Friday, 10 December 2010

Aspirin’s a ‘wonder-drug’ – but can it prevent cancer?

reposted from:

Aspirin’s a ‘wonder-drug’ – but can it prevent cancer?

This is a bit of a long one, but we felt it was important to get it all down in one place… particularly as this is a topic that pops up frequently in the news. As ever, we’re keen for your feedback – so let us know if you think it’s too long…
A hand holding some pills
Can aspirin prevent cancer?
In recent years, there have been frequent reports that our old friend aspirin, the over-the-counter painkiller and anti-coagulant, appears to be able to prevent cancer.
The most recent one was in April, when there was widespread coverage of research looking at breast cancer rates amongst women who regularly took so-called ‘non-steroidal anti-inflammatory drugs’ – NSAIDs – the class of drugs to which aspirin belongs.

This research made the news because it suggested that aspirin might prevent the formation of a common type of breast cancer – ‘oestrogen-positive’ breast cancer.

In fact there’s quite a lot of evidence building up now that NSAIDs might indeed play a role in stopping, or at least slowing down, the development of cancer – at least under certain circumstances.

But does this mean that doctors will one day be able to prescribe a simple pill to reduce your risk of cancer, like they do for people at risk of heart disease?

As usual, it’s a not quite that simple, so let’s have a look at what the science actually shows.

Aspirin – a bit of history
The structure of aspirin
The structure of an aspirin molecule
Aspirin, or acetylsalicylic acid to give it its science-y name, was purified from willow bark in the mid-1800s, and first sold as a drug by Bayer in 1899 for pain relief and to relieve fevers. It became a worldwide money-spinner for pharmaceutical companies in the wake of the 1918 flu pandemic.
In the 50s and 60s, paracetamol and ibuprofen arrived on the market. Since aspirin was found to cause serious side-effects like stomach ulcers and bleeding (see below) under certain circumstances, it fell out of favour. But in the 90s it underwent a resurgence as an anti-heart-disease drug, due to its ability to prevent blood-clots as well as block pain.

As a result, aspirin is a bit of a ‘wonder-drug’, able to block pain, calm fevers, prevent blood clots, and also relieve the symptoms of inflammatory conditions like arthritis and rheumatism. A pretty impressive CV.

How does it work?
NSAIDs block the action of a family of proteins called the cyclooxygenase enzymes (the scientist who discovered this, Sir John Vane, received a knighthood and a Nobel Prize for his work).
Cyclooxygenase, or COX, enzymes produce hormones called prostaglandins, which control pain signalling and inflammation, and thromboxanes, which regulate blood clotting.

So this neatly explains aspirin’s effects. It turns out that the drug chemically alters COX enzymes, so that they can no longer tell the body to produce prostaglandins and thromboxanes. And the lack of prostaglandins ‘turns down’ pain signalling and inflammation, and prevents clots from forming.

There’s also evidence that aspirin works on other systems in the body involved in regulating inflammation.

Side effects
Aspirin’s main drawback is its tendency to cause stomach ulcers and bleeding. Many studies have shown an increase in the chances of this happening in people who regularly take aspirin, even at low doses.

A good example is a Danish paper published in the American Journal of Gastoenterology in 2000. This followed over 27,000 people who regularly took low-dose aspirin, and compared rates of gastrointestinal bleeding in these people with rates in the general population. There were 207 cases of bleeding in the study group – over twice what was found in the general population.

Aspirin also can cause tinnitus (ringing in the ears), although only at high doses.

Regular, long-term use of other non-aspirin NSAIDs has been shown to increase the risk of heart problems, including heart attacks and strokes.

Does it prevent cancer?
Most of the evidence that aspirin might be able to stop or slow cancers from forming comes from studies of people who already take NSAIDs on a regular basis (e.g. for conditions such as chronic pain, heart disease or arthritis).

These studies often find that cancer rates are lower amongst these people than in the general population. Some studies, compellingly, also find a ‘dose-response’ effect – the more you take, the lower your risk.

There are several cancers for which this evidence is particularly strong: bowel cancer, breast cancer, and oesophageal (food-pipe) cancer. Some studies also suggest that it can lower risks of lung, stomach, mouth, prostate and ovarian cancers, although this evidence is much weaker.

Let’s look at the evidence cancer by cancer:
Bowel cancer
Bowel cancer
There’s growing evidence that bowel cancer is caused by long-term, low-level (‘chronic’) inflammation of the walls of the gut. (We discussed inflammation and cancer last July).

So given aspirin’s potent anti-inflammatory properties, it’s reasonable to speculate that it might prevent bowel cancer.

In 1997, a report by the International Agency for Research on Cancer (IARC) concluded that there was indeed ‘limited’ evidence that aspirin reduces bowel cancer risk in humans. Since then, more and more studies have come out in support of this, a good example being a 2005 paper in the Journal of the American Medical Association, which concluded:
“Regular, long-term aspirin use reduces risk of [bowel] cancer. However, a significant benefit of aspirin is not apparent until more than a decade of use, with maximal risk reduction at doses greater than 14 tablets per week.” (Our emphasis)

The women in this study were taking 325mg aspirin tablets. Two of these a day for a decade is a lot of aspirin. The ‘low dose’ aspirin regime recommended for stroke and heart attack prevention is 75mg per day.

In 2007, two large ‘meta-analyses’ also looked at the risks vs benefits for both aspirin and other NSAIDs for bowel cancer prevention, and both concluded that, for the time being, the risks outweigh the benefits.

(Meta-analysis is a mathematical technique that adds up the results from lots of individual studies, to give an overall view of the evidence.)

So, looking at all the evidence for aspirin and bowel cancer, three things become apparent.
  • large regular dose of aspirin over a long time clearly reduces the risk of the disease

  • This dose is far higher than the dose recommended, and proven safe, for long-term use

  • The data for lower doses is nothing like as clear cut (A large randomised trial in 2005 even showed no effect).
Clearly, blocking inflammation seems to be a good thing in terms of bowel cancer prevention, but we don’t yet know how to do this reliably and effectively using aspirin or any other NSAID.

Breast cancer diagram
Breast cancer
Breast cancer
The evidence for breast cancer and aspirin is much less consistent, but still strong enough to make researchers think there’s something interesting going on.
For example, most of the studies that do show an effect tend to show the same sort of protective effect (about 20 per cent lower than among women who don’t take aspirin).
How might aspirin protect against breast cancer? As mentioned above, aspirin blocks the production of prostaglandins by cells containing the COX-2 enzyme. One of the proteins that’s activated by prostaglandins is another enzyme called aromatase. Aromatase makes oestrogen. And oestrogen is known to drive the development of breast cancer.

So there’s a nice route for how aspirin could prevent breast cancer – by indirectly lowering oestrogen levels. This ties neatly into the research mentioned above, showing a protective effect on oestrogen-positive breast cancer.

But once again, the dose needed to produce these effects is generally on the high side – bringing unwanted side effects into play. And it might be that aspirin increases the proportion of oestrogen-negative tumours without affecting overall numbers – which is worrying because oestrogen-negative tumours are generally harder to treat.

Once again, we need to fully understand what’s going on before we could ever start talking about using aspirin to protect against breast cancer, even for women at high risk of the disease.
Oesophagus diagram
Oesophgeal cancer
Oesophageal cancer
Again, there’s compelling evidence that aspirin has an effect, as shown by several meta-analyses (e.g. this 2005 paper).

But there’s even more inconsistency in these results than in the case of breast cancer. Some studies claim that aspirin reduces the risk of oesophageal cancer by 20 per cent, but others claim effects as large as 70 per cent. So there’s more work needed here to find out what’s going on.

Other cancers
Here, the evidence is even less consistent. Some papers show aprotective effect for lung cancer – others show non-aspirin NSAIDs actually increase risk. Research on prostate cancer has suggested a weak protective effect. And a cursory search on PubMed (an online database of published research) using the terms ‘NSAIDs cancer prevention’ shows over 2600 papers, looking at a whole range of cancers.

Non-aspirin NSAIDs
Many of the papers discussed above also looked at NSAIDs other than aspirin, such as ibuprofen. There’s consistent evidence that these also have an effect, although exactly how much, and what doses are needed, is even less clear than for aspirin.

But many of these NSAIDs, although easier on the stomach than aspirin, slightly increase the risk of cardiovascular problems like heart attacks and strokes.

Another finding is that NSAIDs seem to have a greater protective effect if more than one type is used at a time. Unfortunately, this also seems to magnify the severity and frequency of side effects.
Also, there’s a new generation of NSAIDs available that are much more ‘targeted’ than classic NSAIDs like aspirin, and some researchers think these might be a better bet in terms of cancer prevention. But these have run into problems – (in)famously, Vioxx was withdrawn from use in 2004, following the discovery that it led to heart attacks and strokes.

So what’s next?
Taking all the data on aspirin and NSAIDs into account, we can draw a number of conclusions:
  • Inflammation is very important in cancer and we need to understand the mechanisms involved.
  • Blocking chronic inflammation, somehow, is probably going to turn out to be a very important way to prevent cancer, especially in people at high risk.
  • Current anti-inflammatory drugs like aspirin and ibuprofen seem to require larger doses, and longer durations to reduce the risk of cancer, than is regarded as ‘safe’. In short, the benefits don’t seem to outweigh the risks.
  • There are a significant minority of studies suggesting that NSAIDs can increase the risk of some cancers

  • We need to do more research to really get a full understanding of how these drugs prevent cancer, why the trials to date have has such mixed results, and perhaps try to develop new NSAIDs specifically to prevent cancer
As a result of all this, Cancer Research UK is supporting a number of projects looking at this area. For example, we’re funding a trial called ASPECT, investigating whether aspirin and an anti-ulcer drug can prevent oesophageal cancer.

We’re also looking at the potential of anti-inflammatories for treating cancer, with trials ongoing in breastprostate, and bladder cancer

As well as clinical trials, we’re funding basic research into the potential benefits of anti-inflammatory drugs, including investigating whether prostaglandins play a role in helping mouth cancer cells to spread, and probing the molecular processes that enable NSAIDs to do their work.

And in Bristol, Professor Chris Paraskeva and his team are looking at the biological pathways affected by NSAIDs as a route for preventing and treating bowel cancer.

Our work is just one part of an an intense worldwide effort to understand the role of inflammation in cancer. So there’s definitely cause for optimism, and we’re sure to hear more about this in the future.

But we’d like to finish on a note of caution. After reading all of the above, it might be tempting to put yourself on low-dose aspirin, just in case… particularly if you’re worried about your risk of cancer.

Please, don’t. Although it’s easily available over the counter, aspirin, like all drugs, needs to be taken under the supervision of a medical professional for anything other than what it is sold to do.

Go and see your GP if you’re worried.

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