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Efficacy and safety of chemopreventive agents on colorectal cancer incidence and mortality: systematic review and network meta-analysis

Authors Veettil SK, Jinatongthai P, Nathisuwan S, Teerawattanapong N, Ching SM, Lim KG, Saokaew S, Phisalprapa P, Reid CM, Chaiyakunapruk N

Received 14 May 2018

Accepted for publication 9 July 2018

Published 10 October 2018 Volume 2018:10 Pages 1433—1445


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Professor Henrik Toft Sørensen

Sajesh K Veettil,1 Peerawat Jinatongthai,2,3 Surakit Nathisuwan,4 Nattawat Teerawattanapong,2,3 Siew Mooi Ching,5,6 Kean Ghee Lim,7 Surasak Saokaew,3,8–10 Pochamana Phisalprapa,11 Christopher M Reid,12,13 Nathorn Chaiyakunapruk3,9,14,15

1Department of Pharmacy Practice, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia; 2Division of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, Thailand; 3School of Pharmacy, Monash University Malaysia, Subang Jaya, Malaysia; 4Clinical Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 5Department of Family Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia; 6Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Malaysia; 7Clinical School, Department of Surgery, International Medical University, Seremban, Malaysia; 8Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand; 9Center of Pharmaceutical Outcomes Research, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand; 10Unit of Excellence on Herbal Medicine, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand; 11Division of Ambulatory Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 12School of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia; 13School of Public Health, Curtin University, Perth WA, Australia; 14School of Pharmacy, University of Wisconsin, Madison, WI, USA; 15Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Subang Jaya, Malaysia

Background: Various interventions have been tested as primary prevention of colorectal cancers (CRC), but comprehensive evidence comparing them is absent. We examined the effects of various chemopreventive agents (CPAs) on CRC incidence and mortality.
Methods: We did a network meta-analysis based on a systematic review of randomized controlled trials (RCTs) that compared at least one CPA (aspirin, antioxidants, folic acid, vitamin B6, vitamin B12, calcium, vitamin D, alone or in combination) to placebo or other CPA in persons without history of CRC. Several databases were searched from inception up to March 2017. Primary outcomes were early and long-term CRC incidence and mortality.
Results: Twenty-one RCTs comprising 281,063 participants, 9 RCTS comprising 160,101 participants, and 7 RCTs comprising 24,001 participants were included in the network meta-analysis for early risk of CRC incidence, long-term risk of CRC incidence and mortality, respectively. For early CRC incidence, no CPAs were found to be effective. For long-term CRC incidence and mortality, aspirin was the only intervention that showed protective effects with potential dose-dependent effects (risk ratio [RR], 0.74 [95% CI, 0.57–0.97] for high-dose [≥325 mg/day] and RR, 0.81 [95% CI, 0.67–0.98] for very-low-dose [≤100 mg/day]). Similar trend was found for mortality (RR, 0.43 [95% CI, 0.23–0.81] for low-dose [>100–325 mg/day] and RR, 0.65 [95% CI, 0.45–0.94] for very-low-dose). However, in net clinical benefit analysis, when combining risk estimates on mortality from CRC, cardiovascular disease, and pooled risk estimates of major gastrointestinal bleeding, low-dose aspirin provided the highest net survival gain (%) of 1.736 [95% CI, 1.010–2.434].
Conclusion: Aspirin at the dose range of 75–325 mg/day is a safe and effective primary prevention for long-term CRC among people at average risk. None of the other CPAs were found to be effective. There may potentially be differential effects among various doses of aspirin that needs further investigation.

Keywords: colorectal cancer, primary chemoprevention, chemopreventive agents, aspirin, network meta-analysis, net clinical benefit analysis

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