biggest Challenge of All

Background - the disease

The incidence of pancreatic cancer (pancreatic ductal adenocarcinoma) has risen over recent decades and is now one of the commonest causes of cancer death in Europe, USA and other industrialized countries. Worldwide pancreas cancer is responsible for at least 220,000 deaths each year - from Europe there are 60,139 new cases per year, representing 10.4% of all digestive tract diseases and 64,801 deaths per year in the USA.

The UK has an especially high incidence of 10-12 per 100,000 population per year with. There are around 7,000 deaths per year in the UK alone and unfortunately the prognosis is extremely poor. Survival rate for patients is between 4 and 12 months and at five years only 5 in 1,000 patients have a chance of survival.

More than half the patients diagnosed with pancreatic cancer are below the age of 70.

The present treatment for pancreatic cancer is surgery but these results are shown to be poor compared to other cancers. If surgery is not an option other treatment modalities include chemotherapy with cytotoxics (cancer drugs) and radiotherapy (X-ray treatment)but pancreatic cancer is fairly resistant to these forms of treatment.

The reasons for poor prognosis

Why is pancreatic cancer such a terrible disease? There are three main reasons for this.

  • Symptoms that bring attention to the presence of a cancer in the pancreas tend to occur rather late for most patients. By the time a diagnosis is reached the cancer has already spread too far for cure. The symptoms are usually those of non-specific abdominal upset and many doctors often consider the possibility of pancreas cancer at a stage when the cancer is far advanced.
  • Surgery to remove pancreatic cancer is very complicated. The pancreas is a small rather flat solid organ ('pancreas' is a Greek word which means 'all meat') that is deeply situated in the middle of the abdomen behind the stomach. It is criss-crossed by vital vessels that add to the difficulty of safe dissection. The prolonged and complex nature of the operation (the wide extent of the resection, the multiple gastrointestinal tract reconstructions and its long duration) leads to a high post-operative morbidity.
  • For reasons that are incompletely understood the biology of pancreatic cancer makes it an unusually aggressive cancer. Even a small tumour of less than two centimetres in diameter is likely to have spread extensively by the time of diagnosis. Tumours of this or a similar size can lead to rapid and dramatic weight loss (cachexia) and death for reasons that cannot be entirely explained in scientific terms. Why does such an apparently trivial tumour volume kill so readily? Why is this cancer so resistant to treatments (surgery, chemotherapy and radiotherapy) that are relatively effective in many other solid cancer types?

Sadly, the pessimistic outcome from pancreatic cancer has led to the perception that pancreas cancer is too serious a condition to do much about either clinically or scientifically. In recent years however, Cancer Research UK has done a great deal in supporting research that is changing the perception of this cancer by clinicians and research scientists. At last this is beginning to give a glimmer of hope to patients.

What causes pancreatic cancer?

Like many cancers the risk increases with increasing age but this can only be considered as a background factor to the real causes. So far only three strong causative associations have been established. These are tobacco smoking, chronic pancreatitis and genetic factors.

  • Tobacco smoking raises the risk of developing pancreatic cancer by approximately two-fold compared to the general population. Although this risk is not as great as that for developing lung cancer, which is approximately twenty-fold, if people did not smoke then there would be a reduction in pancreatic cancer incidence of about 30%. This would be equivalent to saving over 13,000 lives each year from this cancer in Europe alone.
  • Chronic pancreatitis is almost a life-long disease of the pancreas that is characterized by chronic inflammation and fibrosis. The clinical consequences are debilitating pain often leading to opiate dependency, pancreatic exocrine insufficiency leading to malnutrition and pancreatic endocrine failure and insulin dependent diabetes mellitus. Some studies have indicated a 5-15-fold lifetime risk of contracting pancreatic cancer but this conclusion has been contradicted by other studies. A greater insight into this risk of pancreatic has been obtained by studying patients with Hereditary Pancreatitis (HP). This is an autosomal dominant condition (with 80% penetrance) characterized by the onset of symptoms from an early age. The European Registry for Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC), which is based in Liverpool, has collected over 150 families with HP. The EUROPAC study has revealed a standardized incidence ratio for pancreatic cancer of around 100, translating into a 40% incidence of pancreatic cancer by the age of 70 years.
  • A considerable amount is now known about the genetics and molecular biology that defines pancreatic cancer. The molecular fingerprint of pancreatic cancer is characterized by a unique tetrad of changes: mutational activation of the oncogene KRAS (around 80%) and inactivation by various mechanisms of three tumour suppresser genes known as p53 (60-80%), SMAD4 (40-50%) and p16 (80-90%). In addition other tumour suppresser genes are inactivated in a small percentage of cases notably the breast cancer gene BRCA2. Pancreatic cancer is seen in a number of familial cancer syndromes, including familial atypical multiple mole and melanoma (FAMMM), breast-ovarian cancer families, ataxia telangiectasia (AT) and hereditary non-polyposis colon cancer (HNPCC). There are also familial clusters of pancreatic cancer, some with an apparent autosomal dominant pattern called familial pancreatic cancer (FPC). These families are quite rare and are also being collected by EUROPAC. Identification of the causative gene would be a major breakthrough in furthering the understanding of the molecular pathogenesis of this cancer.

Progress In The Treatment Of Pancreatic Cancer - Surgery for Cure

Surgeons have made a major contribution to changing the nihilistic approach to this cancer. At one time resection for pancreatic cancer was associated with post-operative mortality rates of around 20-50%. Even relatively recent studies from two large UK Regions (the West Midlands and Yorkshire) have revealed post-operative mortality rates of 20-30% if the surgery was performed in District General Hospital by non-specialist consultant surgeons. In contrast contemporary studies reveal a mortality average of <6% if pancreatic cancer resections are performed by specialist pancreatic surgeons. What has also been worrying is the small number of actual resections done by non-specialists amounting to only 2.6-4.0% of cases. In specialist units the resection rates are much higher and cannot be just attributed to biased referral. Resection is worthwhile with five-year survival rates of 10-20% or more. These contrasting data have now led to Government Guidelines that all pancreatic cancer surgery is centralized into specialist units with multidisciplinary teams serving populations of 2-4 million. Thus there has been a remarkable turn around in the perception of this disease within the past few years to the extent that it has become a focus of Government policy.

Treatment of advanced disease.

The majority of patients present with obstructive jaundice and this can now be treated without dangerous surgery. The jaundice can be relieved by stenting the strictured bile duct endoscopically or radiologically. At one time surgery was the only way of dealing with this problem but at great cost in terms of operative mortality (20% or more) and hospital stay. Now with improved methods of diagnosis and pre-operative staging using combinations of computed tomography, endoscopic retrograde cholangio- pancreatography, endoluminal ultrasound, laparoscopy and fine needle aspiration for cytology, patients need only have surgery for curative resection. Although advanced pancreatic cancer is relatively resistant to chemotherapy drugs we now know that SURVIVAL IS INCREASED with drug treatment. Moreover there is evidence that aspects of the quality of life will be better preserved with the use of certain types of chemotherapy. The search is now on to identify the best combination of drugs to use in pancreatic cancer, particularly focusing on the new generation of anti-cancer drugs.