ABSTRACT: We undertook a systematic review to synthesise the data on attitudes and behaviour towards the use of aspirin for cancer prevention, and healthcare providers' attitudes towards implementing aspirin in practice. Searches were carried out across 12 databases (e.g. MEDLINE, EMBASE). We used the Mixed Methods Appraisal Tool to evaluate study quality, and conducted a narrative synthesis of the data. The review was pre-registered (PROSPERO:CRD42018093453). Thirty-eight studies were identified. Uptake and adherence data were all from trials. Trials recruited healthy participants, those at higher risk of cancer, and those with cancer. Four studies reported moderate to high (40.9–77.7%) uptake to an aspirin trial among people who were eligible. Most trials (18/22) reported high day-to-day adherence (≥80%). Three trials observed no association between gender and adherence. One trial found no association between adherence and colorectal cancer risk. Three studies reported moderate to high (43.6–76.0%) hypothetical willingness to use aspirin. Two studies found that a high proportion of healthcare providers (72.0–76.0%) perceived aspirin to be a suitable cancer prevention option. No qualitative studies were identified. The likelihood that eligible users of aspirin would participate in a trial evaluating the use of aspirin for preventive therapy was moderate to high. Among participants in a trial, day-to-day adherence was high. Further research is needed to identify uptake and adherence rates in routine care, the factors affecting aspirin use, and the barriers to implementing aspirin into clinical care.
Colorectal adenomas have the potential of malignant transformation if left untreated. Multiple randomized controlled trials have been performed to evaluate the efficacy of aspirin in preventing colorectal adenoma recurrence in a population with a history of colorectal adenoma but not colorectal cancer, however, the relationship between aspirin dose and colorectal adenoma recurrence remains unclear. We conducted pairwise meta-analysis, meta-regression, trial sequential analysis, and network meta-analysis of all eligible studies. The ROB 2.0 tool was used to assess the risk of bias in the studies. The confidence in network meta-analysis (CINeMA) approach was used to evaluate the confidence of the network meta-analysis results. The network meta-analysis included eight RCTs (nine reports), comprising four on aspirin (low or high dose) alone and four on aspirin combined with another medication, all compared with placebo. In the network meta-analysis, low-dose aspirin (LDA <300 mg per day) was more effective than high-dose aspirin (HDA [≥]300 mg per day) and placebo, with risk ratios of 0.76 (95% CI: 0.58 to 0.99) and 0.7 (95% CI: 0.54 to 0.91), respectively. LDA was the optimal treatment relative to HDA and placebo (P-score = 0.99). In the trial sequential analysis, LDA was only more effective than placebo when the number of included participants exceeded the optimal information size; this was not the case for HDA. LDA has statistically significant efficacy for colorectal adenoma prevention, but compared with HDA, its efficacy remains uncertain. Further trials are therefore required.
ABSTRACT: Colorectal cancer (CRC) is the fourth most common cancer and third leading cause of cancer-related death worldwide. Use of chemopreventive agents (CPAs) to reduce the incidence of precursor colorectal adenomas could lower the future burden of CRC. Many classes of potential CPAs have been investigated. To identify the most effective CPAs, we conducted a systematic review and a network meta-analysis (NMA). An electronic search was performed through August 2020 to identify all randomized controlled trials (RCTs) assessing the efficacy of CPAs in reducing the incidence of colorectal adenomas at the time of surveillance colonoscopy among patients who had previously undergone polypectomy during an index colonoscopy. In total, 33 RCTs were included in the NMA, which was conducted under a Bayesian inference framework. Random effects models were used with adjustment for follow-up length and control group event rates to yield relative risks (RRs) and 95% credible intervals (CrIs). Our full network consisted of 13 interventions in addition to a placebo arm. Of 20,925 included patients, 7766 had an adenoma. Compared to placebo, the combination of difluoromethylornithine (DFMO) + Sulindac (RR 0.24, CrI 0.10-0.55) demonstrated a protective effect, while aspirin had a RR of 0.77 (CrI 0.60-1.00), celecoxib 800 mg had a RR of 0.56 (CrI 0.31-1.01) and metformin had a RR of 0.56 (CrI 0.22-1.39). Our results suggest that select CPAs may be efficacious in preventing the development of adenomas. Further studies are needed to identify those patients most likely to benefit and the minimum effective dosages of CPAs.
PURPOSE: Colorectal cancer is the second most common cause of cancer death worldwide. Aspirin, due to its antineoplastic effects, has been suggested to have chemopreventive effects on colorectal cancer based on recent trials. We conducted this systematic review and meta-analysis to provide an updated evidence about the long-term efficacy of daily aspirin use in the prevention of colorectal cancer.
METHODS: We searched Medline/PubMed, Ovid, Web of Science, and Cochrane Library. We included randomized controlled trials (RCTs) that compared the efficacy of daily aspirin use to placebo in healthy individuals at the time of study entry. The desired outcomes of this review were the incidence of advanced lesions (i.e., adenomas with villous component, adenomas ≥1 cm in diameter, adenomas with high-grade dysplasia, and/or invasive cancer) and colorectal adenomas.
RESULTS: A total of 15 articles representing 11 RCTs were included. Overall, the results indicated that aspirin significantly reduced the risk of developing colorectal adenomas but not advanced lesions at 3 years (risk ratio (RR) = 0.84, P < 0.05 and risk ratio = 0.82, P = 0.10, respectively). At 5 years, the risk of advanced lesions but not adenomas was reduced by aspirin (RR = 0.68, P < 0.05 and RR = 0.87, P = 0.22, respectively). Aspirin was not found to have an effect on the risk of advanced lesions or adenomas beyond 5 years (hazard ratio (HR) = 0.82, P = 0.07 and HR = 0.99, P = 0.82, respectively).
CONCLUSION: Overall, aspirin (particularly high dose) only reduced the risk of advanced lesions up to 5 years.
BACKGROUND: Colorectal cancer (CRC) is the third most common diagnosed cancer and the third leading cause of all cancer deaths in the USA. Some evidences are shown that aspirin can reduce the morbidity and mortality of different cancers, including CRC. Aspirin has become a new focus of cancer prevention and treatment research so far; clinical studies, however, found conflicting conclusions of its anti-cancer characteristics. This study is to summarize the latest evidence of correlation between aspirin use and CRC and/or colorectal adenomas.
METHODS: Databases were searched to identify randomized controlled trials (RCTs) in the salvage setting. The pooled relative risk (RR) with 95% confidence interval (CI) was used to estimate the effect of aspirin on colorectal cancer and/or colorectal adenomas. Subgroup analysis and sensitivity analysis were also conducted.
RESULTS: The result showed that aspirin use was not associated with incidence of CRC (RR 0.97; 95% CI 0.84-1.12; P = 0.66; I2 = 34%), aspirin use was found to be associated with reduced recurrence of colorectal adenomas (RR 0.83; 95% CI 0.72-0.95; P = 0.006; I2 = 63%) and reduced mortality of CRC (RR 0.79; 95% CI 0.64-0.97; P = 0.02; I2 = 14%). Subgroup analysis found a statistically significant association in low dose with a pooled RR of 0.85 (95% CI 0.74-0.99; P = 0.03; I2 = 31%).
CONCLUSIONS: This meta-analysis of randomized controlled trial data indicates that aspirin reduces the overall risk of recurrence and mortality of CRC and/or colorectal adenomas. Incidence of CRC was also reduced with low-dose aspirin. The emerging evidence on aspirin's cancer protection role highlights an exciting time for cancer prevention through low-cost interventions.
TRIAL REGISTRATION: Clinicaltrials.gov no: CRD42020208852; August 18, 2020; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020208852 ).
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).
BACKGROUND/OBJECTIVES: Nutrition and dietary supplementation may modulate outcomes in colorectal cancer (CRC) survivors. However, no recent systematic review has focused on randomised controlled trials (RCTs). The aim of this systematic review was to examine the effects of nutritional RCTs in survivors of colorectal adenomas and cancer.
SUBJECTS/METHODS: Medline, Embase, Scopus, Web of Science and the Cochrane Library were searched to identify research between April 2006 and January 2014. The primary outcomes were colorectal adenoma and cancer recurrence. Each included study was assessed for risk of bias. A meta-analysis using a random-effects model was performed, in which two or more RCTs investigated the same dietary intervention.
RESULTS: Eight completed RCTs, all in colorectal adenoma survivors, were identified, with four investigating the effect of folic acid. A meta-analysis of the four folic acid RCTs showed no statistically significant effect of folic acid on colorectal adenoma recurrence (relative risks=0.93; 95% confidence interval: 0.69, 1.25). The impact of the remaining completed RCTs, investigating antioxidant supplementation, green tea extract, prebiotic fibre and phytooestrogens/insoluble fibre, could not be reliably estimated because of the limited number and heterogeneity of the interventions. In addition, three heterogeneous ongoing RCTs were identified, investigating green tea (n=1) and eicosapentaenoic acid (n=1) in colorectal adenoma survivors and dietary modifications (n=1) in CRC survivors in remission.
CONCLUSIONS: Overall, this systematic review highlights the need for further research, especially in CRC survivors, as we identified no completed and only one ongoing RCT in this population.European Journal of Clinical Nutrition advance online publication, 13 January 2016; doi:10.1038/ejcn.2015.210.
BACKGROUND: Through search the possible randomized control trials, we make a renewed meta-analysis in order to assess the impact of aspirin in preventing the recurrence of colorectal adenoma.
MATERIALS AND METHODS: The Medicine/PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese biomedical literature service system (SinoMed) databases were searched for the related randomized controlled trials until to the April 2016. Three different authors respectively evaluated the quality of studies and extracted data, and we used the STATA software to analyze, investigate heterogeneity between the data, using the fixed-effects model to calculate and merge data.
RESULTS: 7 papers were included the renewed meta- analysis, among these studies, two pairs were identified as representing the same study population, with the only difference being the duration of follow-up. Thus there were only five papers included our meta-analysis, and one Chinese paper were also included the work. Results were categorized by the length of follow-up, different kinds of people, varied dose of oral aspirin. The relative of adenoma in patients taking aspirin vs placebo were 0.73 (95% CI 0.55-0.98, P=0.039) with 1 year follow up; 0.84 (95% CI 0.72-0.98, P=0.484) with greater than 1 year follow up; for the advanced adenoma, the RR 0.68 (95% CI 0.49-0.94, P=0.582),for one year; RR=0.75 (95% CI 0.52-1.07, P=0.552) for greater one year. Furthermore the white population could divided into two subgroups according to the different length of follow-up time. When the length of follow-up time less than 3-year, The RR of two subgroups respective were RR=0.86 (95% CI 0.76-0.98, P=0.332), I2=0%, RR=0.68 (95% CI 0.47-0.98, P=0.552), I2=64.6%, But with the extension of follow-up time greater than 2-year, with the white, oral aspirin without considering dose had no efficacy on preventing the recurrence of any adenoma, the RR was 0.86 (95% CI 0.71-1.05, P=0.302), I2=16.4%.
CONCLUSIONS: This meta-analysis indicated that oral aspirin is associated with a remarkable decrease in the recurrence of any adenoma and advanced adenomas in patients follow-up for 1 year without concerning the dose of aspirin, but with the extension of follow-up time for greater than 1 year, oral aspirin can be effective on preventing the recurrence of any adenoma, but for the advanced adenoma, the result indicated that oral aspirin had no efficacy, According to the inclusion of ethnic groups, we also divided relevant papers into two subgroups as the yellow and white group. Then the follow-up time was less than 3 years, oral aspirin without considering the dose, had an significant efficacy on preventing the recurrence of any adenoma. But with the follow-up greater than 2 years, oral aspirin had no effect in the white.
BACKGROUND: Cancer is the second leading cause of death in United States. The net benefit for aspirin (ASA) in cardiovascular disease (CVD) primary prevention is controversial due to increased risks from bleeding alongside relatively modest cardiovascular benefits. Consideration of additional cancer prevention effects might clarify whether long-term, low-dose ASA may offer an overall health benefit for the two top causes of mortality in the United States.
PURPOSE: We conducted this review, alongside two companion reviews, to support the U.S. Preventive Services Task Force (USPSTF) in making evidence-based recommendations about the use of ASA for primary prevention in adults and to understand the risks of regular ASA use.
DATA SOURCES: We used a systematic evidence review published in 2012 for cancer-specific and all-cause mortality outcomes and conducted a bridge search of PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials from 2011 to October 2013. For bleeding harms, we used four published systematic evidence reviews and conducted a search of PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials from January 1, 2010 to June 3, 2014 in PubMed and MEDLINE. We also reviewed all studies included and excluded for companion USPSTF reviews on ASA for colorectal cancer and CVD prevention and checked for additional relevant studies by reviewing reference lists of included studies and other published reviews or meta-analyses.
STUDY SELECTION: Two investigators independently reviewed 4,393 abstracts and 336 articles against previously established inclusion and exclusion criteria and critically appraised studies for risk of bias using USPSTF methods, supplemented by the Newcastle-Ottawa Scale for cohort studies and the Assessment of Multiple Systematic Reviews for systematic reviews. We included fair- or good-quality trials evaluating the effect of 75 mg or greater ASA at least every other day for 12 months or longer versus no ASA, in the absence of other antithrombotic medications, on cancer mortality, all-cause mortality, cancer incidence, and harms, primarily related to serious bleeding. We also included cohort studies meeting these criteria to evaluate potential harms of ASA.
DATA EXTRACTION AND ANALYSIS: For fair- and good-quality studies, one investigator abstracted study characteristics and outcomes into structured tables and a second verified accuracy. We assessed trials for heterogeneity using I(2) statistics and pooled trial-level results when appropriate using Mantel-Haenszel fixed effects to calculate relative risks (RRs) and Peto's odds ratios (OR). We focused on cancer effects and bleeding harms in CVD primary prevention trials, but also assessed results after including secondary CVD and colorectal adenoma prevention trials. Expected outcome rates with ASA intervention were calculated by multiplying simulated control group event rates for benefits as well as harms from the CVD primary prevention trials by the pooled RR estimate (and bounds of 95% confidence interval [CI]). The expected outcome rates were subtracted from the simulated control group rate to calculate the absolute risk reduction with 95% CI. We calculated expected outcomes using the minimum, maximum, and median control group rate for a given outcome to examine the range of results suggested by the primary studies.
RESULTS: When restricting analyses to 10 CVD primary prevention trials with a median of 6.0 years of followup, we found a nonsignificantly reduced mortality due to cancer among 103,787 individuals randomized to ASA or no ASA over 3.7 to 10.1 years (RR, 0.96 [95% CI, 0.87 to 1.06]), corresponding to 0.14 fewer cancer deaths (95% CI, 0.21 more to 0.45 fewer) per 1,000 person-years. Effects on all cancer mortality remained nonstatistically significant in sensitivity analyses exploring the effect of excluding trials of greater than 100 mg per day, of average length of scheduled treatment less than 5 years, or of every other day dosing. Only when including trials of both primary and secondary CVD prevention with doses up to 1,200 mg per day and requiring daily dosing within a scheduled treatment duration of 4 years or more could we find a statistically significant cancer mortality benefit (RR, 0.83 [95% CI, 0.70 to 0.98]) as reported by others. All-cause mortality in 10 CVD primary prevention trials was statistically significantly reduced (RR, 0.94 [95% CI, 0.88 to 0.99]), corresponding to 0.57 fewer deaths (95% CI, 0.10 fewer to 1.15 fewer) per 1,000 person-years, but was sensitive to including longer-term followup results from one trial and some other changes in inclusion or exclusion criteria. When also including CVD secondary prevention trials, all-cause mortality was similarly reduced and remained statistically significant when requiring daily dosing, dosages of 100 mg or less, or at least 4 years of followup, but not when substituting longer-term followup results. Few reduced deaths were cardiovascular and reduced nonvascular noncancer deaths appeared to play a prominent role, but this deserves further exploration. Among 72,926 participants in six CVD primary prevention trials, cancer incidence was similar between ASA and no ASA groups (RR, 0.98 [95% CI, 0.93 to 1.04]), corresponding to 0.20 fewer incident cases (95% CI, 0.39 more to 0.69 fewer) per 1,000 person-years, and was only statistically significantly reduced when including both primary and secondary CVD prevention trials and restricting to daily dose interventions with at least 4 years of followup with doses ranging from 75 to 500 mg per day (RR, 0.86 [95% CI, 0.74 to 0.99]). Data from primary prevention populations are currently too sparse to robustly examine cancer incidence or mortality for any cancer type other than colorectal cancer, which is examined in a companion report. Among 10 CVD primary prevention trials, the risk of major GI bleeding was increased (OR, 1.59 [95% CI, 1.32 to 1.91]), corresponding to 0.29 more cases of bleeding (95% CI, 0.44 more to 0.16 more) per 1,000 person-years. Sensitivity analyses showed little variation, except nonsignificantly increased risk with daily dosing and nonsignificantly decreased risk with alternate-day dosing. Risk of hemorrhagic stroke or other intracranial bleeding tended to be increased in primary prevention trials (OR, 1.27 [95% CI, 0.98 to 1.66]), corresponding to 0.11 more cases (95% CI, 0.28 more to 0.01 fewer) per 1,000 person-years, with statistically significant effects only when both primary and secondary prevention trials were combined (OR, 1.43 [95% CI, 1.12 to 1.81]). When restricted to all trials of 100 mg or less, the risk tended to decrease (OR, 1.32 [95% CI, 1.00 to 1.75]). Relatively rare events limited analyses. Data from cohort studies indicated that baseline rates of serious bleeding are higher than suggested from trials, and data from trials as well as cohorts indicated considerable baseline bleeding rate variation according to age, sex, diabetes, hypertension, and perhaps other selected cardiovascular risk factors. Comedications such as nonsteroidal anti-inflammatory drugs appeared to modify baseline rates in cohort studies, as well as bleeding risks with low-dose ASA, although data adjusted for other risk factors suggested a more modest combined effect than earlier estimates. These and other bleeding risk factors could potentially have a large impact on the absolute number of excess cases of bleeding and therefore net benefit considerations.
LIMITATIONS: Data on cancer benefits were limited by few trials—particularly of low-dose ASA and in CVD primary prevention populations—with adequate length of followup, which also limited analyses for cancer site-specific effects. Few analyses adjusted for combined impact of risk factors on bleeding risks; intracranial bleeding/hemorrhagic strokes are relatively rare and thus incompletely studied, and other potential risks of long-term ASA use are also understudied. Most currently available trial data are from older studies not specifically designed for outcomes beyond CVD and major bleeding, and not considering contemporary medications such as statins. In-progress research will be very valuable in updating these findings.
CONCLUSIONS: Low-dose ASA use may eventually be shown to provide modest cancer mortality benefits in CVD primary prevention populations, but effects are not clearly established since current estimates are imprecise and relatively unstable. Modest reductions in all-cause mortality effect are more stable, but cannot be completely explained through cancer and/or CVD mortality reduction. Rates of serious bleeding, with and without ASA, are higher than previously suggested in clinical trial populations, and are very important when assessing the likely net benefit of low-dose ASA use as a chemopreventive agent in a more individualized or subpopulation-specific manner.
We undertook a systematic review to synthesise the data on attitudes and behaviour towards the use of aspirin for cancer prevention, and healthcare providers' attitudes towards implementing aspirin in practice. Searches were carried out across 12 databases (e.g. MEDLINE, EMBASE). We used the Mixed Methods Appraisal Tool to evaluate study quality, and conducted a narrative synthesis of the data. The review was pre-registered (
PROSPERO:
CRD42018093453). Thirty-eight studies were identified. Uptake and adherence data were all from trials. Trials recruited healthy participants, those at higher risk of cancer, and those with cancer. Four studies reported moderate to high (40.9–77.7%) uptake to an aspirin trial among people who were eligible. Most trials (18/22) reported high day-to-day adherence (≥80%). Three trials observed no association between gender and adherence. One trial found no association between adherence and colorectal cancer risk. Three studies reported moderate to high (43.6–76.0%) hypothetical willingness to use aspirin. Two studies found that a high proportion of healthcare providers (72.0–76.0%) perceived aspirin to be a suitable cancer prevention option. No qualitative studies were identified. The likelihood that eligible users of aspirin would participate in a trial evaluating the use of aspirin for preventive therapy was moderate to high. Among participants in a trial, day-to-day adherence was high. Further research is needed to identify uptake and adherence rates in routine care, the factors affecting aspirin use, and the barriers to implementing aspirin into clinical care.
