December 18, 2014

expert reaction to non-steroidal anti-inflammatory drugs and reduced skin cancer risk

A paper published in the Journal of Investigative Dermatology has examined the use of non-steroidal anti-inflammatory drugs (NSAIDs) and occurrence of one type of skin cancer, reporting that NSAIDs may have potential for preventing it. These comments were accompanied by a Before the Headlines analysis.

Prof. Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine (LSHTM), said:

“The only randomised study in this meta-analysis, while having results that suggest protection using celecoxib (which has notable adverse cardiovascular effects), did not have skin cancers as its primary outcome investigated. The editors of the journal in which it was published suggest caution: “Celecoxib was not effective in preventing new actinic keratoses, but the study results raise the hypothesis that it may prevent some nonmelanoma skin cancers in patients who have actinic keratoses and thus are at high risk for the disease.”

“The observational studies are much less reliable when used to examine fairly small benefits. With a 15% reduction they are particularly unreliable – with a 50% reduction they would be more trustworthy but the observational studies do not show this magnitude of reduction. The use of meta-analysis of observational studies is to some degree controversial.

“This study is good evidence that it is reasonable to conduct a large randomised trial, probably of a less cardio-toxic drug than celecoxib (aspirin or naproxen are possibilities). It is unlikely to be strong enough evidence that would allow regulatory authorities to allow a license for skin cancer prevention to be granted.”

Prof. Dorothy Bennett, Professor of Cell Biology, St George’s, University of London (SGUL), said:

“This is a meta-analysis – a study that aims to collect together all previous studies on a particular subject, to get the best available degree of certainty on a particular question.  Reviewing the nine suitable studies they found, the authors conclude that people who take NSAIDS have a slightly lower risk (82% of the normal risk) of the second commonest type of skin cancer, called squamous cell carcinoma (SCC).

“The study seems competent, and the results are worth knowing about, being added to the known small but significant tumour-suppressive effect of NSAIDs for colon cancer. There are around 25,000 cases of SCC per year in the UK, so according to this estimate, if everyone were taking NSAIDS, that may result in 4,500 fewer SCCs in the UK. On the other hand, if we all constantly took NSAIDs, we would see many more of their side effects, like indigestion varying up to dangerous stomach ulcers in some people. Noting that most SCCs are curable by surgery if caught early, this reduction in risk is interesting, but it is hard to say whether it is worth taking action over it.”

Dr Mangesh Thorat, Post-Doctoral Researcher, Centre for Cancer Prevention, Queen Mary University of London (QMUL), said:

“Cutaneous Squamous cell cancers (SCC), although common, are a somewhat neglected entity as most of the cancer studies and statistics exclude them. We have known the role of chronic inflammation in causation of cutaneous SCCs for quite some time. The findings of this most up-to-date review on the topic suggest that it may be possible to break this link with the use of non-steroidal anti-inflammatory agents (NSAIDs) and possibly aspirin to prevent development of cutaneous SCCs. Notwithstanding the limitations of this review in terms of inability to assess effect of dose and variations in drug usage in the studies included, it concurs with the growing body of evidence supporting role of aspirin and NSAIDs in cancer prevention. It forms a sound basis for further research, perhaps in the form of a definitive clinical trial employing these agents.”

Prof. Kevin McConway, Professor of Applied Statistics, The Open University, said:

“This paper is a competent pulling together of results, from nine previous studies, of potential links between NSAID drugs and one type of skin cancer. Given what they had to go on, the researchers have made a good job of the meta-analysis, but the problem is that the evidence that was available to them is not always terribly clear.

“Eight of the nine studies that they reviewed were observational – that is, the researchers observed people and tried to record what NSAIDs they took and whether they had a skin cancer. The trouble with such a study is that there might be many differences between the people studied, apart from how many NSAIDs they took, which might contribute to whether they get a skin cancer. So it is difficult to sort out what is caused by taking NSAIDs and what is caused by other things. One can try to allow for those differences (so-called confounders) statistically, and indeed the researchers on these studies did all try to do that, in different ways, but they can only allow for things they recorded. Some of the studies could not take account of people’s exposure to the sun, and again in some, the recording of how many NSIADs people took was not very precise.

“The ninth study was a randomised clinical trial. In that kind of study it’s much easier to make sense of what is causing what, but the study was on people at particularly high risk of these skin cancers, so not very typical of the average population.

“Putting all these studies together, the new paper did find some evidence of a protective effect of NSAIDs, but there remains considerable uncertainty. Also some of their results indicate considerable lack of homogeneity between the studies they reviewed – that is, there’s some room for doubt that they were all really measuring the same kind of thing.

“The researchers were quite up-front about all these limitations in their paper. Despite the title of the paper, their conclusions are all expressed in terms of a suggested link or a potential use of NSAIDs in preventing these cancers, and they make it clear that further research is required to make sense of what is really going on.”

Prof. Peter Barrett-Lee, Consultant Clinical Oncologist and Medical Director, Velindre NHS Trust, said:

“This is a well conducted meta-analysis (by Australian and UK researchers) of a variety of published studies looking at the association of skin cancers with the usage of NSAIDs predominantly for musculo-skeletal conditions. Confounding factors were adjusted for where possible but limitations were the lack of data on the degree of sun-exposure (which is a risk factor for SCC) and the inability to perform any sort of dose-dependent analysis of the NSAIDs used. People taking non-aspirin NSAIDs appear to have about a 15% lower risk of developing SCC, which is a significant clinical effect. The data on aspirin itself was in the same range but not as strong due to smaller numbers. There is a biological basis for thinking that this effect may be real in that NSAIDs are known to inhibit one of the inflammatory molecules COX-2 which is itself implicated in carcinogenesis.”

Prof. Brian Diffey, Emeritus Professor of Photobiology, Dermatological Sciences, Newcastle University, said:

“This analysis from Australia examined a number of epidemiological studies and reported that people taking non-steroidal anti-inflammatory drugs (NSAIDs), commonly used to treat chronic conditions like arthritis, were at a reduced risk of developing squamous cell skin cancer by about 15-20%. On the basis of their findings the authors suggested that their results raise the possibility that this family of drugs could be used as a means of preventing this form of skin cancer.

“In any study like this it is important to control for other factors that could account for the findings. Sun exposure is the major cause of squamous cell skin cancer and so one factor that may influence the results is that patients taking NSAIDs are generally less mobile than the general population and as a consequence may spend less time outside and receive less sun exposure.

“Reducing skin cancer risk is best achieved by reducing our sun exposure and achieving the same reduction in risk as may be delivered by taking NSAIDs requires just a 5-10% reduction in sun exposure, since the risk of squamous cell skin cancer increases roughly with the square of our sun exposure. Given that long-term therapy with NSAIDs is not without risk, a safer option for those who wish to reduce their likelihood of skin cancer may be to spend a few minutes a day less outside.”

‘Aspirin and non-steroidal anti-inflammatory drugs can prevent cutaneous squamous cell carcinoma: a systematic review and meta-analysis’ by Chiho Muranushi et al. published in the Journal of Investigative Dermatology on Thursday 18 December 2014. 

Declared interests

None declared