posted on Thursday, 27th February 2020
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I saw my first daffodils this week. Spring is coming soon
and with it good news.
The first event of note is the completion of the
NICE*
approval of aspirin as a preventive agent in Lynch
syndrome. This guidance became official in January,
complementing the decision of the British Society of
Gastroenterology to make the same
recommendation and international endorsement via the formal
voting system among members of the European Hereditary Tumour
Group. Aspirin is still not formally licensed for cancer
prevention in the UK but we are working on that too.
Meanwhile doctors can prescribe aspirin, if they agree with this
guidance.
The NICE endorsement will, hopefully, be stronger following the
imminent publication by the Lancet of our latest paper documenting
the planned CAPP2 trial 10 year follow up, supplemented by registry
data in England, Wales and Finland for the second decade. The
bottom line is that the effect of aspirin (600mg daily) on
colorectal cancers (CRC) is even more secure, with a significant
reduction with the rigorous method of Hazard Ratio on the basis of
Intention to Treat. In plain English, this means that even when we
count only the first colon cancer and include all the people
allocated to the aspirin group, even if they dropped out early,
there are significantly fewer cancers in the people in the aspirin
group. When we focus on people who actually took the two
aspirins a day for two years and including all their primary
colorectal cancers in the analysis, the relative risk is 0.50. That
means they had half as many colorectal cancers over an average of
ten years.
There were also fewer non-CRC Lynch syndrome cancers but
overall, the statistical significance was lost by 10 years.
This probably means that the effect is not as long lasting and may
not apply to all types of cancer. We do, however, have new
information on resistant starch, the diet supplement in
CAPP2. Those of you who follow me on twitter (@CaPP3) will have
seen that I reported to the recent Clinical Genetics Society
meeting in Cambridge that the non-CRC Lynch cancers were reduced in
the people who were given the active diet supplement compared to
the placebo group.
CaPP3 is still on course and has become even more important as
NICE recognise the importance of our ongoing trial. They
endorsed our suggestion that while we await the result of CaPP3 the
"best guess" is that people should take 150mg (two "cardio"
aspirins) if they are below 70kg (11 stone) and 300mg (a standard
aspirin) if they are over that weight. This is based on our
overall reading of the literature. I hope people who are in
CaPP3 will continue for the five years, as planned on their study
dose so that we can see if the different doses do have a different
effect. The first recruit to the trial, Nick from Newcastle,
has now completed his five years along will several more early
participants while the last recruit will complete the 2 year
"blind" phase next spring. That means we still have four
years to wait but it will be worth it. Some
experimental work by Rick Boland and colleagues in America has
supported the CaPP3 plan; they simulated the three doses using
cancer cells in the laboratory and saw a bigger effect with the
higher doses. On the other hand, of course, we expect more
side effects with the higher doses so there will need to be a
careful assessment of the pros and cons at the end of the
trial. If you are still in CaPP3, thanks again! Please keep
in touch. We are always keen to hear from you.
*NICE stands for the National Institute for Health and Care
Excellence
John Burn
27th February 2020
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