Timing of Aspirin use in Colorectal Cancer Chemoprevention

A Prospective Cohort Study

Yin Zhang, MD; Andrew T. Chan, MD, MPH; Jeffrey A. Meyerhardt, MD, MPH; Edward L. Giovannucci, MD, ScD


J Natl Cancer Inst. 2021;113(7):841-851. 

In This Article

Abstract and Introduction


Background: Prior epidemiological and intervention studies have not been able to separate independent effects of dose, timing, and duration of aspirin use in colorectal cancer (CRC) chemoprevention. We examined aspirin-based CRC chemoprevention according to timing in the Nurses' Health Study and Health Professionals Follow-Up Study.

Methods: The exposures include cumulative average dose and total duration of aspirin use in more than 10 years before follow-up started (remote period) and in the immediate 10 years before follow-up started (recent period). Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for exposures and CRC risk.

Results: Aspirin use of longer than 10 years before follow-up started (HR = 0.88, 95% CI = 0.83 to 0.94) per 5-year increment and the immediate 10 years before follow-up started (HR = 0.90, 95% CI = 0.84 to 0.96) were similarly important in CRC chemoprevention, though a 5-year lag was required for a clear benefit in the recent period. In the remote period, the association was not dose dependent; compared with less than 0.5 standard-dose (325 mg) tablets per week; hazard ratios were 0.78 (95% CI = 0.63 to 0.98), 0.81 (95% CI = 0.72 to 0.91), and 0.74 (95% CI = 0.64 to 0.86) for doses of 0.5 to less than 1.5, 1.5 to less than 5, and 5 and more tablets per week, respectively. However, there was dose dependency in the recent period (with respective HR = 0.91, 95% CI = 0.79 to 1.06; HR = 0.87, 95% CI = 0.77 to 0.98; and HR = 0.76, 95% CI = 0.64 to 0.91).

Conclusions: A suggestive benefit necessitates at least 6–10 years and most clearly after approximately 10 years since initiation of aspirin. Remote use and use within the previous 10 years both contribute independently to decrease risk, though a lower dose may be required for a benefit with longer term use.


The global disease burden of colorectal cancer (CRC) is substantial.[1,2] CRC accounted for 10% of all new cancer diagnoses and 9% of cancer deaths worldwide[1] and is estimated to be the third-most common incident cancer and the second leading cause of cancer death in the United States in 2020.[2] Aspirin (acetylsalicylic acid) is the most promising chemopreventive agent for CRC, with convincing evidence having emerged over the past 3 decades[3–8] since the hypothesis and initial observational studies and trials in this field were reported.[3,9–15] In 2016, after systematic evidence reviews[16] and the balance of benefits and harms,[17] the US Preventive Services Task Force (USPSTF) recommended low-dose aspirin for CRC primary prevention among US adults with specific age and cardiovascular risk profiles as a crucial first step.[18]

Although the USPSTF recommendation reflects mounting evidence for the potential of aspirin in the complex landscape of CRC primary prevention, several important issues remained unsatisfactorily resolved entering the 2020s. Timing is a critical issue in aspirin-based CRC chemoprevention strategies.[4,6,18] The concept of "delayed chemoprevention," initially suggested by the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) analyses,[10,11] borne out over time, indicates that the observable benefit of aspirin on CRC would require approximately 10 or more years after initiation of aspirin use.[4,11,12,18–20] Aspirin may act at early stages of CRC carcinogenesis. However, important questions regarding timing remain, including if there is a time lag to demonstrate an apparent benefit, is continuing use necessary to reduce risk, or does it add benefit over remote use? If a benefit occurs in the remote period (eg, use before 10 years in the past), what is the dose and duration effect during this period? Is benefit of long-term aspirin use dose dependent? Is there heterogeneity in minimal effective dose across timing? Prior studies have not been able to adequately distinguish the effect of aspirin use according to timings (ie, in the remote and recent periods separately).

The NHS[21] and HPFS[22] longitudinal cohorts afford rich sources to consistently add high-quality evidence to this field.[4,10,11,20,23] We thus comprehensively investigated the pivotal role of timing in aspirin-based primary CRC chemoprevention.