Summary
The vast majority of pancreatic cancers are adenocarcinomas (cancers arising from glandular linings). Given that the role of the pancreas is to secrete digestive juices/enzymes into the gut, it is not surprising that this is the type of cancer that arises here. There is no useful subtyping of the pancreatic adenocarcinoma into better outlook and worse.
The pancreas is also a hormone gland, secreting insulin and glucagon. Tumours of these cell types give rise to malignant apudomas.
Causes
Whilst there is not direct single cause for pancreatic cancer, there may be factors that increase an individual’s risk of developing the disease.
Smoking
On average, a smoker has 2.5 times the risk of developing pancreatic cancer compared with a non-smoker; the risk increases with the number smoked. The risk falls if the smoker gives up, eventually returning to normal after 10 to15 years. Smoking may account for a quarter of deaths from pancreatic cancer.
Obesity
There is an increased risk of pancreatic cancer in obese individuals; especially if the Body Mass Index is greater than 30kg per meter squared (the body mass index is calculated by dividing the weight in kilograms by the height squared).
Diet, coffee and alcohol
There is no convincing evidence that these have a role in the development or protection against pancreatic cancer
Chronic pancreatitis
Patients with chronic pancreatitis, which is a long term inflammation of the pancreas form infection or heavy alcohol consumption, have a raised risk of developing pancreatic cancer.
Family member with pancreatic cancer
Between one in 10 and 20 patients with pancreatic cancer have a first degree relative (parent or sibling) who has had the disease as well. Sometimes a number of member of the same family have one of a group of cancers, of which pancreatic cancer is one. In such families, the disease sometimes occurs at a younger than average age, and its development is more strongly linked to smoking.
Incidence
The incidence of pancreatic cancer is increasing, and it is currently the fifth leading cause of cancer in the Western world. There were 6860 cases in the UK during 1999 and in the USA there are approximately 37000 cases per year.
Symptoms & diagnosis: Cancer of the pancreas
The main symptoms of pancreatic cancer are pain, weight loss and jaundice.
Pain
Most patients have pain at some point in the diagnosis. It is usually in the upper part of the abdomen and may be felt in the back at the same time. Pain is not always present at the time of diagnosis and there are many ways of controlling the pain if it occurs
Weight Loss
Weight loss can be substantial; often more than 10% of the original body weight. There may also be a loss of appetite.
Jaundice
Jaundice, when the skin turns yellow, happens if the tumour blocks the thin tube that runs from the liver to the small bowel. This leads to a build up for bilirubin in the blood stream which accounts for the yellowness. The jaundice may also cause itching. As well as jaundice, the urine may turn very dark and the stools very pale.
The symptoms can vary according to where in the pancreas the tumour is.
By the time the tumour causes symptoms, it is not removable by an operation in half of cases.
Diagnosis
The critical test is the abdominal scan (usually an ultrasound scan or CT scan is performed). An ultrasound scan will show the mass/tumour in the pancreas, the dilated bile duct system above the obstruction to its drainage and may be used to perform a diagnostic biopsy via a needle.
CA 19-9 is a cell surface antigen, an oligosaccharide (related to a blood group antigen), and this is expressed particularly in gastrointestinal cells and cancers derived from these cells and secreted into the blood stream where it is measurable; pancreatic cancer cells seem a rich source for CA 19-9. Serum levels of CA 19-9 more than 100 U/ml are rarely found in benign disease (although they may occur in some forms of obstructive jaundice producing a conflict in diagnostic accuracy if the cancer of the pancreas presents with jaundice) and can be used to diagnose and monitor disease activity in pancreatic cancer.
Stages
The ‘stage’ of any cancer is a description of its size, local spread and distant spread. Defining the stage is crucial in deciding the most appropriate treatment and whether it is possible to aim to cure the disease. Scans are the most important method of working out the stage of the disease.
Oncologist will use internationally recognised systems of staging, but the principles are to decide the following:
The main concern whether the growth is confined to the pancreas or whether it has spread outside the gland and thereby is definitely incurable.
Where the disease is localised surgical removal may be curative in a minority of patients.
Where the disease is has spread to other organs, palliative chemotherapy may be useful.
Where the disease is locally infiltrative but non-metastatic, chemo-radiotherapy is considered.
Treatment & outcomes: Cancer of the pancreas
Once the staging tests have been done, the first decision to be made is whether treatment is aimed at cure or at controlling the disease and symptoms for as long as possible.
If the tumour is only in the pancreas, and the scan looks as though the tumour can be removed surgically without leaving any visible disease behind, then the standard operation is offered. The usual procedure is called a ‘pancreas preserving pancreatico duodenectomy’, also known as a Whipple’s operation. It is a major procedure, and patients need to be fit enough for the surgery and the recovery afterwards. The surgery should be done by a specialist surgeon in a unit that specialises in such operations.
There is now evidence that giving chemotherapy after a Whipple’s operation improves the probability of cure. The chemotherapy that is used is usually gemcitabine and abraxane (nano-particle, albumin bound paclitaxel) or a combination of 5-fluorouracil with oxaliplatin and irinotecan (‘Folfirinox’ chemotherapy regime) is the current optimal therapy in adjuvant situation or as therapy for advanced disease. Most oncologists aim for 6 months of treatment.
If, after the operation, it turns out that the tumour is close to the edge of what has been removed, a combination of chemotherapy and radiotherapy may improve the chance of cure. The radiotherapy is usually given daily, Monday to Friday, for 5 weeks. Simultaneously, a continuous intravenous delivery of chemotherapy is given throughout the 5 weeks of treatment. So the treatment can be given as an outpatient, a long lasting tube is place into one of the veins in the arm, and a small portable pump containing the chemotherapy is attached. This delivers the chemotherapy continuously and can be carried around, similar to carrying a portable music player. The portable pump is changed every week, and the tube is removed at the end of the treatment.
Where the patient has disease localised to the pancreas on scanning, then consideration to radical pancreatectomy should be given. Only radical surgical resection has a chance of cure and therefore this large operation must be therefore considered. In the operation called Whipple’s operation, the pancreas, duodenum and far end of stomach are removed, leaving a patients biliary tree draining into bowel. If the patient is an insulin requiring diabetic, then following the removal of the pancreas will require a pancreatic enzymal replacement. The operation is a major undertaking and undoubtedly one for which results are better when the operator specialises in the procedure and performs a large number of these operations. Before the operation, the patient must be in the best possible condition and any jaundice may be best alleviated by a stent placed at endoscopic examination through the obstructed segment of the bile duct. The jaundice is then allowed to settle before the operation itself.
Even under these circumstances, there is a small operative mortality and the ultimate cure rate only a minority, therefore this radical operation is performed in a carefully selected, perceived better outlook and localised cases.
Post-operative radiotherapy to the pancreatectomy ‘bed’ is carried out to improve local control (i.e. in the region where the pancreas lay) in selected patients (e.g. R1 resection cases – i.e. where the margins of resection are not microscopically clear).
Unfortunately, the majority of patients (up to 70% of the total) are not suitable for radical surgery as this disease often presents in too advanced a stage. Where this more advanced disease is still apparently localised in the pancreatic region and has not yet invaded the liver on PET/CT scanning, then there are some useful chemo-radiotherapy protocols which stand a reasonable chance of holding the disease at least for some time (the timing of the development of liver metastases being an unpredictable event that may not happen for some time in a significant minority of patients; it is for these that a chemo-radiotherapy programme will be of most use). For localised disease that is inoperable (usually due to encasement of that vital superior mesenteric artery – one which cannot be resected as it is supplying blood to the gut) then chemotherapy with highly focussed radiation therapy (body stereotactic radiosurgery – usually by us with Cyberknife) is used to enhance the local control and then adjuvant chemotherapy to try to reduce the appearance of liver metastatic disease – the liver being the first and most common site of such relapse
The term chemo-radiotherapy is used for a course of therapy during which both chemotherapy drug treatment of cancer is delivered at the same time as a course of conventionally fractionated radiotherapy. Let us discuss each in turn; the chemotherapy drugs for this disease are not highly effective but can cause some worthwhile regressions and can delay the occurrence of liver disease, which, as implied before, is the potentially most lethal development in the natural history of this disease. The chemotherapy is usually given by intravenous injection once three weekly, although there are some interesting protocols with longer infusions of drugs during the radiotherapy course. The radiotherapy is the usual external beam therapy with high energy x-rays; the patient lies on the treatment couch and the beam is concentrated onto the pre-mapped area using a combination of approaches. Usually, the course of radiation therapy lasts several weeks; either the patient receives chemotherapy in the first and last weeks of the radiation, or, as stated above, there may be a continuous infusion during the course. The side effects of this therapy are nausea and languor which are difficult to fully control, but standard best anti-sickness drugs certainly help.
The results of this therapy can be well worthwhile in the group of patients who will not develop rapidly progressive liver metastases, but the overall outlook for life (prognosis in medical speak) remains suboptimal.
For patients presenting with metastatic disease, the use of combination chemotherapy (as discussed above: Folfirinox or Gemcitabine with Abraxane) may provide partial regressions for some time and are reasonably well tolerated in patients without severe jaundice at the time of presentation.
Sometimes an aggressive approach in patients with jaundice, by first stenting an obstructed biliary tree by the cancer, can improve the patient’s liver function and allow chemotherapy to be later instigated.
Recently, it has been demonstrated that the tyrosine kinase inhibitor: erlotinib (tarceva) adds to the benefit of chemotherapy in advanced disease.
Other forms of attack on liver metastases include thermo-ablation, a technique which seems effective at eliminating a small number liver metastases which are less than a couple of centimetres in diameter.
Two studies (both multicentre American studies) reported at The American Society of Clinical Oncology Meeting this year looked at the addition of two ‘molecular’ agents, bevacizumab (avastin) and cetuximab, to the standard first line chemotherapy for advanced pancreatic cancer, gemcitabine. Neither found that these interesting compounds added to the response rates of the basic chemotherapy regime. This is a set back to the attempts to enhance the response rates in this disease, and surprising in that early studies had suggested that the addition of cetuximab, in particular, would improve the results.
What to do if the foregoing therapies have been tried and the cancer is resistant?
Pancreatic cancer is an ultimately difficult cancer to treat, and particularly so after the patient has had the chemotherapy that has been cited above.
For local relapse in the region of the pancreas (and without concomitant metastatic disease) then radiation options (perhaps with concomitant chemotherapy such as the oral agent: capecitabine) is useful – for highly focal lesions (e,g, around the superior mesenteric artery ) then we have found Cyberknife is useful.
However, the usual problem is that of metastatic disease (and then mainly in the liver). If the foregoing chemotherapy has been tried and failed, then it is worth getting genomic profiling of the cancer – either from a fresh tissue biopsy or from (if the cancer is releasing) cell-free DNA (cfDNA) – analysed by Next Generation Sequencing (NGS); the chance of a ‘druggable’ activating mutation being found is low but the NGS can be useful for the complete analysis of options and perhaps other reasons: – e.g. detecting mismatch repair deficiency (MMR deficiency) which predicts for response to immunotherapy
Although Immunotherapy has not been very successful in therapy of pancreatic cancer to this time, nevertheless, if there is evidence of hypermutation or MMR, then there is reason to try immunotherapy with a checkpoint inhibitor for a carefully audited period.
Other new ‘Smart’ drugs have not been very successful up to now.
Credit: Dr. P. N. Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics). Tel: +44-207-631-1632
Outcomes of cancer of the pancreas
A significant minority of patients are cured by radical surgery and adjuvant chemotherapy for anything beyond very early cases and some, who are deemed inoperable, may survive a considerable time after therapies such as the chemo-radiotherapy approach outlined above, although it has to be said that regrettably the majority of patients with this type of cancer die of their disease within three to five years.
Stenting for jaundice due to obstructed bile ducts can be very useful.
Where the disease has spread further afield, and the liver is the usual organ at risk, then chemotherapy (and the drug, gemcitabine, used alone or in combination with others e.g. oxaliplatin, would be first line (and the addition of erlotinib has been mentioned already) and second line regimes include the triplet, fluorouracil, cis-platinum and epirubicin used in combination); however, nothing is curative and it is necessary for the doctor to assess the progress of the chemotherapy by repeat scanning and blood tests every few courses.
Screening for pancreatic cancer
There is no routine screening for this cancer. However, the realisation of the malignant potential for some pancreatic cysts has brought realisation that serial scanning of these cases (usually picked up incidentally) is worthwhile – acting by surgery if there is progression.
Research into techniques that are able to detect genetic changes in pancreatic samples are ongoing and may have a role in the future for families where there is a possible inherited risk.