Chemoprevention of colorectal cancer in individuals with previous colorectal neoplasia: systematic review and network meta-analysis

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Abstract

Objective To assess the comparative efficacy and safety of candidate agents (low and high dose aspirin, non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), calcium, vitamin D, folic acid, alone or in combination) for prevention of advanced metachronous neoplasia (that is, occurring at different times after resection of initial neoplasia) in individuals with previous colorectal neoplasia, through a systematic review and network meta-analysis.

Data sources Medline, Embase, Web of Science, from inception to 15 October 2015; clinical trial registries.

Study selection Randomized controlled trials in adults with previous colorectal neoplasia, treated with candidate chemoprevention agents, and compared with placebo or another candidate agent. Primary efficacy outcome was risk of advanced metachronous neoplasia; safety outcome was serious adverse events.

Data extraction Two investigators identified studies and abstracted data. A Bayesian network meta-analysis was performed and relative ranking of agents was assessed with surface under the cumulative ranking (SUCRA) probabilities (ranging from 1, indicating that the treatment has a high likelihood to be best, to 0, indicating the treatment has a high likelihood to be worst). Quality of evidence was appraised with GRADE criteria.

Results 15 randomized controlled trials (12 234 patients) comparing 10 different strategies were included. Compared with placebo, non-aspirin NSAIDs were ranked best for preventing advanced metachronous neoplasia (odds ratio 0.37, 95% credible interval 0.24 to 0.53; SUCRA=0.98; high quality evidence), followed by low-dose aspirin (0.71, 0.41 to 1.23; SUCRA=0.67; low quality evidence). Low dose aspirin, however, was ranked the safest among chemoprevention agents (0.78, 0.43 to 1.38; SUCRA=0.84), whereas non-aspirin NSAIDs (1.23, 0.95 to 1.64; SUCRA=0.26) were ranked low for safety. High dose aspirin was comparable with low dose aspirin in efficacy (1.12, 0.59 to 2.10; SUCRA=0.58) but had an inferior safety profile (SUCRA=0.51). Efficacy of agents for reducing metachronous colorectal cancer could not be estimated.

Conclusions Among individuals with previous colorectal neoplasia, non-aspirin NSAIDs are the most effective agents for the prevention of advanced metachronous neoplasia, whereas low dose aspirin has the most favorable risk:benefit profile.

Registration PROSPERO (CRD42015029598).

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Most cited references 32

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A randomized trial of aspirin to prevent colorectal adenomas.

John A. Baron, Bernard F Cole, Robert Sandler … (2003)

Laboratory and epidemiologic data suggest that aspirin has an antineoplastic effect in the large bowel. We performed a randomized, double-blind trial of aspirin as a chemopreventive agent against colorectal adenomas. We randomly assigned 1121 patients with a recent history of histologically documented adenomas to receive placebo (372 patients), 81 mg of aspirin (377 patients), or 325 mg of aspirin (372 patients) daily. According to the protocol, follow-up colonoscopy was to be performed approximately three years after the qualifying endoscopy. We compared the groups with respect to the risk of one or more neoplasms (adenomas or colorectal cancer) at least one year after randomization using generalized linear models to compute risk ratios and 95 percent confidence intervals. Reported adherence to study medications and avoidance of nonsteroidal antiinflammatory drugs were excellent. Follow-up colonoscopy was performed at least one year after randomization in 1084 patients (97 percent). The incidence of one or more adenomas was 47 percent in the placebo group, 38 percent in the group given 81 mg of aspirin per day, and 45 percent in the group given 325 mg of aspirin per day (global P=0.04). Unadjusted relative risks of any adenoma (as compared with the placebo group) were 0.81 in the 81-mg group (95 percent confidence interval, 0.69 to 0.96) and 0.96 in the 325-mg group (95 percent confidence interval, 0.81 to 1.13). For advanced neoplasms (adenomas measuring at least 1 cm in diameter or with tubulovillous or villous features, severe dysplasia, or invasive cancer), the respective relative risks were 0.59 (95 percent confidence interval, 0.38 to 0.92) and 0.83 (95 percent confidence interval, 0.55 to 1.23). Low-dose aspirin has a moderate chemopreventive effect on adenomas in the large bowel. Copyright 2003 Massachusetts Medical Society

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J Hartung, Rebecca G Knapp (2001)

For the meta-analysis of controlled clinical trials with binary outcome a test statistic for testing an overall treatment effect is proposed, which is based on a refined estimator for the variance of the treatment effect estimator usually used in the random-effects model of meta-analysis. In simulation studies it is shown that the proposed test keeps the prescribed significance level much better than the commonly used tests in the fixed-effects and random-effects model, respectively. Moreover, when using the test it is not necessary to choose between fixed effects and random effects approaches in advance. The proposed method applies in the same way to the analysis of a controlled multi-centre study with binary outcome, including a possible interaction between drugs and centres. Copyright 2001 John Wiley & Sons, Ltd.

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Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2.

Patricia McGettigan, David Henry (2006)

Evidence that rofecoxib increases the risk of myocardial infarction has led to scrutiny of other nonsteroidal anti-inflammatory drugs (NSAIDs). Regulatory agencies have provided variable advice regarding the cardiovascular risks with older nonselective NSAIDs. To undertake a systematic review and meta-analysis of controlled observational studies to compare the risks of serious cardiovascular events with individual NSAIDs and cyclooxygenase 2 inhibitors. Searches were conducted of electronic databases (1985-2006), scientific meeting proceedings, epidemiological research Web sites, and bibliographies of eligible studies. Eligible studies were of case-control or cohort design, reported on cardiovascular events (predominantly myocardial infarction) with cyclooxygenase 2 inhibitor, NSAID use, or both with nonuse/remote use of the drugs as the reference exposure. Of 7086 potentially eligible titles, 17 case-control and 6 cohort studies were included. Thirteen studies reported on cyclooxygenase 2 inhibitors, 23 on NSAIDs, and 13 on both groups of drugs. Two people independently extracted data and assessed study quality with disagreements resolved by consensus. Data were combined using a random-effects model. A dose-related risk was evident with rofecoxib, summary relative risk with 25 mg/d or less, 1.33 (95% confidence interval [CI], 1.00-1.79) and 2.19 (95% CI, 1.64-2.91) with more than 25 mg/d. The risk was elevated during the first month of treatment. Celecoxib was not associated with an elevated risk of vascular occlusion, summary relative risk 1.06 (95% CI, 0.91-1.23). Among older nonselective drugs, diclofenac had the highest risk with a summary relative risk of 1.40 (95% CI, 1.16-1.70). The other drugs had summary relative risks close to 1: naproxen, 0.97 (95% CI, 0.87-1.07); piroxicam, 1.06 (95% CI, 0.70-1.59); and ibuprofen, 1.07 (95% CI, 0.97-1.18). This review confirms the findings from randomized trials regarding the risk of cardiovascular events with rofecoxib and suggests that celecoxib in commonly used doses may not increase the risk, contradicts claims of a protective effect of naproxen, and raises serious questions about the safety of diclofenac, an older drug.

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Author and article information

Contributors

Parambir S Dulai: Role: clinical fellow

Siddharth Singh: Role: assistant professor

Evelyn Marquez: Role: research fellow

Rohan Khera: Role: research fellow

Larry J Prokop: Role: librarian

Paul J Limburg: Role: professor

Samir Gupta: Role: associate professor

Mohammad Hassan Murad: Role: professor

Journal

Journal ID (nlm-ta): BMJ

Journal ID (iso-abbrev): BMJ

Journal ID (publisher-id): bmj

Title: The BMJ

Publisher: BMJ Publishing Group Ltd.

ISSN (Print): 0959-8138

ISSN (Electronic): 1756-1833

Publication date Collection: 2016

Publication date (Electronic): 5 December 2016

Volume: 355

Electronic Location Identifier: i6188

Affiliations

[1 ]Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA

[2 ]Division of Biomedical Informatics, University of California San Diego, La Jolla, CA, USA

[3 ]Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

[4 ]Department of Library Services, Mayo Clinic, Rochester, MN, USA

[5 ]Divison of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

[6 ]Veterans Affairs San Diego Healthcare System, San Diego, CA, USA

[7 ]Moores Cancer Center, University of San Diego, La Jolla, CA, USA

[8 ]Evidence-based Practice Center, Mayo Clinic, Rochester, MN, USA

[9 ]Robert D and Patricia E Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA

Author notes

Correspondence to: S Singh sis040@ 123456ucsd.edu

Article

Publisher ID: dulp033783

DOI: 10.1136/bmj.i6188

PMC ID: 5137632

PubMed ID: 27919915

SO-VID: ab7ec3e5-2e63-4254-be3f-80e53ed4e522

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This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/.

Chemoprevention of colorectal cancer in individuals with previous colorectal neoplasia: systematic review and network meta-analysis

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Most cited references 32

A randomized trial of aspirin to prevent colorectal adenomas.

A refined method for the meta-analysis of controlled clinical trials with binary outcome.

Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2.

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