Pancreas cancer accounts for 2.3% of new cancers in Australia. The age standardised incidence is 6.6 per 100,000 persons, and mortality is similar at 5.6 per 100,000 as the majority of people will not survive.
The major histological subtype is adenocarcinoma arising from epithelial cells in the pancreatic duct. Cancers arising from neuroendocrine cells in the pancreas (NETs) account for just less than 5% of pancreatic cancers. Survival at 1 year is only 17% of Australians with pancreatic adenocarcinoma, compared with 78% with pancreatic NETs.
Up to 20% of pancreatic adenocarcinoma may be attributed to inherited risk. Pancreatic adenocarcinoma can cluster in families due to an unknown predisposition, but can also occur in people with recognised cancer syndromes such as BRCA2, BRCA1, Peutz-Jegher syndrome, Familial Atypical Multiple Mole Melanoma, Ataxia-Teleangectasia, Lynch syndrome, and Familial Adenomatous Polyposis. Risk of pancreatic cancer is also higher in people with hereditary pancreatitis.
Rates of pancreatic adenocarcinoma are higher in people with diabetes, although in some cases this is a consequence of the disease rather than the cause of it. Environmental factors associated with pancreas adenocarcinoma include smoking and obesity.
A small proportion of pancreatic NETs are recognised in the inherited syndromes Multiple Endocrine Neoplasia 1, von Hippel Lindau syndrome, Tuberous Sclerosis and Neurofibromatosis Type 1.
Like all cancers, pancreatic cancer is caused by a series of changes in genes in a single cell that leads to malignant transformation. In a few cases the gene changes are sequential in a manner similar to colon adenocarcinoma, an observation supported by two recognised pre-cancerous states called intraductal pancreatic mucinous neoplasia (IPMN) and pancreatic intraepithelial neoplasia (PanIN). However, in the majority of cases the pattern or sequence of gene changes that lead to the cancer is not known.
Pancreas adenocarcinomas are genetically heterogenous, and multiple oncogenes and tumour suppressor genes have been identified by whole genome mapping of large numbers of pancreatic adenocarcinomas. The genes implicated in pancreas cancer control fundamental cell characteristics such as growth, chromatin remodelling and DNA damage repair.
The most common symptoms are jaundice, pain and weight loss. These usually occur late, and approximately 80% have cancer that cannot be resected at diagnosis. Jaundice occurs because of obstruction of the biliary tree by the primary mass or a metastasis. Pain is typically epigastric and radiates to the back or sides, and can be difficult to manage if due to invasion of nerves in the coeliac plexus. Weight loss can be due to high tumour metabolism or pancreatic insufficiency.
Diagnosis and staging
The diagnostic test is usually cross-sectional imaging with an abdominal CT scan. This might supplement ERCP in cases of biliary obstruction. Biopsy is usually required, but is technically difficult and false negatives are common. In some settings therefore the radiological appearances and an elevated tumour marker CA19-9 will be the basis of the diagnosis.
Staging is conducted using the TNM system.
- Stage 1 – within the pancreas
- Stage 2 – extends beyond the pancreas by invasion or nodal metastases, but does not involve the coeliac axis or superior mesenteric artery (i.e. technically resectable)
- Stage 3 – involves the coeliac axis or superior mesenteric artery (i.e. unresectable)
- Stage 4 – distant metastases
Survival from pancreatic adenocarcinoma is poor. At 5 years after surgery, less than 30% of patients with stage 1 disease will be alive, and only 10% with Stage 2 disease. Median survival in Stage 3 and 4 disease is approximately 6 months, but less without any treatment.
The outcome is often more favourable in pancreatic NETs, although not in all cases. Small low grade single NETs can be considered cured after resection. However, by contrast, high grade metastatic pancreatic NETs have a prognosis similar to adenocarcinoma.
Patients with Stage 1 and 2 pancreatic adenocarcinoma who are fit enough for an operation will undergo surgical resection aiming for cure. Resection typically requires pancreaticoduodenectomy (Whipple’s procedure), although some localised cancers in the pancreatic tail might be suitable for partial pancreatectomy. After surgery, patients will also be offered adjuvant chemotherapy, which aims to treat any microscopic metastatic disease. In pancreatic adenocarcinoma this gives a small increase in survival. Sometimes adjuvant radiotherapy is used to reduce the rate of local relapse.
Patients with Stage 3 and 4 pancreatic adenocarcinoma do not have resectable cancers by definition. The aim of treatment is palliation to increase duration of survival and minimise symptoms. Options include chemotherapy, and occasionally radiotherapy. Chemotherapy with single agent Gemcitabine is only mildly effective at best, providing a small improvement in symptom control and survival up to a median of 6 months. More recently the addition of nab-paclitaxel or the use of multidrug regimens such as FOLFIRINOX has increased median survival up to 9-11 months in patients physically strong enough to tolerate them. In general, the role for radiotherapy is more limited in pancreatic cancer than most other cancers because of the systemic nature of the disease, and rapid progress at sites outside the radiation field.
Patients with pancreatic NETs have a very variable outcome and management. Management options include traditional surgery and chemotherapy, but also peptide receptor radionuclide therapy and somatostatin analogues in some metastatic cases.
Supportive care without additional treatment is a realistic treatment option that should be discussed with all patients with unresectable or metastatic pancreatic adenocarcinoma. This would include analgesia, maintaining patency of the biliary tree with biliary stenting, pancreatic enzyme replacement and nutritional supplementation.
Patients who have undergone resection of pancreas cancer are closely followed with history, clinical examination, liver function test, plasma CA19-9 and CT scans. Detection of relapse provides an opportunity for palliative chemotherapy, but not cure.
The follow-up of patients with pancreatic NETs varies widely depending on the size, grade and stage of the resected tumour.
Screening and prevention
There is no proven role for population level screening. There is no known method of pancreas cancer prevention.
A slim 62 year old man with no other medical problems is referred to your surgical clinic with epigastric pain radiating to his back. On examination you get the impression of an epigastric mass. You order a CT scan which shows an irregular mass in the head of the pancreas which extends beyond the pancreas, but does not involve the celiac axis or any blood vessels. There are no metastases. CA19-9 is only slightly elevated.
- What is the next diagnostic test?
- Endoscopic Ultrasound-guided biopsy
- What Stage is this cancer?
- Stage 2
- How would you treat this patient?
- Pancreaticoduodenectomy followed by adjuvant chemotherapy. Some centres would also offer radiotherapy.
- What is the chance of survival at 5 years?
- Approximately 10%
An otherwise well 48-year-old woman is referred to your medical oncology clinic by a gastroenterologist. She had presented to hospital with jaundice and CT scan showed a mass in the head of the pancreas, which was compressing the distal common bile duct, causing biliary dilatation. The scan also showed enlarged lymph nodes around the pancreas and multiple lesions in the liver consistent with metastases. A stent was successfully inserted into the bile duct and jaundice resolved. Biopsy of one of the liver lesions was consistent with a pancreatic adenocarcinoma.
- What stage is this cancer?
- Stage 4
- You have discussed best supportive care, but she wants active anti-cancer treatment. What would you advise?
- Chemotherapy (with gemcitabine with nab-paclitaxel or FOLFIRINOX).
- What is the median survival for people in her situation, if treated?
- 9 months using gemcitabine with nab-paclitaxel, or 11 months using FOLFIRINOX
- Her family history shows a mother and a maternal aunt with breast cancer. What inherited cancer syndrome should you consider first?
- BRCA2 then BRCA1
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