Pancreatic Cancer symptoms, diagnosis and treatment

While most patients present with obstructive jaundice, weight loss and back pain, pancreatic cancer often has vague presenting symptoms, developing at a late stage of disease 1-,5. Patients may also present with late onset diabetes mellitus and acute pancreatitis 6. While there is currently insufficient evidence to support the introduction of population screening for pancreatic cancer 7 there may be a place for secondary (targeted) screening for high risk groups in the future 8,9.

Carbohydrate antigen 19-9 (CA 19-9) levels are often raised in people with obstructive jaundice, chronic pancreatitis and pancreatic, biliary and gastrointestinal cancers 10,11. While people with early tumours often have normal levels of CA 19-9, it remains the most accurate and frequently used biomarker for pancreatic cancer. It is particularly useful in assessing treatment response in advanced cases 12,13 and identifying early recurrence following surgery 14.

While trans-abdominal ultrasound is often used as the first line of patient investigation and can detect most tumours larger than 2cm in size 15. Contrast enhanced computerised tomography (CE-CT scan) is the current gold standard and can achieve diagnostic rates of 97% 16. Magnetic resonance imaging (MRI) is similarly effective 17 but less easy to interpret. It is usually reserved for patients who cannot receive CT contrast. Endoluminal ultrasound (EUS) is valuable in imaging early pancreatic tumours as small as 2-3mm 18,19.

For diagnostic biopsy, percutaneous fine needle aspiration (FNA) has good sensitivity and specificity 20 but there are concerns about its role in intra-peritoneal and needle tract seeding 21. The incidence of peritoneal carcinomatosis has been shown to be less following EUS guided biopsy 22. Laparoscopy can be used to assess patients prior to surgery and also to obtain biopsy material. Laparoscopic ultrasound (LUS) enables intra-operative scanning of the liver and pancreas, correctly predicting resectability in >90% of cases. However, recent improvements in multislice CT scanning mean that diagnostic laparoscopy is now used less 23.

Major pancreatic centres use a combination of multislice CT with EUS or Endoscopic Retrograde Cholangio-Pancreatography (ERCP) or Magnetic Resonant Cholangio-Pancreatography (MRCP) and selective use of laparoscopy combined with LUS to stage tumours. The pathological staging of pancreatic ductal adenocarcinoma is based on the 2002 International Union Against Cancer (UICC) tumour node metastasis (TNM) classification 24.

Cancer can occur in the head, the body, or the tail of the pancreas. Around 70% of tumours are in the head of the pancreas and these are often easier to remove.

The only potentially curative treatment for pancreatic cancer is surgery. Patients with liver or peritoneal metastases and distant lymph node metastases are unlikely to be considered for resection 25.

The classical Kausch-Whipple procedure and the pylorus-preserving procedure are the most common approaches for cancer of the head of pancreas. Tumours of the body and tail require left-sided resections. Total pancreatectomy is not routinely performed for cancer of the pancreatic head, but may be used for more widespread disease or intra-ductal papillary mucinous neoplasms. The majority of patients develop disease recurrence within 1 to 2 years after resection 26-,28.

While evidence for benefits of adjuvant therapy has been lacking, chemoradiotherapy and follow-on chemotherapy have been used commonly in America for a number of years 29-,31. Few randomised studies have looked at these treatments and, with the exception of ESPAC-1 (a European randomised controlled trial to assess the roles of adjuvant chemotherapy and adjuvant chemoradiation in resectable pancreatic cancer), most studies have been underpowered. The ESPAC-1 trial showed a survival advantage for adjuvant chemotherapy but not adjuvant chemoradiotherapy 32. Early results from a randomised trial reported an almost doubling of median disease free survival for patients receiving adjuvant gemcitabine compared with surgery alone 33.

The ESPAC-3 trial is comparing gemcitabine and 5-Flouroracil & Folinic Acid (5FU/FA). A recent meta-analysis of adjuvant therapy concluded that chemotherapy is an effective adjuvant therapy for pancreatic cancer, with a survival advantage for chemoradiotherapy in patients with positive margins 34.

The majority of patients with pancreatic cancer present with inoperable disease. Symptom control and quality of life are extremely important in these patients as well as therapies aimed at extending survival. The main symptoms which require palliation are pain, obstructive jaundice and duodenal obstruction.

Randomised trials have demonstrated a survival benefit in patients who receive chemotherapy 35-,38. While 5FU has been the most widely used chemotherapy drug in patients with advanced pancreatic cancer, the improved survival and clinical benefit demonstrated for gemcitabine 39 has led to its adoption as standard first-line treatment. With the exception of erlotinib 40, no survival advantage has been demonstrated for gemcitabine in combination with a variety of cytotoxic and novel agents. 41-,44

Capecitabine has shown encouraging results in phase II trials 45. The Cancer Research UK GEM-CAP phase III trial compared capecitabine and gemcitabine with gemcitabine alone and the results are expected to change clinical practice. They show a significant improvement in overall survival with the addition of capecitabine to gemcitabine with acceptable levels of toxicity.

Benefits for combination therapy compared to chemoradiotherapy or chemotherapy alone are not widely established. Several small randomised studies have shown slight or no improvements in median survival with chemoradiotherapy plus follow-on chemotherapy vs. chemotherapy alone 30,46 and results from a number of small randomised studies of radiotherapy vs. radiotherapy plus follow-on chemotherapy have shown inconsistent results 47-,49.