posted on Wednesday, 7th August 2019
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Well it has taken three decades but we now have an official
recommendation that doctors should offer aspirin for at least two
years to people with Lynch syndrome. The good news is that the
National Institute for Healthcare and Clinical Excellence (NICE),
has responded to our submission in 2017 with this recommendation
that is now out for public review over the coming month (see web
links below). We will reinforce the decision with a response to say
that our new data based on double the length of follow up used in
the CAPP2 2011 paper, shows continued protection. We are in the
process of submitting the CAPP2 10 year follow up for
publication.
The downside is that doctors have a relatively negative view of
aspirin due to the side effects. These can include life threatening
bleeds from ulcers. It has become increasingly clear that these
side effects are much more common in old and frail people so we
need to consider stopping or greatly reducing aspirin intake once
we get past pension age. The problems experienced in Australia and
USA among the over 70s in the recently reported ASPREE trial, who
were randomised to receive aspirin versus placebo, were made worse
by the fact that many had not taken aspirin before. The side
effects tend to decrease as people get used to the aspirin. Side
effects can also be reduced by taking an acid blocker and by
getting rid of Helicobacter pylori, a common stomach infection.
However, we can't get away from the fact that there is a small
but significant chance of side effects if people take aspirin, so
the benefits need to be clear. In the case of people with Lynch
syndrome, the risk of colorectal cancer is much higher than the
general population so the "risk benefit ratio" is clearly in favour
of taking the tablets.
The big question is 'what is the best dose of aspirin?' To
answer this we are relying on the 1882 people who signed up to
CaPP3, which is comparing the effect of three different doses of
aspirin. It's vital that we keep in touch with these volunteers
over the coming years. Our first recruit started in 2014 and
reaches the five-year mark in October of this year. We will
continue to follow their progress, as we will all the people who
joined up unless they actively tell us to stop. This is because the
experts put great store in the analysis of all the people who
started, not just the people who stay in to the end of the study.
This so-called "intention to treat" analysis is the most robust way
of comparing the groups. We hope that people who signed up for
CaPP3 will stick with us to the end of the five years but even if
they don't, we need to know what happened next. If we lose contact,
the trial is weakened and we will be left guessing what the optimal
dose is for the future. This is where the CaPP3 teams, both
national and international, are key to gathering this follow up
data and entering the data on to MACRO. It is essential to
the study that all follow up and contact information is entered on
to MACRO for study analysis. Do let us know if you are
having problems contacting study participants and/or data
entry.
We are now being asked, 'what should people do once they have
completed the CaPP3 study?' The obvious answer is to continue
taking aspirin. A low dose aspirin (75-100mg) may be enough but two
low dose aspirin or half a standard (300mg) aspirin morning and
night is a good guide for people between 25 and 65. NICE state 'a
commonly used dose in current practice is either 150mg (75mg x 2)
or 300mg, sometimes depending on other gastrointestinal risk
factors.' Both CAPP2 and CaPP3 have used enteric coated aspirin.
It's important to remember that this is a best guess. It may be
that we find that the people on the bigger dose of two aspirins a
day (600mg) will do the best in CaPP3. It's also important to
remember that the people who took that dose of aspirin in CAPP2 did
not have significantly more side effects than the people on placebo
tablets, probably because they were younger than the people who
usually turn up at the hospital with aspirin side effects.
Thanks again to all the people taking part in CaPP3 and to the
army of doctors, nurses and scientists who make it possible.
John Burn
6th August 2019
Web links:
https://www.nice.org.uk/news/article/offer-daily-aspirin-to-those-with-inherited-genetic-condition-to-reduce-the-risk-of-colorectal-cancer
https://www.cancerresearchuk.org/about-us/cancer-news/news-report/2019-08-02-daily-aspirin-reduces-bowel-cancer-risk-in-people-with-lynch-syndrome-says-nice
http://www.pharmatimes.com/news/aspirin_should_be_offered_to_lynch_syndrome_patients_1296182
https://www.telegraph.co.uk/science/2019/08/01/prescribe-aspirin-prevent-common-cancers-doctors-told/?fbclid=IwAR1DpbYrzfvGKyQtNyJ8G5HdonC39T80j2cpSjE8RF85P9LN92Y9FiHUV2E
posted on Thursday, 25th October 2018
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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