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Do aspirin and other NSAIDs protect against colorectal cancer?Sarah Kraus and Nadir Arber

a recent study by Din et al. has demonstrated that a low dose of aspirin (75 mg per day) can decrease the incidence of colorectal cancer (CrC) after only 5 years of treatment. the study also shows that use of an nsaID before diagnosis of CrC does not improve survival.Kraus, s. & Arber, n. Nat. Rev. Gastroenterol. Hepatol. 8, 125–126 (2011); published online 18 January 2011; doi:10.1038/nrgastro.2010.217

evidence clearly indicates that aspirin and other nsaiDs have a protective effect against colorectal cancer (CrC); however, the lowest effective doses, treatment dura­tion, target populations and the effects on survival have not been defined as yet. in a recent report, Din and colleagues attempt to explore the relationship between nsaiD dose and duration of therapy, CrC risk and overall survival in patients with CrC.1

several epidemiological, clinical and observational studies have shown that nsaiDs can protect against CrC and sub­stantially reduce its incidence.2,3 moreover, prospective, randomized, controlled trials in patients at high risk of developing CrC have demon strated that nsaiDs can cause regression of existing colo rectal adenomas and prevent the formation of new polyps. in addition, studies in large groups of patients at high risk of sporadic CrC have shown consider able reductions in adenoma recurrence following treatment with nsaiDs.4,5

although the protective effect of nsaiDs in patients with CrC has been clearly demon strated in 60 of 62 epidemiologi­cal studies evaluated,6 the us Preventive services task Force (usPtF) has not recom mended aspirin for primary chemo­prevention.2 However, the usPtF has highlighted the need to establish the most effective aspirin dose, duration of intake and the age at which treatment should be started.2 two randomized, controlled trials that assessed the use of low­dose aspirin—the Physicians’ Health study 7 and the women’s Health study8—did not show a protective effect, mainly because the data for CrC mortality were limited.2 thus, while an aspirin dosage of 325 mg per day

for 5 years did not substantially reduce the incidence of adenomas in patients with an average risk of CrC, in those with a history of colo rectal adenomas, the use of aspirin at dosages of 81–325 mg per day for 1 year resulted in a statistically significant reduction in the relative risk of adenoma.5 the usPtF also concluded that benefits from chemo prevention were more evident when aspirin was used at a high dose (>325 mg per day) for long periods of time (>10 years).2 studies with the aim of defin­ing the lowest effective dose of nsaiD, optimal treatment duration, age of treat­ment initiation and identification of sub­populations where the risk to benefit ratio is optimized are still lacking.9

the main objective of the study by Din et al.1 was to investigate the hypoth­esis that regular use of aspirin and other nsaiDs reduces the incidence of CrC and to determine whether nsaiD use before diagnosis of CrC influences sur­vival. the authors analyzed data from a large, population­based, case–control study that included 2,279 patients with CrC and 2,907 controls. they compared the incidence of CrC and overall survival among three nsaiD categories; low­dose aspirin (75 mg), nonaspirin nsaiDs (na­nsaiDs), and any nsaiD. the main finding demonstrates that the lowest dose of aspirin (75 mg per day) protects against CrC after only 5 years of use in the general

population. among the patients with CrC, 354 (15.5%) were taking low­dose aspirin compared with 526 control participants (18.1%). low­dose aspirin use was associ­ated with a decreased risk of developing CrC, which was evident after 1 year and increased with duration of use. the use of na­nsaiDs and any nsaiDs were also inversely associated with the risk of developing CrC. the reduction in risk remained statistically significant after adjusting for confounding factors, such as age, sex and Bmi.

interestingly, a study by Johnson et al.10 in a large, general­risk population, sup­ports the findings from previous studies showing that regular use of aspirin (≥4 times per month) and ibuprofen is associ­ated with a decreased risk of colorectal adenomas, and demonstrates that this pro­tective effect might be stronger in certain subgroups. thus, as the frequency of aspirin use increased, the prevalence of polyps consider ably decreased. the overall pro­tection following heavy use of combined aspirin and ibuprofen (≥2 times per day) was more evident in men than in women; the protective effect of nsaiDs for women were apparent only among those with Bmi <25 kg/m2. in addition, the protective effect of nsaiDs was slightly stronger in the group aged 70–74 years old compared with those aged 55–69 years.10

Din and colleagues have shown that doubling the dosage of aspirin does not lead to a proportional reduction in CrC risk, which suggests that the lowest aspirin dose of 75 mg is indeed effective. of note, dose­dependency has not been demon­strated by other studies. For example, in an analysis of two large trials, Flossmann

‘‘…the lowest dose of aspirin (75 mg per day) protects against CRC after only 5 years of use…’’

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et al.3 did not find that aspirin had a dose­dependent protective effect against CrC. this study also demonstrates that taking 300 mg or more of aspirin a day for ~5 years is effective in primary prevention of CrC in randomized, controlled trials, with a follow­up of ~10 years, in agreement with previous findings.3

Din et al.1 have systematically reviewed the literature on cohort and case–control studies that examined the relationship between low­dose aspirin and CrC. meta­analysis of data from studies that assessed use of low­dose aspirin confirmed that this therapy reduces CrC incidence. the data provided by Din et al., therefore, is in line with other published studies, further sup­porting this associa tion. However, these results are differ ent to those obtained in the Physicians’ Health study 7 and the women’s Health study,8 which reflects the use of selected populations in these particular studies.

Finally, the authors attempted to examine whether the use of aspirin and other nsaiDs affects survival from CrC after diagnosis. the use of nsaiDs before diag­nosis was not associated with improved all­cause or CrC­specific survival. as stated by the authors, this lack of effect might reflect limitations related to the sample size and duration of nsaiD intake.

the study has a few other drawbacks, such as lack of knowledge regarding the continuation of nsaiD intake after diag­nosis and no outcome measures that use blood tests to assess the levels of nsaiD consumption. Despite these limitations, the study highlights the need for detailed data collection and long­term follow­up of cohort studies and randomized, controlled trials to determine the benefits and risks of aspirin and other nsaiD treatments, and to finally establish the effects of low or less frequent doses of aspirin.

Currently, cancer, cardiovascular dis­orders and alzheimer disease are the main causes of morbidity and mortality in the general population. the study by Din et al. further supports the notion that low­dose aspirin could serve as a magic bullet in primary prevention of these diseases. Further studies are needed to evaluate sub­populations that could maximize their risk to benefit ratio (maximal efficacy and lowest toxicity) with aspirin treatment.

The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv University, 6 Weizmann Street, Tel Aviv 64239, Israel (S. Kraus, N. Arber).

Correspondence to: N. Arber nadira@tasmc.health.gov.il

Competing interestsThe authors declare no competing interests.

1. Din, F. v. et al. effect of aspirin and nsAiDs on risk and survival from colorectal cancer. Gut 59, 1670–1679 (2010).

2. Dubé, C. et al. The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the Us Preventive services Task Force. Ann. Intern. Med. 146, 365–375 (2007).

3. Flossmann, e. & Rothwell, P. M.; 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 369, 1603–1613 (2007).

4. Baron, J. A. et al. A randomized trial of aspirin to prevent colorectal adenomas. N. Engl. J. Med. 348, 891–899 (2003).

5. Cole, B. F. et al. Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the

randomized trials. J. Natl Cancer Inst. 101, 256–266 (2009).

6. Arber, n. & Levin, B. Chemoprevention of colorectal neoplasia: the potential for personalized medicine. Gastroenterology 134, 1224–1237 (2008).

7. Gann, P. H., Manson, J. e., Glynn, R. J., Buring, J. e. & Hennekens, C. H. Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J. Natl Cancer Inst. 85, 1220–1224 (1993).

8. Cook, n. R. et al. Low-dose aspirin in the primary prevention of cancer: the women’s Health study: a randomized controlled trial. JAMA 294, 47–55 (2005).

9. Cuzick, J. et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol. 10, 501–507 (2009).

10. Johnson, C. C., Hayes, R. B., schoen, R. e., Gunter, M. J. & Huang, w. Y. non-steroidal anti-inflammatory drug use and colorectal polyps in the Prostate, Lung, Colorectal, and Ovarian Cancer screening Trial. Am. J. Gastroenterol. 105, 2646–2655 (2010).

IBD

Measuring what counts—safety of IBD medications in pregnancyBarrett G. Levesque and Sunanda V. Kane

Uncertainty about the risks of medications for IBD during pregnancy is a challenge for clinicians and patients. a recent prospective cohort study suggests that women under medical care for their disease have few adverse events.Levesque, B. G. & Kane, s. v. Nat. Rev. Gastroenterol. Hepatol. 8, 126–128 (2011); published online 8 February 2011; doi:10.1038/nrgastro.2011.18

women with iBD who plan to become pregnant seek medical care to help them reach their goals of healthy pregnancies and healthy children. active Crohn’s disease and ulcerative colitis during concep tion and pregnancy have been associ ated with an increased risk of adverse perinatal out­comes, such as preterm delivery and low birth weight.1,2 thiopurines have been associ ated with increased rates of steroid­free remission and maintenance of remis­sion in both ulcerative colitis and Crohn’s disease compared with placebo.3,4 these agents are available as an addition or alternative to other medical options avail­able to treat patients with iBD, including 5­amino salicylic acid preparations, bio­logic therapies, steroids and ciclosporin. a recent paper by the Cesame study group describes the pregnancy outcomes of a cohort of 204 women with iBD in France.5 the study examined pregnancy outcomes in three different groups of patients: women taking thio purines with or without

other medications; women taking other medica tions for iBD; and women taking no medica tions for iBD.

the benefits of thiopurines in efficacy of induction or maintenance of remission must be balanced against their risks to mother and neonate. Clinicians are faced with differ ent clinical scenarios. First, and probably most commonly, if a woman is planning pregnancy or becomes pregnant and is in steroid­free remission, do the

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