Case for aspirin against cancer is not proven

Dr Paul Clayton 2013

As recently as the turn of the century, there was no medical consensus on the thorny subject of aspirin and cancer. A few scientists were suggesting that aspirin might be chemoprotective but the majority of medics were sceptical or downright hostile. How could
aspirin, an old-fashioned, out-of-patent (hence unprofitable) medicine protect against one of the most feared and most common of diseases?

In fact, the first hints that aspirin might reduce cancer risk emerged from trials designed to
measure its cardio-protective effects, which found – to the surprise of the researchers – that myocardial and cancer deaths were both reduced by aspirin (Peto et al ’88, MRC ’98).

But the fact that aspirin was rapidly becoming an important weapon in the fight against heart attacks initially cut little ice in cancer circles. If anything it made the cancer claims seem even more outlandish. The current medical model is very specific, and purportedly relies on precisely machined magic bullets to hit very specific targets. The fact that this strategy kills huge numbers of patients (Starfield 2000 see p.1) is embarrassing but irrelevant; the current medical paradigm rules out the very concept of a panacea.

Aspirin not a drug but a phytonutrient?

Aspirin, however, is no ordinary drug. In fact, it can be argued that aspirin is not a drug at all but a phytonutrient. Many people know that salicylic acid was first identified in willow bark, a traditional treatment for arthritis, but there are many other plant sources. Salicylates are found in abundance in most spices, many types of fruit and some vegetables, and – like other phytonutrients – are actually plant defence compounds.

Salicylic acid is involved in defending against dehydration, for example, and closes leaf
stomata so that water loss is reduced during dry spells. [This is why adding aspirin to the water in a vase delays wilt in cut flowers.]

Salicylates are also part of the plant’s defence against harmful microbes; when a plant is
attacked it produces salicylates which in turn trigger the production of anti-pathogen
proteins. Some salicylates pass through the plant, transferring resistance from the infection site throughout the rest of the plant’s leaves and roots. Others, such as the volatile compound methyl salicylate, trigger defence activity in neighbouring plants before the infection can even reach them.

Salicylates—and the modified salicylate aspirin—are very like vitamins Aspirin is a slightly chemically modified version of salicylic acid. Adding an acetyl group makes it slightly less prone to causing gastric irritation, but not completely safe; indeed aspirin and related NSAIDs are the most common cause of adverse drug reactions requiring hospitalisation, due to gastrointestinal bleeding.

But that is beside the point. The main fact is that salicylate, and by implication aspirin, is
very like a vitamin. The definition of a vitamin is something that we need to maintain health,
and cannot make in our own bodies but must obtain, in trace amounts, from our diet. Salicylate fits this description. We cannot make it ourselves but must obtain it in small amounts from our diet, and, judging by our experience with aspirin, it extends our healthy life expectancy by reducing the risk of some very major chronic degenerative diseases.

If we consider aspirin as a phytonutrient rather than a drug, the idea that it can confer such
generalised protection is not so outlandish after all. And given our new understanding of the role of chronic inflammation in causing degenerative disease, aspirin may be protecting us via an anti-inflammatory mechanism, such as the inhibition of the pro-inflammatory and cancer-promoting enzyme COX-2 (Sheehan et al ’99). COX-2 is also involved in angiogenesis, a key process in cancer growth and spread (metastasis); so here is another way in which aspirin and other COX-2 blockers might slow or prevent cancer growth.

But how relevant is this to clinical practice?

Clinical trials on aspirin in cancer

There have been many clinical trials of aspirin in cancer during the last decade, and lately  the pace is picking up. In the spring of last year, no fewer than three studies were  published in The Lancet journals by an eminent Oxford University group, which, together with their earlier work, formed a rather convincing case for the drug/phytonutrient in cancer prevention (prophylaxis) and management.

Preventing cancer and its spread

One paper looked at the effect of aspirin in preventing cancer. It was a meta-analysis of 51 trials, involving more than 77,000 patients, comparing people who took aspirin every day
with people who took no aspirin. This showed that taking daily low-dose aspirin (less than
300mg) for 3 years or more cut the risk of developing any type of cancer by roughly 25%
(Rothwell et al ’12a).

The second and third papers looked at the effect of aspirin on cancer spread. These found
that during an average 6½ years of taking aspirin (75mg+ a day), the risk of metastatic
(spreading) cancer was cut by up to 46%. Aspirin also lowered the risk of non-metastatic
cancer progressing to metastatic cancer, especially in patients with colon cancer; and there was significantly lower risk of cancer and metastasis in colon, throat, gastric, biliary and breast cancer (Algra & Rothwell ’12, Rothwell et al ’12b).

These studies provided important evidence that long-term daily low-dose aspirin lowered the risk of developing cancer, but this does not mean that everyone should start taking aspirin. As with cardio-protection, we need to be a little more specific. Some individuals are particularly prone to gastric bleeds with aspirin, and they should be very cautious about
aspirin prophylaxis. And as aspirin has an anticlotting effect, it should not be used by  anyone with uncontrolled hypertension or a history of haemorrhagic stroke.

Aspirin for certain specific cancer therapies
Cancer research is moving in a parallel direction, ie it is also becoming more specific.
Aspirin appears to be particularly effective at reducing the risk and spread of colorectal
cancer, but new research shows that this does not mean that every colorectal cancer patient should take aspirin. A follow-up paper from the Oxford group shows that aspirin prophylaxis is only effective in patients with the genetic marker mutated PIK3CA (Langley & Rothwell ’13), a marker which otherwise denotes poor prognosis. And although preliminary evidence suggested that aspirin might have a role in breast cancer, a recent large prospective observational study found no relationship between aspirin use and breast cancer incidence in post-menopausal women (Zhang et al ’12).

In many cancers, however, aspirin and similar anti-inflammatory drugs are already being
used, generally in conjunction with other therapies. Aspirin plus radiotherapy seems to
be a useful combination (Kim et al ’03), as does aspirin plus anti-cancer monoclonal antibodies (Pennarun et al ’13).

For healthy individuals, any reduction of cancer risk must be offset against the increased risk of haemorrhage, typically in the gut or less frequently the brain. This risk is real, as was shown in a prospective cohort study of 200,000 subjects in Italy where low dose aspirin use was associated with a 50% increase in bleeds (de Berardis et al ’12). This means that about 1 in 769 people treated with lowdose aspirin suffer significant bleeding. Butbecause cancer is so common in our unhealthy age, medics are increasingly recommending that new guidelines be issued to recommend the wider use of low-dose
aspirin in healthy adults.

So where do we go from here?

Improve aspirin pills?

Well, aspirin pills could be improved, because not all aspirin is the same. There are different isomers of aspirin, specifically there are ortho-, meta- and para- versions of the
acetyl salicylic acid molecule; and these have rather different biochemical effects. Of these three forms, only the ortho-isomer generates a permanent inhibition of COX-2 (Kodela et al ’13). This strongly suggests that a more refined form of aspirin, consisting only of the orthovariant, would pack a more powerful anticancer punch. This would allow the use of lower doses, and might reduce the risk of gastric and other bleeds.

Or look at other therapeutic phytonutrients

Or we could be more ambitious, and look at other phytonutrients with even better therapeutic profiles. It is well known that diets rich in fruits and vegetables reduce the
risk of almost all cancers, and while such diets contain above-average levels of salicylates, they also contain above-average levels of many other chemo-protective
compounds such as the polyphenols.

Salicylic acid is a phenolic compound, distantly related to polyphenols such as the flavonoids (for instance, curcuminoids), which have a range of similar but better
properties. Like salicylic acid, the polyphenols are anti-inflammatory agents,
and like salicylic acid, they protect against heart disease and cancer, and Alzheimer’s,
and many other disease besides. And far from causing bleeding and ulceration, they actively protect against it (ie Mahattanadul et al ’09).

In short, I am pretty sure that modern medicine has barked up the wrong willow tree. The
focus on aspirin, due to its medicalisation by Bayer back in the 1890s, has been a missed
opportunity; the related polyphenols were discovered 40 years later, by which time the
pharmaceutical business had already begun to dominate medical training and practice, and hence these critically important natural products were mostly ignored.

In any case, I do not share my colleagues’ new-found enthusiasm for aspirin. I believe that non-medicinal prevention should be prioritised. Smoking cessation, the avoidance of distilled spirits, regular exercise, maintaining a healthy weight and a healthy diet, including
food supplements, should be the first steps in any cancer prevention programme. If that diet is designed to reduce levels of the pro-inflammatory compounds formed in fast
foods, and to provide high levels of polyphenols and the other chemo-protective phytonutrients, the evidence suggests that we could reduce the cancer burden by up to 90% (Clayton & Rowbotham ’09).