Pass the Aspirin

And so you should if you’ve got a headache – unless, of course, you prefer paracetamol. There can scarcely be anyone who hasn’t resorted to a dose of slightly modified salicylic acid (For the chemists: its hydroxyl group is converted into an ester group (R-OH → R-OCOCH3) in aspirin), given that the world gobbles up an estimated 40,000 tonnes of the stuff every year. It’s arguable, therefore, that an obscure clergyman by the name of Edward Stone has done more for human suffering than pretty well anyone, for it was he who, in 1763, made a powder from the bark of willow trees and discovered its wondrous property. The bark and leaves had actually been used for centuries – back at least to the time of Hippocrates – for reducing pain and fever, although it wasn’t until 1899 that Aspirin made its debut on the market and it was 1971 before John Vane discovered how it actually worked. He got a Nobel Prize for showing that it blocks production of things called prostaglandins that act a bit like hormones to regulate inflammation (for the chemists – again! – it irreversibly inactivates the enzyme cyclooxygenase, known as COX to its pals).

Daily pill popping

Aside from fixing the odd ache, over the years evidence has gradually accumulated that people at high risk of heart attack and those who have survived a heart attack should take a low-dose of aspirin every day. In addition to decreasing inflammation (by blocking prostaglandins) aspirin inhibits the formation of blood clots – so helping to prevent heart attack and stroke. Almost as a side-effect the studies that have lead to this being a firm recommendation have also shown that aspirin may reduce the risk of cancers, particularly of the bowel (colorectal cancer). Notably, Peter Rothwell and colleagues from Oxford showed that daily aspirin taken for 10 years reduced the risk of bowel cancer by 24% and also protected against oesophageal cancer – and a more recent analysis has broadly supported these findings. In addition they have also found that aspirin lowers the risk of cancers spreading around the body, i.e. forming distant metastases.

Why is aspirin giving us a headache – again?

First because a large amount of media coverage has been given to a report from Leiden University Medical Center, presented at The European Cancer Congress in September, that used Dutch records to see whether taking aspirin after being diagnosed with gastrointestinal cancer influenced survival. Their conclusion was that patients using aspirin after diagnosis doubled their survival chances compared with those who did not take aspirin. Needless to say, these words have been trumpeted by newspapers from The Times to the Daily Mail in the usual fashion (“Aspirin could almost double your chance of surviving cancer”). Unfortunately we can’t lay all the blame on the press: the authors of the report used the tactic of issuing a Press Release, a thoroughly reprehensible ploy for gaining attention when the work involved has not been peer reviewed. (The point here for non-scientists is that you can stand up at a meeting and say the moon’s made of blue cheese and it’s fine. Only after your work has been assessed by colleagues in the course of the normal publication process does it begin to have some credibility). So there’s a problem here, with what was an ‘observational study’, as to just what the findings mean – and the wise thing is to wait for the results of a ‘randomised controlled trial’ that is under way. 

The second source of mental strain is down to the ferociously named United States Preventive Services Task Force that has just (September 2015) come up with the recommendation that we should take aspirin to prevent bowel cancer. Why should we pay any attention? Because the ‘Force’ are appointed by the US Department of Health and they wield great influence upon medical practice – and because it’s the first time a major American medical organization has issued a broad recommendation to take aspirin to prevent a form of cancer.

In this latest oeuvre they confirm that the well-known risks attached to aspirin-eating (ulcers and stomach bleeding) are out-weighed by the protection against heart disease in those between the ages of 50 and 69 who are at high risk (e.g., have a history of heart attacks). If you feel your heart can take the strain you can find out your risk by using the National Heart, Lung, and Blood Institute’s online risk assessment tool. To get an answer you need to know your age, sex (i.e. gender, as its called these days), cholesterol levels (total and high density lipoproteins, HDLs – they’re the ‘good’ cholesterol), whether you smoke and your systolic blood pressure (that’s the X in X/Y).

This is such a critical issue it’s worth seeing what the Task Force actually said: “The USPSTF recommends low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and colorectal cancer in adults ages 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years.”

If you’re younger than 50 or over 70 you’re on your own: the Force doesn’t recommend anything. And if you’re 60 to 69 the wording of their advice is wonderfully delicate: The decision to use low-dose aspirin to prevent CVD (cardiovascular disease) and colorectal cancer in adults ages 60 to 69 years who have a greater than 10% 10-year CVD risk should be an individual one.”

So that’s cleared that up …

Er, not quite. Various luminaries have been quick to demur. For example, Dr. Steven Nissen, the chairman of cardiology at the Cleveland Clinic has opined that the Task Force “has gotten it wrong.” In other words aspirin does more harm than good – though he might be a bit late as seemingly an astonishing 40% of Americans over the age of 50 take aspirin to prevent cardiovascular disease. I reckon that’s about 40 million people. Mmm … so that’s where the 40,000 tonnes goes (well, about one-fifth of it).

What’s the advice?

We’re more or less where we came in. I take an aspirin, or more usually a paracetamol, when I’ve got a stonking headache. Otherwise I wouldn’t take any kind of pill or supplement unless there is an overwhelming medical case for so doing. And pill-poppers out there might note the findings of Eva Saedder and her pals at Aarhus University that the single, strongest independent risk factor for drug-induced serious adverse events is the number of drugs that the patient is taking.

References

Rothwell, P. et al. (2012). Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials, Lancet DOI:1016/S0140-6736(11)61720-0

Rothwell P. et al. (2012). Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trial, Lancet DOI:1016/S0140-6736(12)60209-8

Lancet editorial on Rothwell et al. 2011.

Algra, A. and Rothwell, P. (2012). Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials, Lancet Oncology DOI:10.1016/S1470-2045(12)70112-2.

Frouws M et al. Aspirin and gastro intestinal malignancies; improved survival not only in colorectal cancer? Conference abstract. European Cancer Congress 2015

Press release: Post diagnosis aspirin improves survival in all gastrointestinal cancers. The European Cancer Congress 2015. September 23 2015

Cuzick J, Thorat MA, Bosetti C, et al. Estimates of benefits and harms of prophylactic use of aspirin in the general population. Annals of Oncology. Published online August 5 2014

U.S. Preventive Services Task Force Draft Recommendation Statement: Aspirin to Prevent Cardiovascular Disease and Cancer

Saedder, E.A. et al. (2015). Number of drugs most frequently found to be independent risk factors for serious adverse reactions: a systematic literature review. British Journal of Clinical Pharmacology 80, 808–817.

 

Obesity and Cancer

Science, you could say, comes in two sorts. There’s the stuff we more or less understand – and there’s the rest. We’re pretty secure with the earth being round and orbiting the sun, the heart being a pump connected to a network of tubes that keeps us alive, DNA carrying the genetic code – and a few other things. But human beings are curious souls and we tend to be fascinated by what we don’t know and can’t see – why the Dance of the Seven Veils caught on, I guess.

Scientists are, of course, the extreme example – they spend their lives pursuing the unknown (and, as Fred Hoyle gloomily remarked, they’re always wrong and yet they always go on). But in this media era they pay a public price for their doggedness because they get asked the pressing questions of the moment. Is global warning going to finish us off soon, why is British sport generally so poor and – today’s teaser – does being fat make you more likely to get cancer?

A few facts go a long way

The major cancers have become familiar because the numbers afflicted are so staggering – but the one good thing is that the epidemiology can tell us something about the disease. Thus for cancers of the bowel, endometrium, kidney, oesophagus and pancreas and also for postmenopausal breast cancer there is clear evidence that being overweight or obese makes you more susceptible. In other words, if you compare large groups with those cancers to equally large numbers without, the disease groups contain significantly more people who are fat. We should add that the above list is conservative. A number of other cancers are almost certainly more common in those who are overweight (brain, thyroid, liver, ovary, prostate and stomach tumours as well as multiple myeloma, leukaemia, non-Hodgkin lymphoma and malignant melanoma in men).

Sizing up the problem

The usual measure is Body Mass Index (BMI) – your weight (in kilograms) divided by the square of your height (in metres). A BMI of 25 to 29.9 and you’re overweight; over 30 is obese. In England in 2009 just over 61% of adults and 28% of children (aged 2-10) were overweight or obese and of these, 23% of adults and 14% of children were obese. And every year these figures get bigger.

How big is the risk?

Impossible to say exactly – for one thing we don’t know how long you need to be exposed to the risk (i.e. being overweight) for cancer to develop but in 2010 just over 5% of the total of new cancer cases in the UK was due to excess weight. That’s another conservative estimate, but it means at least 17,000 out of 309,000 cases, with bowel and breast cancers being the major sites.

What’s going on?

Showing an association is a good start but the important thing is to find out which molecules make that link. For obesity and cancer detail remains obscure but broad outlines are emerging, summarised in the sketch. In obesity fat (adipose) cells increase in both number and size (so it’s a double problem: more cells – and the fat cells themselves are fatter). As this happens other cells are recruited to adipose tissue and, from this cellular cooperative, signalling proteins are released that have the potential to drive tumours. This picture is similar to that of the microenvironment of tumours themselves, where many types of cell infiltrate the new growth. Initially this inflammatory and immune response aims to kill the tumour but if it fails the balance of signalling shifts so that it actually helps the tumour grow. In addition to signals from fat cells themselves, obesity is usually associated with increased levels of circulating growth hormones (e.g., insulin) and of lipids, both of which may also promote tumour development.

Thus many signals with cancerous potential arise in obese individuals. In principle these could initiate tumour growth or they could accelerate it in cancers that have started to develop independently of obesity. So it is complicated – but at least as new signalling strands emerge they offer new targets for drug therapy.

In obesity abnormal signals from fatty tissue can combine with others arising from perturbed metabolism to help cancers develop

Reference

World Cancer Research Fund (WCRF) Panel on Food, Nutrition, Physical Activity, and the Prevention of Cancer (WCRF, 2007).

Surviving cancer in the UK and other places

Over the years a number of surveys have concluded that, despite progressive improvements, the UK five-year survival rates for common cancers are worse than the European average by 5 to 15%. The most recent of these has just emerged, comparing survival from four of the most important cancers – breast, bowel, lung and ovarian – at one and five years following diagnosis between 1995 and 2007 in the UK, Denmark, Norway, Sweden, Australia and Canada. Their conclusion was that, despite improvements in survival rates, the disparities remain and that the life expectancy of cancer patients in the UK is shorter than in other countries.

Before we get too downcast by these facts we should note that the UK five-year survival rate for breast cancer, for example, has now reached 82% whereas 40 years ago it was 40%. However, the UK clearly has a problem for which there might be three broad causes: (1) later diagnosis, (2) more aggressive forms of the disease, (3) variable standard of treatment.  It seems probable that all three play a part.

Where you live in the UK bears significantly on your cancer risk.  The National Cancer Intelligence Centre has produced a Cancer Atlas that compares incidence and death rate from the 21 most common cancers in different counties of the UK.  The differences reflect levels of smoking, drinking, poor diet and social deprivation and show that regions of northern England and Scotland are cancer ‘hot spots’.  Their estimate is that if the worst areas could be converted to the best there would be 25,000 fewer new cases and 17,000 fewer deaths a year: with about 156,000 cancer deaths per year that would represent an 11% decrease.

One sensible plan might be to concentrate cancer care into a smaller number of centres of expertise, along the lines of what has been proposed for heart disease.

World, USA and UK cancer deaths 2008.

Reference

Coleman, M.P., Forman, D., Bryant, H., Butler, J., Rachet, B., Maringe, C., Nur, U., Tracey, E., Coory, M., Hatcher, J., McGahan, C.E., Turner, D., Marrett, L., Gjerstorff, M.L., Johannesen, T.B., Adolfsson, J., Lambe, M., Lawrence, G., Meechan, D., Morris, E.J., Middleton, R., Steward, J., Richards, M.A. and the ICBP Module 1 Working Group. (2011). Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995—2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data. The Lancet, 377, 127–138.

Third-hand smoke

Most people who read this will know that the major cancer world-wide is lung cancer (both new cases and deaths), most of which (about 90%) are due to tobacco use. Anti-smoking publicity has been effective in parts of the developed world, and it’s drawn attention to the risks of ‘second-hand’ or ‘passive’ smoking – known since the 1930s – with the result that, at last, smoking is now banned in many public places.  This has contributed to the decline in the number of men dying from lung cancer in both the USA and the UK since 1980. It’s also helped to stabilise over the last 10 years the lung cancer death rate of American women although, as ever, the Brits are lagging behind and the rate for British women is still rising.

An additional facet of this problem has recently begun to be recognized in the form of ‘third-hand smoke’ – meaning that residual contamination may be present long after someone has smoked in the area. Inevitably, Sod’s Law appears to apply in that the chemicals that hang around by sticking to surfaces include some of the more toxic of the 1000 or so in cigarette smoke. No non-smoker who has tried snuggling up to a smoker or merely been ushered into a hotel room previously occupied by one will need convincing of the reality of  ‘third-hand smoke’. However, a recent study from the University of Rochester Medical Center in New York has thrown an alarming light on the combined effects of second- and third-hand smoking by showing that children living in apartments suffered substantially greater exposure to tobacco smoke compared with those living in detached homes, even when no one smoked in their household. The conclusion came from measurement of the blood levels of a substance called cotinine, which is produced from nicotine and gives a quantitative estimate of exposure to tobacco smoke.

No study of this type is without its weaknesses – an obvious one in this case being that you can only go on what you are told about whether people smoke in their own homes. However, 5,002 children were studied, which is a reasonable number from which to make preliminary deductions, and the finding that those living in apartments had a 45% increase in cotinine over those living in detached houses is an arresting result.

It is clear that in explaining these results the distinction between ‘second’ and ‘third’-hand smoke becomes blurred but one factor would appear to be tobacco smoke disseminating through multi-unit apartments. Regardless of precise mechanisms, the authors leave us with the fact that most children in the US are exposed to tobacco smoke, including a proportion of those whose parents don’t smoke, despite the fact that we know the damage it can do. Recall that it is associated not only with the long-term risk of lung cancer but with a variety of illnesses of increasing incidence, particularly asthma, and that there is no such thing as a ‘safe level’ of exposure.

Reference

Wilson, K.M., Klein, J.D., Blumkin, A.K., Gottlieb, M. and Winickoff, J.P. (2011). Tobacco-Smoke Exposure in Children Who Live in Multiunit Housing. Pediatrics 127, 85-92.

http://www.quit-smoking-central.com/third-hand-smoke.html