CaPPtain's Blog: John Burn, October 2018

You wait for an aspirin trial to report, then, FOUR arrive at once. They all have catchy names: ASCEND, ARRIVE, ASPECT and ASPREE, all with different target populations. There is some interesting new information about aspirin in the elderly (over 70) from the ASPREE trial, but I don't think it will have much impact on CaPP3 ASPECT showed that aspirin (300mg) combined with acid blockade was good for reducing cancer risk in Barrett's oesophagus, a chronic effect of acid damage due to reflux from the stomach. ARRIVE and ASCEND concluded there wasn't much mileage in terms of preventing cardiovascular events in giving aspirin (100mg) to people with a moderate risk of such problems or diabetics respectively. These studies did not address the recent publication from Peter Rothwell linking the effects of aspirin to bodyweight; 75/100mg aspirin was only effective in preventing vascular events in patients who weighed less than 70kg. The studies were too short term to look at cancer chemoprevention in any detail. The most important information for the CaPP community was from ASPREE, which stands for Aspirin in Reducing Events in the Elderly. Based on over 19,000 recruits in Australia and the United States, the trial randomised people aged over 70, to aspirin 100mg aspirin EC or placebo over 5 years. There were a significant number of adverse events, which wasn't surprising. Other research has previously shown that the risk of bleeds rises steeply in old people. The surprising result was that the risk of dying of cancer actually increased over the 4.7 years of the study. This fits with an analysis of aspirin trials and cancer incidence in the elderly, carried out by Peter Rothwell's team in Oxford, which he spoke about at the International Aspirin Foundation meeting in Edinburgh recently.

The idea that older people might not benefit from aspirin cancer prevention has been a subject of discussion for many years. In the 1990's a string of studies looked at cancer rates in people who had taken aspirin and noted a significant reduction in cancers. The one exception was a study by Paganini-Hill and colleagues. Their study of the Leisure World Cohort looked at people in retirement homes in California, and through questionnaires, including self-reported aspirin usage, reported higher cancer rates. Paganini-Hill proposed that the aspirin self-medication used by the cohort was primarily low dose to prevent myocardial infarction and that a higher dose was needed for cancer chemoprevention.

We have two theories about the ASPREE & the Leisure World Cohort studies, which might be connected.

The first is that we know aspirin can act to reduce the inflammatory changes around an early cancer. This might provide improved access for the immune system leading to its destruction. But, what if the cancer cells have already picked up genetic changes that mean the immune system cannot "recognise" the cancer? Removal of the inflammatory response would then make it easier for the cancer to progress.

A second idea is that, in plants, salicylates, from which aspirin is made, act as a trigger for programmed cell death. This energy- dependent process, also known as apoptosis, is used by plants to kill off faulty cells, usually because of infection. If triggering apoptosis is part of the way that aspirin works in early cancers, then it might not work so well in the very old. Research done over the last 15 years by the Mitochondrial Genetics team in Newcastle (which involved our own Gill Borthwick when she worked as a research scientist) showed that the stem cells in the bowel slowly lose the normal function of their mitochondria. By the age of 70, about 10% of the stem cells are no longer working properly. Mitochondria are the energy units inside cells and are critical to normal functions, including the process of apoptosis.

So we have two overlapping ideas; damping down inflammation might let any cancers already in the system progress and "old colons" might not respond as well to the benefits of aspirin in the same way as they do earlier in life.

All this is based on people from the general population and not people with Lynch syndrome. There are reasons to think the response to aspirin might be greater in Lynch syndrome, based on what we already know. In addition, when the risk of cancer is much higher, the benefits of, say, a 30% reduction are much greater so the risk / benefit ratio is different.

We also need to think about our biological fitness rather than take age as a number. Over the last century, our life expectancy has increased for reasons we are still learning about. That means that an average 70 year old now is biologically younger than a 70 year old in the last generation. Putting together the evidence now emerging, we need to be alert to a slight increase in cancers when people start taking aspirin later in life. People with Lynch syndrome are already alert to any unusual symptoms and LS cancers tend to be less able to spread to the rest of the body, giving time in most cases for curative treatment. In our European Prospective LS Database, the risk of dying of cancer is much lower than would be predicted from similar cancers in the general population. While the protection against bowel cancer may decline in older people, there will almost certainly still be benefit and this will show through once any tumours already "in the system" have been dealt with.

These latest studies, along with the Rothwell paper earlier in the year on the effects of different aspirin dosages, have reinforced the importance of CaPP3 for future generations. CAPP2 demonstrated a reduction with 600mg aspirin, in Lynch syndrome cancers after 5 years. We need to know the relative benefits of different doses in people with LS of different shapes, sizes and ages.

How does this all relate to CaPP3 study participants over the age of 70? We should emphasise to people around 70 or older who are thinking of starting the trial that the side effect risk is higher in older people and that we should be extra vigilant for unusual symptoms in the early years of the study. For those CaPP3 study participants over the age of 70 already in CaPP3, regular contact addressing any adverse events and symptoms should be maintained.

The CaPP3 study, this week, in the UK has now reached 1405 patients (total with international 1658). The UK recruitment target is 1500. Thank you to all the recruiting centres both national and international I think it is reasonable to use that phrase now popular with poster makers in the UK, "keep calm and carry on."

John Burn

23rd October 2018