Interview conducted by April Cashin-Garbutt, BA Hons (Cantab) on 25th July 2012
Please could you explain what antioxidants are and where they are found?
The antioxidants that we mainly looked at were selenium, vitamin C and vitamin E. They are chemicals which inactivate pro-oxidants or free radicals. Smoking and normal metabolism can lead to the production of free radicals.
Free radicals are toxic on cells and they may induce cancer. Antioxidants are essentially chemicals that can inactivate or nullify these pro-oxidants.
Vitamin C is found mainly in citrus fruits. Vitamin E is found in vegetables oils; nuts; seeds; egg yolks and so forth. The level of selenium in food depends on the selenium content of the soil. It can be found in cereals, nuts and fish. Thus antioxidants have many different sources.
Please could you give us a brief introduction to pancreatic cancer?
In the world there are around a quarter of a million cases of pancreatic cancer each year. Unfortunately, the number of people being diagnosed with pancreatic cancer is going up.
It is a cancer which generally presents its symptoms when it is at an advanced stage. The pancreas is deep within the abdomen. The cancer often has to have spread to the liver, the lungs or other places before it displays any symptoms.
Once the diagnosis has been made then unfortunately the prognosis and outlook is very poor. It has the worst outlook of any cancer, predominantly because it presents at such an advanced stage. Most patients survive about 5 months after they have been diagnosed with pancreatic cancer.
About 1 in 10 patients are suitable to have surgery, but it is major surgery. Of the 90% left, about half may be suitable for chemotherapy. This is still very toxic and it only increases patient’s survival by about several months. For the other 50% of people, palliative care is the focus. This involves relieving pain, jaundice and any other symptoms.
Unfortunately, it is a cancer with a very bad prognosis and there are very rarely any cures available. Hence, in our work we are looking at it from the other direction. We are focussing on what may be the causes of pancreatic cancer to see if people could alter their lifestyle in order to reduce their risk.
What causes pancreatic cancer?
The complete causes of pancreatic cancer are not known. Probably about a quarter of cases are caused by cigarette smoking. Carcinogens in cigarette smoke can get to the pancreas and induce cancer.
Generally it is known that smoking is bad for heart disease, lung cancer and so forth; but very few people know that it is one of the causes of pancreatic cancer. Smoking is a definite cause of pancreatic cancer, but it is probably only responsible for a quarter of cases.
We know that people with type 2 diabetes, which tends to present in later life, are associated with an increased risk of pancreatic cancer. Nobody knows for sure why that happens but it may be as a result of the metabolic consequences of diabetes which are toxic on the pancreas.
There is emerging, but not complete, evidence that the rise in obesity in the western world may be important as well. Possibly by inducing generalised body chemical changes which may be toxic on the pancreas.
Roughly about two thirds of cases we don’t really know what the cause is, hence why we are looking at diet to see if different aspects may be involved. This is the first study in the series where we have looked at the potential protective features of antioxidants.
In the future we will look at other nutrients which may possibly be causative or protective. This is an on-going work to try to build up a complete picture of what the causes may be.
How significant was the intake of dietary antioxidants on the risk of pancreatic cancer?
We found a threshold effect of the more antioxidants people ate above a certain level the lower their risk. This meant that once you got to a particular level of consumption, it didn’t really matter how many more you ate. It seemed to be the people at very low intakes who were at increased risk of pancreatic cancer.
If you divided people into quarters across the population: the risk of the people in the top three quarters – 25%-100% intake – was, in all the antioxidants, about 2/3rd’s lower than those who didn’t.
Specifically for selenium, the people, who ate the top amounts, in the top three quarters’ risk was about half that of people who didn’t.
What seems to be important is that it is bad if you consume very low amounts of antioxidants. Once you eat more, your risk levels off. There is a very big inverse association with risk of pancreatic cancer at very low intakes of antioxidants.
Do you think the association between pancreatic cancer risk and dietary antioxidant intake was causal, and how can we find out if it is?
Currently we cannot say whether it is causal. What we need to do over the next 5 years or so is work out whether it is causal.
The research needs to progress in several areas. We need to look at other nutrients in the diet and adjust for antioxidants in them and see if the antioxidant effect is still there.
We have also only being studying a population in the UK in Norfolk. Other studies need to look at their populations as well.
The answer is we don’t know for sure and the next step forward is to look for consistencies in other populations. We also need to advance our own research in order to build a complete picture.
Was your research carried out using food diaries, and was there a problem with the subjective nature of this methodology?
The food diaries are the most accurate measure of measuring people’s regular diet in large-scale epidemiological studies where you are measuring the intake of hundreds of thousands of people.
Back in 1993-1997 in Norfolk, people completed food diaries over a week where they recorded what they ate; what brand; the recipe; the amount and the frequency.
These were then returned to the study’s headquarters in Cambridge where the information was coded by specially trained dieticians. It took about 4 hours to code each one. They used a particular database called DINER – Data Into Nutrients for Epidemiological Research.
They looked at what people had recorded in their diary and then went into the database programme of 50,000 different foods and portion sizes, to identify them and how many nutrients they contained. This allowed them to build up a complete picture for people.
Most people completed at least 200 lines of text on the food they ate and the database could be used to work out how much of each type of nutrient they were eating.
This is the only type of study in the world that has done this. Other studies, including other centres in the EPIC Study - European Prospective investigation into cancer and nutrition - used food frequency questionnaires where people were given a list of foods and they ticked how often they ate them.
The main strength of the study is the accuracy of measuring the diet with the food diaries.
If the association is causal, what do you think would be the mechanism underlying the reduction in the risk of pancreatic cancer by high dietary antioxidant intake?
We can postulate on this. Other factors such as cigarette smoking and the extremes of normal metabolism produce free radicals. These free radicals, which are present in cigarette smoke, are toxic on the pancreas. They damage the pancreas. They damage the DNA, the lipid cell membranes, proteins by removing electrons from them.
Basically these free radicals are toxic to pancreatic cells. By the antioxidants actually inactivating them, you are inactivating these potential carcinogens.
Although we can’t say it is a causal link, it is encouraging that this does not seem to be just a random chance find, there does seem to be biology to explain it as well.
Also, what suggests that it may be causal is that you have natural enzymes which have antioxidant properties anyway. These work in the body to remove free radicals. The fact that you have these and we have looked at chemicals with similar properties supports a causal link.
Do you think that vitamin supplements could help prevent pancreatic cancer, or do you think the antioxidants would need to be consumed in food?
We didn’t specifically assess the effects of supplements in this work. Although in some of the analysis we did correct for them. However, we just don’t know the answer to this question from the work that we did.
It is encouraging that you may get what antioxidants you need from a normal diet. People eating more foods with antioxidants in, rather than supplements, would be a better public health preventative intervention.
How do you think the future of our knowledge of diet and pancreatic cancer will progress?
I think what we are currently doing is generally quite encouraging. Our aim over the next five years is to look at many different aspects of diet, such as fatty acids – N-3’s N-6’s polyunsaturated fatty acids– amount of sugar in the diet, amount of red meat in the diet and so forth.
We are looking at many different aspects and the advantage that we have is that we have the most accurate way of recording people’s diet. So, we are quite enthusiastic that hopefully we will be able to build up a model of what causes and protects against pancreatic cancer.
There are other studies also going on in the world, but they don’t have the access to the food diaries, so their conclusions may not be as accurate as the ones we have. But, I think the future is encouraging for helping to elucidate the precise role of diet in this aggressive cancer.
What are your future plans for further research into this field?
We have other dietary hypotheses than antioxidants to consider. One of the ones we want to look at are N-3 polyunsaturated fatty acids in fish which may be good. They do tend to have anti-inflammatory effects which may help to reduce the risk of cancer. Some of the N-3’s may also have specific anti-cancer properties as well.
Sometimes N-6 fatty acids can be bad as they might stimulate inflammation, which may or may not be a pre-requisite for cancer. So we can look at the N-3’s as possibly good and the N-6’s as possibly bad. This is probably one of our next aims.
Antioxidants are frequently linked to positive health benefits, but can they also cause harm?
I am not aware of any negative effects of antioxidants within the normal range.
Would you like to make any further comments?
I would just like to acknowledge other people. This work only happened as 25,000 people in Norfolk filled out the diaries years ago. Also the study was run by many colleagues at Cambridge University. The Norfolk cancer charity, the big C, funded this particular work. Medical Research Council UK and Cancer Research, UK.
Overall, this was a collaboration with many people in the population and different institutions and funding bodies. We are grateful for all the people who have helped.
Where can readers find more information?
They can read our paper here: http://gut.bmj.com/content/early/2012/06/28/gutjnl-2011-301908
UK cancer research also has good information for people concerned about pancreatic cancer: http://www.cancerresearchuk.org/
About Dr Andrew Hart
Dr Andrew R Hart qualified in medicine from The University of Leeds in 1987. He undertook his training in gastroenterology in Leicester, where he was responsible for the pilot centre in the UK flexible sigmoidoscopy screening programme for colorectal cancer, the results of which were reported in The Lancet in 2010.
In 1997, he completed a master of philosophy degree in epidemiology at The University of Cambridge. His research interests are the aetiology of upper gastrointestinal cancers and inflammatory bowel disease, and the translation of these findings into clinical applications.
Dr Hart is currently the chairman of the inflammatory bowel disease study in EPIC (European prospective investigation into cancer) and in 2011 won the research prize in the oesophageal section at The British Society of Gastroenterology.