Elsevier

The Lancet

Volume 363, Issue 9414, 27 March 2004, Pages 1049-1057
The Lancet

Seminar
Pancreatic cancer

https://doi.org/10.1016/S0140-6736(04)15841-8Get rights and content

Summary

Pancreatic cancer remains a major unsolved health problem, with conventional cancer treatments having little impact on disease course. Almost all patients who have pancreatic cancer develop metastases and die. The main risk factors are smoking, age, and some genetic disorders, although the primary causes are poorly understood. Advances in molecular biology have, however, greatly improved understanding of the pathogenesis of pancreatic cancer. Many patients have mutations of the K-ras oncogene, and various tumour-suppressor genes are also inactivated. Growth factors also play an important part. However, disease prognosis is extremely poor. Around 15ā€“20% of patients have resectable disease, but only around 20% of these survive to 5 years. For locally advanced, unresectable, and metastatic disease, treatment is palliative, although fluorouracil chemoradiation for locally advanced and gemcitabine chemotherapy for metastatic disease can provide palliative benefits. Despite pancreatic cancer's resistance to currently available treatments, new methods are being investigated. Preoperative chemoradiation is being advocated, with seemingly sound reasoning, and a wider role for gemcitabine is being explored. However, new therapeutic strategies based on the molecular biology of pancreatic cancer seem to hold the greatest promise.

Section snippets

Epidemiology and molecular epidemiology

In many studies risk factors associated with pancreatic cancer have been explored (panel). The only risk factors consistently reported are age and cigarette smoking.2 Cigarette smoking is estimated to account for 25ā€“29% of pancreatic cancer incidence, with reported odds ratios ranging from 1Ā·6 to 5Ā·4.3 Another risk factor for pancreatic cancer might be family history.4, 5 Several genetic syndromes are associated with an increased risk of pancreatic cancer, including hereditary pancreatitis,

Molecular pathology

In the past few years, our knowledge of the pathogenesis of pancreatic cancer has been significantly advanced due to the rapid accumulation of our understanding of the molecular biology of the disease. Like many other malignant diseases, pancreatic ductal carcinoma results from the accumulation of acquired mutations (table 1). The multigenic nature of most pancreatic ductal cancers is reflected in the abnormalities of three broad classifications of genesā€”ie, oncogenes, tumour-suppressor genes,

Diagnosis and management

For most patients diagnosed as having cancer of the exocrine pancreas life expectancy is measured in months. Three factors underlie this poor outlook. First, pancreatic cancer disseminates to distant sites early in its natural history. Second, as the disease progresses it is associated with substantial morbidity, characterised by cachexia and asthaenia. Third, pancreatic cancer is resistant to most forms of treatment studied to date.

Diagnosis and staging

For patients who present with painless jaundice, the diagnostic work-up is generally straightforward. CT of the abdomen is recommended as the first diagnostic procedure rather than endo-scopic retrograde cholangiopancreatog-raphy because the appearance of the biliary tree and the pancreas are better defined before endoscopic retrograde cholangiopancreatography and stent placement. Once the biliary tree has been manipulated, visualisation of small tumours might be obscured on CT because of the

Preoperative chemoradiation for resectable pancreatic cancer

In single-institution and multicentre trials 20ā€“30% of patients who undergo pancreaticoduodenectomy are not eligible for postoperative chemoradiation. Therefore, preoperative chemoradiation for patients with resectable disease has been advocated by some groups. The rationale for this approach is sound. First, all patients who have potentially resectable disease receive the treatment. Second, a subset of patients will develop overt metastatic disease in the 8ā€“12 weeks of preoperative treatment

The way forward

Pancreatic cancer will remain a challenging problem into the 21st century. However, improvements in early detection, screening, and staging of patients will be expected to facilitate progress in the management of patients with this disease. Most promising, is the potential to base treatment on our rapidly evolving understanding of the molecular biology of pancreatic cancer. Already various agents are being developed that target signal-transduction pathways or nuclear transcription factors. In

Search strategy and selection criteria

We identified reports by MEDLINE search through the PubMed database (1986ā€“2002) by combining the keywords ā€œpancreatic cancerā€ with the following topics: carcinogenesis, angiogenesis, progression, metastasis, pathology, pathobiology, pathophysiology, molecular genetics, and genetics. We searched citation lists in retrieved papers to identify additional references. Papers were selected on the basis of the best available evidence for each specific question discussed. To limit the number of

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