Background: Evidence from clinical trial populations suggests low-dose aspirin reduces the risk of colorectal cancer (CRC). Part of this reduction in risk might be due to protection against metastatic disease.

Methods: We investigated the risk of CRC among new-users of low-dose aspirin (75-300 mg), including risk by stage at diagnosis. Using The Health Improvement Network, we conducted a cohort study with nested case-control analysis. Two cohorts (N = 170,336 each) aged 40-89 years from 2000 to 2009 and free of cancer were identified: i) new-users of low-dose aspirin, ii) non-users of low-dose aspirin, at start of follow-up, matched by age, sex and previous primary care practitioner visits. Patients were followed for up to 12 years to identify incident CRC. 10,000 frequency-matched controls were selected by incidence density sampling where the odds ratio is an unbiased estimator of the incidence rate ratio (RR). RRs with 95% confidence intervals were calculated. Low-dose aspirin use was classified 'as-treated' independent from baseline exposure status to account for changes in exposure during follow-up.

Results: Current users of low-dose aspirin (use on the index date or in the previous 90 days) had a significantly reduced risk of CRC, RR 0.66 (95% CI 0.60-0.74). The reduction in risk was apparent across all age groups, and was unrelated to dose, indication, gender, CRC location or case-fatality status. Reduced risks occurred throughout treatment duration and with all low-dose aspirin doses. RRs by aspirin indication were 0.71 (0·63-0·79) and 0.60 (0.53-0.68) for primary and secondary cardiovascular protection, respectively. Among cases with staging information (n = 1421), RRs for current use of low-dose aspirin were 0.94 (0.66-1.33) for Dukes Stage A CRC, 0.54 (0.42-0.68) for Dukes B, 0.71 (0.56-0.91) for Dukes C, and 0.60 (0.48-0.74) for Dukes D. After 5 years' therapy, the RR for Dukes Stage A CRC was 0.53 (0.24-1.19).

Conclusions: Patients starting low-dose aspirin therapy have a reduced risk of Stages B-D CRC, suggesting a role for low-dose aspirin in the progression of established CRC; a substantial reduction in the risk of Dukes A CRC may occur after 5 years' therapy.

Background: A recent comprehensive review concluded that additional research is needed to determine the optimal use of aspirin for cancer prevention.

Objective: To assess associations between the use of low-dose aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) and colorectal cancer risk.

Design: Population-based, case-control study.

Setting: Northern Denmark.

Patients: Patients with first-time colorectal cancer in northern Denmark between 1994 and 2011. Population control participants were selected by risk set sampling.

Measurements: Data on drug use, comorbid conditions, and history of colonoscopy were obtained from prescription and patient registries. Use of low-dose aspirin (75 to 150 mg) and nonaspirin NSAIDs was defined according to type, estimated dose, duration, and consistency of use.

Results: Among 10 280 case patients and 102 800 control participants, the adjusted odds ratios (ORs) for colorectal cancer associated with ever use (≥2 prescriptions) of low-dose aspirin and nonaspirin NSAIDs were 1.03 (95% CI, 0.98 to 1.09) and 0.94 (CI, 0.90 to 0.98), respectively. Continuous long-term use (≥5 years) of low-dose aspirin was associated with a 27% reduction in colorectal cancer risk (OR, 0.73 [CI, 0.54 to 0.99]), whereas the overall OR for cumulative long-term use (continuous or noncontinuous) was close to unity. Nonaspirin NSAID use was associated with a substantial reduction in colorectal cancer risk, particularly for long-term, high-intensity use (average defined daily dose ≥0.3) of agents with high cyclooxygenase-2 selectivity (OR, 0.57 [CI, 0.44 to 0.74]).

Limitations: Data were unavailable on over-the-counter purchases of high-dose aspirin and low-dose ibuprofen or NSAID dosing schedules, there were several comparisons, and the authors were unable to adjust for confounding by some risk factors.

Conclusion: Long-term, continuous use of low-dose aspirin and long-term use of nonaspirin NSAIDs were associated with reduced colorectal cancer risk. Persons who continuously used low-dose aspirin comprised only a small proportion of the low-dose aspirin users.

Primary Funding Source: Danish Cancer Society, Aarhus University Research Foundation.

Background And Methods: Experiments in animals and two epidemiologic studies in humans suggest that aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) may be protective against colon cancer. We tested this hypothesis in a prospective mortality study of 662,424 adults who provided information in 1982 on the frequency and duration of their aspirin use. Death rates from colon cancer were measured through 1988. The possible influence of other risk factors for colon cancer was examined in multivariate analyses for 598 case patients and 3058 matched control subjects drawn from the cohort.

Results: Death rates from colon cancer decreased with more frequent aspirin use in both men and women. The relative risk among persons who used aspirin 16 or more times per month for at least one year was 0.60 in men (95 percent confidence interval, 0.40 to 0.89) and 0.58 in women (95 percent confidence interval, 0.37 to 0.90). The risk estimates were unaffected when we excluded persons who reported at entry into the study that they had cancer, heart disease, stroke, or another condition that might influence both their aspirin use and their mortality. Adjustment for dietary factors, obesity, physical activity, and family history did not alter the findings significantly. No association was found between the use of acetaminophen and the risk of colon cancer.

Conclusions: Regular aspirin use at low doses may reduce the risk of fatal colon cancer. Whether this is due to a direct effect of aspirin, perhaps mediated by the inhibition of prostaglandin synthesis, or to other factors indirectly associated with aspirin use is unclear.

BACKGROUND &

Aims: The antiplatelet effect of low-dose aspirin, via inhibition of cyclooxygenase-1, might contribute to its ability to reduce the risk of colorectal cancer (CRC). Antiplatelet agents with a different mechanism, such as clopidogrel, might have the same effects. We aimed to quantify the effects of low-dose aspirin and clopidogrel on the risk of CRC in a Mediterranean population.

Methods: We performed a nested case-control study using a primary care database (Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria) in Spain. We collected data, from 2001 through 2014, on 15,491 incident cases of CRC and 60,000 randomly selected individuals (controls), frequency-matched to cases by age, sex, and year. To estimate the association between exposure to different antiplatelet agents and the risk of colorectal cancer, we built multiple logistic regression models and computed the adjusted-odds ratios (AORs) and their respective 95% CIs.

Results: Use of low-dose aspirin was associated with a reduced risk of CRC overall (AOR, 0.83; 95% CI, 0.78-0.89) and in patients receiving treatment for more than 1 year (AOR, 0.79; 95% CI, 0.73-0.85). Use of clopidogrel was associated with a decreased risk of CRC overall (AOR, 0.8; 95% CI, 0.69-0.93) and in patients receiving treatment for more than 1 year (AOR, 0.65; 95% CI, 0.55-0.78). Dual antiplatelet therapy had the same effect as either drug taken as monotherapy. No modification by sex or age was observed.

Conclusions: In a nested case-control study of a primary care database in Spain, we found clopidogrel use, alone or in combination with low-dose aspirin, to reduce the risk of CRC by 20% to 30%, a magnitude similar to that of low-dose aspirin alone. These data support the concept that inhibiting platelets is an effective strategy for prevention of CRC.

Purpose: Aspirin (acetylsalicylic acid) has been reported to protect against certain cancers. However, patient-related risk factors may moderate protective effects, including excess weight, smoking, risky alcohol use, and diabetes. We explore the cancer-risk relationship between aspirin intake and those four factors.

Methods: Retrospective cohort study of cancers, aspirin intake, and four risk factors in persons aged ≥50 years. Participants received medication during 2007-2016, and cancers were diagnosed in 2012-2016. Adjusted hazard ratios (aHR) for 95% confidence intervals (95%CI) were calculated for aspirin intake and risk factors using Cox proportional hazard modeling.

Results: Of 118,548 participants, 15,793 consumed aspirin, and 4003 had cancer. Results indicated a significant protective effect of aspirin against colorectal (a

Hr: 0.7; 95%

Ci: 0.6-0.8), pancreatic (a

Hr: 0.5; 95%

Ci: 0.2-0.9), prostate (a

Hr: 0.6; 95%

Ci: 0.5-0.7) cancers and lymphomas (a

Hr: 0.5; 95%

Ci: 0.2-0.9), and also, although not significantly, against esophageal (a

Hr: 0.5; 95%

Ci: 0.2-1.8), stomach (a

Hr: 0.7; 95%

Ci: 0.4-1.3), liver (a

Hr: 0.7; 95%

Ci: 0.3-1.5), breast (a

Hr: 0.8; 95%

Ci: 0.6-1.0), and lung and bronchial (a

Hr: 0.9; 95%

Ci: 0.7-1.2) cancers. Aspirin intake was not significantly protective against leukemia (a

Hr: 1.0; 95%

Ci: 0.7-1.4) or bladder cancer (a

Hr: 1.0; 95%

Ci: 0.8-1.3).

Conclusions: Our results suggest that aspirin intake is associated with a reduced incidence of colorectal, pancreatic, and prostate cancers and lymphomas.

Background: Aspirin has been associated with a reduced risk of colorectal cancer, and possibly of a few other digestive tract cancers. The quantification of risk reduction and the optimal dose and duration of aspirin use for the prevention of colorectal and other digestive tract cancers remains unclear.

Methods: To provide an up-to-date quantification of this association, we conducted a systematic review and meta-analysis of all observational studies on aspirin and cancers of the digestive tract sites published through March 2019. We estimated the pooled relative risk (RR) of cancer for regular aspirin use versus non-use using random-effects models, and, whenever data were available, we investigated the dose- and duration-risk relations.

Results: Regular aspirin use is associated with a reduced risk of colorectal cancer [RR = 0.73, 95% confidence interval (CI) = 0.69-0.78, 45 studies], squamous-cell esophageal cancer (RR = 0.67, 95% CI = 0.57-0.79, 13 studies), adenocarcinoma of the esophagus and gastric cardia (RR = 0.61, 95% CI = 0.49-0.77, 10 studies), stomach cancer (RR = 0.64, 95% CI = 0.51-0.82, 14 studies), hepato-biliary tract cancer (RR = 0.62, 95% CI = 0.44-0.86, five studies), and pancreatic cancer (RR = 0.78, 95% CI = 0.68-0.89, 15 studies), but not of head and neck cancer (RR = 0.94, 95% CI = 0.76-1.16, 10 studies). The associations are somewhat stronger in case-control than in cohort and nested case-control studies and are characterized by some between-study heterogeneity. Risk estimates are consistent across sex, geographical areas, and other selected covariates. For colorectal cancer, an aspirin dose between 75 and 100 mg/day conveys a risk reduction of 10%, and a dose of 325 mg/day of 35%. For all neoplasms, except head and neck cancer, inverse duration-risk relations with aspirin use are found.

Conclusion: The present comprehensive meta-analysis supports and further quantifies the inverse association between regular aspirin use and the risk of colorectal and other digestive tract cancers, including some rare ones. The favorable effect of aspirin increases with longer duration of use, and, for colorectal cancer, with increasing dose.

Screening strategies have demonstrated their potential for decreasing the incidence and mortality of cancers, particularly that of colorectal cancer (CRC). Another strategy that has been developed to reduce CRC occurrence is the use of chemoprevention agents. Among them, aspirin is the most promising. Aspirin acts in colorectal tumourigenesis through several mechanisms, either directly in tumor cells or in their microenvironment, such as through its anti-inflammatory activity or its effect on the modulation of platelet function. Many retrospective studies, as well as follow-up of large cohorts from trials with primary cardiovascular end points, have shown that long-term treatment with daily low-dose aspirin decreases the incidence of adenomas and colorectal cancers. Therefore, aspirin is currently recommended by the United States Preventive Services Task Force (USPSTF) for primary prevention of CRC in all patients aged 50 to 59 with a 10-y risk of cardiovascular events greater than 10%. Furthermore, several studies have also reported that long-term aspirin treatment taking after CRC resection decreases recurrence risk and increases overall survival, especially in patients with -mutated tumors. This review summarizes current knowledge on the pathophysiological mechanisms of aspirin chemoprevention, discusses the primary clinical results on CRC prevention and highlights the potential biomarkers identified to predict aspirin efficacy.

Objective: To assess the association between low-dose aspirin and the incidence of colorectal cancer (CRC), gastric cancer (GC), oesophageal cancer (EC) and gastrointestinal bleeding (GIB) in adults without established atherosclerotic cardiovascular disease.

Design: Cohort study with propensity score matching of new-users of aspirin to non-users.

Setting: Clinical Data Analysis and Reporting System database, Hong Kong.

Participants: Adults ≥40 years with a prescription start date of either low-dose aspirin (75-300 mg/daily) or paracetamol (non-aspirin users) between 1 January 2004 to 31 December 2008 without a history of atherosclerotic cardiovascular disease.

Main Outcome Measures: The primary outcome was the first diagnosis of gastrointestinal cancer (either CRC, GC or EC) and the secondary outcome was GIB. Individuals were followed from index date of prescription until the earliest occurrence of an outcome of interest, an incident diagnosis of any type of cancer besides the outcome, death or until 31 December 2017. A competing risk survival analysis was used to estimate HRs and 95% CIs with death as the competing risk.

Results: After matching, 49 679 aspirin and non-aspirin users were included. The median (IQR) follow-up was 10.0 (6.4) years. HRs for low-dose aspirin compared with non-aspirin users were 0.83 for CRC (95% CI, 0.76 to 0.91), 0.77 for GC (95% CI, 0.65 to 0.92) and 0.88 for EC (95% CI, 0.67 to 1.16). Patients prescribed low-dose aspirin had an increased risk of GIB (HR 1.15, 95% CI, 1.11 to 1.20), except for patients prescribed proton pump inhibitors or histamine H2-receptor antagonists (HR 1.03, 95% CI, 0.96 to 1.10).

Conclusion: In this cohort study of Chinese adults, patients prescribed low-dose aspirin had reduced risks of CRC and GC and an increased risk of GIB. Among the subgroup of patients prescribed gastroprotective agents at baseline, however, the association with GIB was attenuated.

Although early detection and treatment of colorectal cancer (CRC) have improved, it remains a significant health-care problem with high morbidity and mortality. Data indicate that long-term intake of low-dose aspirin reduces the risk of CRC; however, the mechanisms underlying this chemopreventive effect are still unclear. Different mouse models for inflammation-associated, sporadic, and hereditary CRC were applied to assess the efficacy and mechanism of low-dose aspirin on tumor prevention. An initial dosing study performed in healthy mice indicates that aspirin at a dose of 25 mg/kg/d has a similar pharmacodynamic effect as low-dose aspirin treatment in human subjects (100 mg/d). Chronic low-dose aspirin treatment suppresses colitis-associated and to a lesser extent spontaneous tumorigenesis in mice. Aspirin's antitumor effect is most pronounced in a preventive approach when aspirin administration starts before the tumor-initiating genotoxic event and continues for the duration of the experiment. These effects are not associated with alterations in cell proliferation, apoptosis, or activation of signaling pathways involved in CRC. Aspirin-induced reduction in tumor burden is accompanied by inhibition of thromboxane B formation, indicating reduced platelet activation. Aspirin treatment also results in decreased colonic prostaglandin E formation and tumor angiogenesis. With respect to colitis-triggered tumorigenesis, aspirin administration is associated with a reduction in inflammatory activity in the colon, as indicated by decreased levels of pro-inflammatory mediators, and tumor-associated iNOS-positive macrophages. Our results suggest that low-dose aspirin represents an effective antitumor agent in the context of colon tumorigenesis primarily due to its well-established cyclooxygenase inhibition effects.

Screening strategies have demonstrated their potential for decreasing the incidence and mortality of cancers, particularly that of colorectal cancer (CRC). Another strategy that has been developed to reduce CRC occurrence is the use of chemoprevention agents. Among them, aspirin is the most promising. Aspirin acts in colorectal tumourigenesis through several mechanisms, either directly in tumor cells or in their microenvironment, such as through its anti-inflammatory activity or its effect on the modulation of platelet function. Many retrospective studies, as well as follow-up of large cohorts from trials with primary cardiovascular end points, have shown that long-term treatment with daily low-dose aspirin decreases the incidence of adenomas and colorectal cancers. Therefore, aspirin is currently recommended by the United States Preventive Services Task Force (USPSTF) for primary prevention of CRC in all patients aged 50 to 59 with a 10-y risk of cardiovascular events greater than 10%. Furthermore, several studies have also reported that long-term aspirin treatment taking after CRC resection decreases recurrence risk and increases overall survival, especially in patients with -mutated tumors. This review summarizes current knowledge on the pathophysiological mechanisms of aspirin chemoprevention, discusses the primary clinical results on CRC prevention and highlights the potential biomarkers identified to predict aspirin efficacy.

Considerable interest has emerged over the last decade regarding the role of aspirin in prevention of colorectal cancer. This disease is one of the commonest cancers in the Western World, therefore, the existence of a simple "everyday" agent, which could have the ability to prevent the disease, represents an invaluable opportunity clinicians may be able to exploit. Evidence from case-control and cohort studies, and recent updates of randomised controlled trials have been very encouraging-indicating benefit from long term use of aspirin at low dose. Possible mechanisms of chemoprevention include inhibition of the cyclooxygenase (COX) pathway, or COX-independent mechanisms, for example, the PIK3CA pathway, or therapy-induced senescence of cancer cells. The most serious side effect of prolonged aspirin treatment is haemorrhage, especially from the GI tract. This is likely to be less of a problem with chemoprevention at lower doses. One also needs to consider the impact if aspirin resistance, an increasingly recognised clinical entity.

At 125, aspirin still represents the cornerstone of anti-platelet therapy for the acute treatment and long-term prevention of atherothrombosis. The development of a selective regimen of low-dose aspirin for the inhibition of platelet thromboxane production was key to maximizing its antithrombotic efficacy and minimizing its gastrointestinal toxicity. Based on about 50 observational studies, published over the past 30 years, aspirin and other cyclooxygenase inhibitors have been associated with a reduced risk of colorectal cancer, and possibly other digestive tract cancers. The apparent chemopreventive effect of aspirin has been confirmed in post-hoc analyses of randomized cardiovascular trials and their meta-analyses. Moreover, prevention of sporadic colorectal adenoma recurrence was demonstrated by randomized controlled trials of low-dose aspirin and selective cyclooxygenase-2 inhibitors. A single placebo-controlled randomized trial of aspirin has shown long-term colorectal cancer prevention in patients with the Lynch syndrome. The sequential involvement of thromboxane-dependent platelet activation and cyclooxygenase-2-driven inflammatory response in the early stages of colorectal carcinogenesis may explain these clinical benefits. The aim of this mini-review is to analyze the existing evidence for a chemopreventive effect of aspirin and other cyclooxygenase inhibitors and discuss the missing pieces of this mechanistic and clinical puzzle.

Significance Statement: Low-dose aspirin and other cyclooxygenase inhibitors have been associated with a reduced risk of colorectal cancer, and possibly other digestive tract cancers. The sequential involvement of thromboxane-dependent platelet activation and cyclooxygenase-2-driven inflammatory response in the early stages of colorectal carcinogenesis may explain these clinical benefits. The aim of this mini-review is to analyze the evidence for a chemopreventive effect of aspirin and other cyclooxygenase inhibitors and discuss the missing pieces of this mechanistic and clinical puzzle.