The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial

Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial
Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial

Background: Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population. Methods: In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990. Findings: Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43–0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39–0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34–0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31–0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43–0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously. Interpretation: The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results. Funding: Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.

0140-6736
1855-1863
Burn, John
455f5bd0-3b49-4784-a924-de7861508290
Sheth, Harsh
ca3fcce3-d6cd-4b26-8bcb-6164a95d5646
Elliott, Faye
ebf9247f-1916-4e36-90ff-adf98a0192d3
Reed, Lynn
324d2da9-fe5a-48bd-9425-a77255fb0862
Macrae, Finlay
1563da0e-d7e9-4f37-8095-041739cf4e09
Mecklin, Jukka Pekka
5e4b3d86-d108-401b-9199-39e97c1c333e
Möslein, Gabriela
2130db23-3edb-4705-b48a-c98bfa12b4ff
McRonald, Fiona E.
32226b69-dfbd-4763-aa33-441c6dd57774
Bertario, Lucio
4e19d5e5-a4f2-4797-b305-56a6c8e6ca96
Evans, D. Gareth
4e1ed170-9119-4b35-a45f-55f8d07fa24e
Gerdes, Anne Marie
60e03234-c7bd-4659-a642-432c0f943474
Ho, Judy W.C.
68f0bd21-0e06-453b-8307-48f4c5097ac2
Lindblom, Annika
855a20de-8712-44cb-9a0a-01d4176a666f
Morrison, Patrick J.
0fb9bdda-83c3-446b-ae97-28858f06d2d8
Rashbass, Jem
5fe51eb2-4850-4b4c-9be9-9143daf32005
Ramesar, Raj
72654228-6b26-42bb-9d30-56aea6b3617e
Seppälä, Toni
e9061419-aa0d-42e0-8b9e-5de25692a66a
Thomas, Huw J.W.
b0296ab1-0ca0-4107-acfa-bcc9f47052c6
Pylvänäinen, Kirsi
9752a592-e32f-4326-b1d2-6819d0fa114c
Borthwick, Gillian M.
cf7d2af4-9ac8-470a-ac61-d5e6e673194b
Mathers, John C.
4dfcad8f-65ea-46f8-a219-3573b131be52
Bishop, D. Timothy
0b8e307a-d30e-4402-917d-9db867f694a1
Boussioutas, Alex
d749f0c2-0484-47d1-910f-cd320b6f9b37
Brewer, Carole
f497c7f3-050d-4494-aecb-7e6a23101d18
Cook, Jackie
b24e3336-f47a-4590-bc3f-7e2ab7d78e0d
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Ellis, Anthony
78703fb9-3e93-4cbb-8f27-a843e6cec661
Hodgson, Shirley V.
d30bfe9d-092f-4e12-8327-04386bb77c77
Lubinski, Jan
e7a9709c-36b3-44ed-a5e0-675177ca3d51
Maher, Eamonn R.
577b8856-f8a8-49c2-9484-288d9f964aed
Porteous, Mary EM
1edf5173-bc14-44d2-93f4-bff38caefae2
Sampson, Julian
3ba59b69-352a-4c82-b8ae-7ddffb2a283d
Scott, Rodney J.
260625d6-e0c1-40df-92c3-cac44df0f612
Side, Lucy
197fd9f8-2bd8-4e7e-b46f-4a87df3f20d2
CAPP2 Investigators
Burn, John
455f5bd0-3b49-4784-a924-de7861508290
Sheth, Harsh
ca3fcce3-d6cd-4b26-8bcb-6164a95d5646
Elliott, Faye
ebf9247f-1916-4e36-90ff-adf98a0192d3
Reed, Lynn
324d2da9-fe5a-48bd-9425-a77255fb0862
Macrae, Finlay
1563da0e-d7e9-4f37-8095-041739cf4e09
Mecklin, Jukka Pekka
5e4b3d86-d108-401b-9199-39e97c1c333e
Möslein, Gabriela
2130db23-3edb-4705-b48a-c98bfa12b4ff
McRonald, Fiona E.
32226b69-dfbd-4763-aa33-441c6dd57774
Bertario, Lucio
4e19d5e5-a4f2-4797-b305-56a6c8e6ca96
Evans, D. Gareth
4e1ed170-9119-4b35-a45f-55f8d07fa24e
Gerdes, Anne Marie
60e03234-c7bd-4659-a642-432c0f943474
Ho, Judy W.C.
68f0bd21-0e06-453b-8307-48f4c5097ac2
Lindblom, Annika
855a20de-8712-44cb-9a0a-01d4176a666f
Morrison, Patrick J.
0fb9bdda-83c3-446b-ae97-28858f06d2d8
Rashbass, Jem
5fe51eb2-4850-4b4c-9be9-9143daf32005
Ramesar, Raj
72654228-6b26-42bb-9d30-56aea6b3617e
Seppälä, Toni
e9061419-aa0d-42e0-8b9e-5de25692a66a
Thomas, Huw J.W.
b0296ab1-0ca0-4107-acfa-bcc9f47052c6
Pylvänäinen, Kirsi
9752a592-e32f-4326-b1d2-6819d0fa114c
Borthwick, Gillian M.
cf7d2af4-9ac8-470a-ac61-d5e6e673194b
Mathers, John C.
4dfcad8f-65ea-46f8-a219-3573b131be52
Bishop, D. Timothy
0b8e307a-d30e-4402-917d-9db867f694a1
Boussioutas, Alex
d749f0c2-0484-47d1-910f-cd320b6f9b37
Brewer, Carole
f497c7f3-050d-4494-aecb-7e6a23101d18
Cook, Jackie
b24e3336-f47a-4590-bc3f-7e2ab7d78e0d
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Ellis, Anthony
78703fb9-3e93-4cbb-8f27-a843e6cec661
Hodgson, Shirley V.
d30bfe9d-092f-4e12-8327-04386bb77c77
Lubinski, Jan
e7a9709c-36b3-44ed-a5e0-675177ca3d51
Maher, Eamonn R.
577b8856-f8a8-49c2-9484-288d9f964aed
Porteous, Mary EM
1edf5173-bc14-44d2-93f4-bff38caefae2
Sampson, Julian
3ba59b69-352a-4c82-b8ae-7ddffb2a283d
Scott, Rodney J.
260625d6-e0c1-40df-92c3-cac44df0f612
Side, Lucy
197fd9f8-2bd8-4e7e-b46f-4a87df3f20d2

CAPP2 Investigators (2020) Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. The Lancet, 395 (10240), 1855-1863. (doi:10.1016/S0140-6736(20)30366-4).

Record type: Article

Abstract

Background: Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population. Methods: In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990. Findings: Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43–0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39–0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34–0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31–0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43–0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously. Interpretation: The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results. Funding: Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.

Text
13_06p1855_1863R3_(19TL7751) - Version of Record
Download (367kB)
Text
19TL7751 Appendix - Version of Record
Download (344kB)

More information

Accepted/In Press date: 7 February 2020
e-pub ahead of print date: 11 June 2020
Published date: 13 June 2020

Identifiers

Local EPrints ID: 443493
URI: http://eprints.soton.ac.uk/id/eprint/443493
ISSN: 0140-6736
PURE UUID: 5d619589-c8ab-45e3-9457-1e3a50c68978
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

Catalogue record

Date deposited: 26 Aug 2020 16:37
Last modified: 26 Nov 2021 02:34

Export record

Altmetrics

Contributors

Author: John Burn
Author: Harsh Sheth
Author: Faye Elliott
Author: Lynn Reed
Author: Finlay Macrae
Author: Jukka Pekka Mecklin
Author: Gabriela Möslein
Author: Fiona E. McRonald
Author: Lucio Bertario
Author: D. Gareth Evans
Author: Anne Marie Gerdes
Author: Judy W.C. Ho
Author: Annika Lindblom
Author: Patrick J. Morrison
Author: Jem Rashbass
Author: Raj Ramesar
Author: Toni Seppälä
Author: Huw J.W. Thomas
Author: Kirsi Pylvänäinen
Author: Gillian M. Borthwick
Author: John C. Mathers
Author: D. Timothy Bishop
Author: Alex Boussioutas
Author: Carole Brewer
Author: Jackie Cook
Author: Diana Eccles ORCID iD
Author: Anthony Ellis
Author: Shirley V. Hodgson
Author: Jan Lubinski
Author: Eamonn R. Maher
Author: Mary EM Porteous
Author: Julian Sampson
Author: Rodney J. Scott
Author: Lucy Side
Corporate Author: CAPP2 Investigators

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×