Aspirin and Delayed Chemoprevention of Colorectal Cancer.
Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz GA, Willett WC, Speizer FE. Aspirin and the risk of colorectal cancer in women. N Engl J Med 1995;333:609-14. 
In the 1980s, emerging epidemiologic evidence suggested that risk of colorectal cancer was lower in aspirin users. This finding drew interest from researchers. The Physicians' Health Study was a randomized, double-blinded, placebo-controlled trial of aspirin (325 mg taken every other day) and [beta]-carotene. The trial was terminated in 1988 after 4.7 years because of a significant reduction in myocardial infarction in aspirin users. The investigators resourcefully used the data to consider aspirin use in relation to colorectal cancer risk. They published in 1993 that aspirin did not reduce colorectal cancer incidence during 5 years of randomized treatment and follow-up evaluation (1). This disappointing result led many to suspect that the observational data were unreliable and prone to selection bias, recall bias, and confounding.
Yet, the possibility remained that the intervention of 5 years was not long enough to elicit an effect on cancer, which may develop over a course of decades. We had collected detailed information on aspirin use in 2 large existing cohorts, the Health Professionals Follow-Up Study (HPFS)  and the Nurses' Health Study (NHS), primarily interested in cardiovascular disease. Because aspirin use was updated every 2 years, we could study the critical issue of timing in relation to colorectal cancer risk. Our initial publication in 1994 on this topic in the HPFS did indicate that long-term users had about one-third lower risk of incident colorectal cancer and about half the risk of metastatic colorectal cancer. Shortly thereafter, we conducted a more detailed duration analysis in the NHS, which had a longer follow-up period. When we examined colorectal cancer risk by years of use of aspirin, we found no association up to 5 years, a hint of a benefit after 5 to 9 years of use, but a clearer benefit only after [greater than or equal to] 10 years of usage. We extensively examined the potential influence of various biases, but the results appeared robust.
The use of aspirin as a chemopreventive agent for colorectal cancer remained promising but unresolved entering the new millennium. Randomized studies of aspirin, mostly designed for cardiovascular benefit, continued to not show a benefit for colorectal cancer even after a decade of aspirin use. Yet, some randomized trials of aspirin and colorectal adenoma recurrence supported a benefit (2). Newly onset adenomas generally require at least 10 years to develop into carcinoma. If aspirin were operative at early stages of colorectal carcinogenesis, an observable effect on cancer would require at least a decade, consistent with our findings for cancer. In 2007, extended follow-up of 2 large randomized trials showed use of [greater than or equal to] 300 mg a day of aspirin for 5 years effectively reduced risk of colorectal cancer after a latency of about 10 years (3). In 2013, extended follow-up of 100 mg, alternate-day aspirin use in the Women's Health Study showed a posttrial reduction of 43%, after a previous analysis showed no benefit in the first 10 years (4). In a randomized trial published in 2011, aspirin use reduced the occurrence of colorectal cancer in patients with Lynch syndrome (5). Interestingly, the effect became apparent only after 3 to 4 years from the start of the aspirin intervention, consistent with the faster cancer development in these patients than for sporadic colorectal cancer.
The initial clues for a benefit of aspirin on colorectal cancer extend back to the 1980s. It is sobering that >2 decades were required to establish a definitive effect, and even after 3 decades, practical questions about clinical use remain unresolved (6). The concept of "delayed chemoprevention," suggested by the NHS and HPFS analyses, was borne out over time. For cancer, prevention may not always emerge overnight. Most interventional studies are <10 years, with many much shorter. These studies may be missing important effects for some cancer prevention agents that act at earlier stages of carcinogenesis.
Author Contributions: AH authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.
Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
Received July 16, 2018; accepted July 17, 2018.
Previously published online at DOI: 10.1373/clinchem.2018.290809
(1.) Gann PH, Manson JE, Glynn RJ, Buring JE, Hennekens CH. Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Nat Cancer Inst 1993;85:1220-4.
(2.) Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, McKeown-Eyssen G, et al. A randomized trial of aspirin to prevent colorectal cancer. N Engl J Med 2003;348:891-9.
(3.) Flossmann E, Rothwell PM, British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 2007; 369:1603-13.
(4.) Cook NR, Lee IM, Zhang SM, Moorthy MV, Buring JE. Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Ann Intern Med 2013;159:77-85.
(5.) Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2011;378:2081-7.
(6.) Drew DA, Cao Y, Chan AT. Aspirin and colorectal cancer: the promise of precision chemoprevention. Nat Rev Cancer 2016;16:173-86.
Edward Giovannucci  *
 Harvard T.H. Chan School of Public Health, Boston, MA.
 This article has been cited 654 times since publication.
 This article has been cited 552 times since publication.
 Nonstandard abbreviations: HPFS, Health Professionals Follow-Up Study; NHS, Nurses' Health Study.
* Address correspondence to the author at: Harvard T.H. Chan School of Public Health, 665 Huntington Ave., Boston, MA 02115. Fax 617-432-2435; e-mail firstname.lastname@example.org.
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|Title Annotation:||Citation Classic|
|Article Type:||Clinical report|
|Date:||Nov 1, 2018|
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