2010-04-12 19:04:06 UTC

Should Aspirin Become Standard Adjuvant Therapy in CRC Management?

April 12, 2010

Andrew T. Chan, MD, MPH

Andrew T. Chan, MD, MPH

Assistant Professor of Medicine, Harvard Medical School; Assistant in Medicine, Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA  


A compelling body of evidence demonstrates that aspirin can reduce the risk of colorectal adenoma and cancer. However, concern about aspirin’s side effect profile has engendered limited enthusiasm about recommending widespread, long-term aspirin use for colorectal cancer (CRC) prevention in the general population. Because a U.S. individual’s lifetime risk of developing CRC is 6 percent, implementation of widespread aspirin chemoprevention would expose needlessly 94 percent of the general population to the potential risk of aspirin-related toxicities.1 Thus, the U.S. Preventative Task Force recently recommended against the routine use of aspirin for chemoprevention, but did suggest the possibility that aspirin may be appropriate for specific subgroups of high-risk individuals.2

Such a subgroup would likely include individuals at high risk of developing CRC and dying from the disease. Perhaps the most definable such population is patients with established CRC that have undergone a resection for curative intent. Although such patients generally enjoy a favorable prognosis compared to those diagnosed with unresectable disease, they remain at high risk of recurrence. For example, approximately 30 percent of CRC patients with lymph node involvement develop a recurrence within five years, and nearly all such recurrences lead to death.1 Thus, such patients would stand to benefit considerably if aspirin therapy could lower the risk of recurrence and improve the odds of survival. In animal models, aspirin or other NSAIDs have been shown to inhibit tumor growth and metastases, as well as prolong survival.3, 4 A randomized trial by Sandler et al. of standard-dose aspirin (325 mg) in patients with prior Dukes’ stage A or B1 colon or rectal cancer who had undergone curative resection of their primary tumor demonstrated a 35 percent reduction in risk of colorectal adenoma after a median of 30 months of treatment.5 However, studies specifically examining if aspirin use can influence the prognosis of patients with established CRC are lacking.

To investigate this potential, we embarked on an analysis of 1,279 patients with established stage I, II, or III CRC enrolled in two large, ongoing prospective cohort studies: the Nurses’ Health Study and the Health Professionals Follow-up Study.6 We found that use of aspirin after diagnosis of non-metastatic CRC is associated with improved survival from the disease. Compared with non-users, participants who regularly used aspirin after diagnosis (12-year median follow-up) experienced a multivariate hazard ratio for CRC-specific mortality of 0.71 (95 percent confidence interval [CI], 0.53-0.95) and for overall mortality of 0.79 (95 percent CI, 0.65-0.97). Regular aspirin use after diagnosis was associated with a particularly lower risk of CRC-specific mortality among participants in whom primary tumors overexpressed cyclooxygenase-2 (COX-2), a key enzyme in the pathway underlying aspirin’s anti-cancer effect.7 Although we had limited data on specific dose or frequency categories, it appeared that the optimal dose of aspirin was at least one standard tablet (325 mg) per day.

The unique strengths of our study were 1) participants were enrolled prior to their diagnosis of CRC, permitting an analysis of prospectively collected, detailed and biennially updated data on aspirin use before and after diagnosis, 2) data on aspirin use was obtained from health professionals who are more likely to accurately report usage of over-the-counter drugs, 3) the biennial follow-up rate of participants exceeded 92 percent, 4) ascertainment of CRC-specific and overall mortality was nearly 98 percent complete and 5) a large number of tumor specimens were available for analysis of COX-2 expression. Our results suggest that aspirin may influence the biology of established CRCs, in addition to preventing their occurrence. Moreover, our data underscore the potential for using COX-2 or related markers to tailor aspirin use among patients with newly diagnosed CRC. If confirmed in other prospective studies, testing tumors for COX-2 status could be used as a means of identifying patients who are relatively sensitive to the anti-cancer effect of aspirin, and should be considered for treatment after an examination of the risks and benefits. In contrast, patients with COX-2 negative tumors may be relatively aspirin-resistant and could be spared unnecessary exposure to aspirin’s potential side effects.

Nonetheless, because our study is observational, we cannot exclude the possibility that our findings are not causal and instead reflect the benefit of other potential factors associated with aspirin use. Thus, randomized trials are needed to confirm these results before routine clinical recommendations can be implemented. Recently, a large, placebo-controlled trial examining the use of 200 mg of daily aspirin has begun enrolling patients with stage III CRC in several centers in Southeast Asia and India. This trial will hopefully offer results by 2015. However, physicians caring for individual patients diagnosed with CRC in 2009 may not have the luxury of waiting for these results. For such patients, I would argue that the present state of evidence might be considered sufficiently compelling to consider aspirin treatment for appropriately selected patients in the absence of direct randomized trial data with mortality endpoints. First, our study not only demonstrates an association between post-diagnosis aspirin treatment and improved survival, but also mechanistic specificity for the association with COX-2 positive tumors that enhances the case for causality.8 Second, the placebo-controlled randomized control trial by Sandler et al. already has shown a specific benefit in reducing the risk of recurrent neoplasia among patients with early-stage CRC.5 Based on this evidence alone, there is a rationale to consider aspirin therapy while we await randomized evidence of a survival benefit. Finally, although gastrointestinal toxicity is an important concern for patients embarking on long-term aspirin treatment, such episodes are usually manageable and rarely life threatening. Thus, for the highly selected patient at high risk for recurrence, a careful discussion of the potential risks and benefits of closely monitored aspirin therapy, in the context of the best available evidence at hand, would appear to be warranted.


  1. American Cancer Society. Cancer Facts and Figures 2009. Atlanta: American Cancer Society 2009.
  2. Dube C, Rostom A, Lewin G, Tsertsvadze A, Barrowman N, Code C, Sampson M, Moher D. The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med 2007;146:365-75.
  3. Yao M, Zhou W, Sangha S, Albert A, Chang AJ, Liu TC, Wolfe MM. Effects of nonselective cyclooxygenase inhibition with low-dose ibuprofen on tumor growth, angiogenesis, metastasis, and survival in a mouse model of colorectal cancer. Clin Cancer Res 2005;11:1618-28.
  4. Lundholm K, Gelin J, Hyltander A, Lonnroth C, Sandstrom R, Svaninger G, Korner U, Gulich M, Karrefors I, Norli B, et al. Anti-inflammatory treatment may prolong survival in undernourished patients with metastatic solid tumors. Cancer Res 1994;54:5602-6.
  5. Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, Petrelli N, Pipas JM, Karp DD, Loprinzi CL, Steinbach G, Schilsky R. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 2003;348:883-90.
  6. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009;302:649-58.
  7. Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 2007;356:2131-42.
  8. Neugut AI. Aspirin as adjuvant therapy for colorectal cancer: a promising new twist for an old drug. JAMA 2009;302:688-9.

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