Aspirin has long proved to be a multipotent drug, with efficacy as a pain reliever, anti-inflammatory agent, antiplatelet agent, and cardioprotective agent. In the cancer world, a large literature has accumulated demonstrating its ability to prevent various epithelial malignancies, most notably colorectal cancer,1 primarily by its inhibitory effect on cyclo-oxygenase-2 (COX-2). Despite this effect, neither aspirin nor other COX-2 inhibitors are recommended for general use as chemopreventive agents because of the fairly common adverse effects of aspirin, mainly upper gastrointestinal toxicity, including gastritis and gastrointestinal bleeding, and the risk of hemorrhagic stroke.
Five Observational Studies
Since 2009, at least five observational studies have reported a significant survival benefit from the use of aspirin in the therapeutic setting for colorectal cancer.2-6 These studies focused on the initiation of aspirin use in patients with stage III colorectal cancer who have generally also had standard adjuvant chemotherapy. Thus, the benefit of the aspirin on survival has been over and above that of conventional chemotherapy. Furthermore, those who were using aspirin prior to the cancer diagnosis generally were aspirin-resistant, similar to what happens with the use of tamoxifen as a chemopreventive agent.7,8
While one may have a reasonable sense of skepticism for the utilization of observational studies (vs prospective trials) as evidence in the evaluation of a therapeutic intervention, this is usually because of concern about confounding, selection bias, and the use of retrospectively collected data. In the observational studies regarding aspirin, however, the benefits of the adjuvant aspirin were generally limited to those who were COX-2–positive2,6 or PIK3CA mutation–negative.5,6,9 These observations are very reassuring that this is a true effect of the drug and not due to confounding or selection bias. Furthermore, most of the studies used prospectively rather than retrospectively collected data.
Sixth Study
As reported in this issue of The ASCO Post, Ng and colleagues have now presented a sixth study to add to the prior mix. This prospectively collected observational study, published in the Journal of the National Cancer Institute,10 included patients who were entered in the randomized CALGB 89803 trial of adjuvant therapy for stage III colon cancer, which enrolled 843 patients between 1999 and 2001.11
Aspirin and nonsteroidal anti-inflammatory drug use was determined by questionnaire, and improved survival was reported at the Annual ASCO Meeting in 2005 at 2.7 years of follow-up.12 So, in truth, this was the first of the studies to discover the therapeutic benefits of aspirin. Now, the investigators report the 5-year follow-up results and find continued significant improvements in survival for those who used aspirin, including in overall survival at 5 years. Marker studies were not included in this study.
There are now randomized trials in progress to assess aspirin13,14 and celecoxib15 as adjuvant therapy for colorectal cancer. But what of patients in the intervening years before these trials reach maturity? I have argued previously16 that the observational evidence is strong enough to make adjuvant aspirin a standard of care, in light of its consistent efficacy and low-toxicity profile, as illustrated in the studies cited above. In my view, the Ng study10 just adds more evidence to this argument. Some observers, however, in considering the same evidence, suggest awaiting the results of the randomized trials now in progress.
Closing Thoughts
In oncology, we often treat patients with toxic chemotherapy based on phase II trials that show partial remission benefits and have no comparison arms. Here, at least in theory, we have an agent that can reduce mortality in several patients per hundred of those treated. Certainly, the evidence adduced here for aspirin—a relatively nontoxic agent—for reducing mortality in stage III colon cancer merits serious consideration for adoption as adjuvant therapy in stage III colorectal cancer patients who have not previously been on aspirin and have no contraindications to aspirin therapy. ■
Disclosure: Dr. Neugut is a paid consultant for Pfizer, Otsuka, Teva, and United Biosource Corporation.
References
1. Rothwell PM, Wilson M, Elwin CE, et al: Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376:1741-1750, 2010.
2. Chan AT, Ogino S, Fuchs CS: Aspirin use and survival after diagnosis of colorectal cancer. JAMA 302:649-658, 2009.
3. Bastiaannet E, Sampieri K, Dekkers OM, et al: Use of aspirin postdiagnosis improves survival for colon cancer patients. Br J Cancer 106:1564-1570, 2012.
4. McCowan C, Munro AJ, Donnan PT, et al: Use of aspirin post-diagnosis in a cohort of patients with colorectal cancer and its association with all-cause and colorectal cancer specific mortality. Eur J Cancer 49:1049-1057, 2013.
5. Domingo E, Church DN, Sieber O, et al.: Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol 31:4297-4305, 2013.
6. Reimers MS, Bastiaannet E, Langley RE, et al: Expression of HLA class I antigen, aspirin use, and survival after a diagnosis of colon cancer. JAMA Intern Med 174:732-739, 2014.
7. Esserman LJ, Ozanne EM, Dowsett M, et al: Tamoxifen may prevent both ER+ and ER- breast cancers and select for ER- carcinogenesis: An alternative hypothesis. Breast Cancer Res 7:R1153-R1158, 2005.
8. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388, 1998.
9. Liao X, Lochhead P, Nishihara R, et al: Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367:1596-1606, 2012.
10. Ng K, Meyerhardt JA, Chan AT, et al: Aspirin and COX-2 inhibitor use in patients with stage III colon cancer. J Natl Cancer Inst 107(1):dju345, 2015.
11. Saltz LB, Niedzwiecki D, Hollis D, et al: Irinotecan and fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: Results of CALGB 89803. J Clin Oncol 25:3456-3461, 2007.
12. Fuchs C, Meyerhardt JA, Heseltine DL, et al: Influence of regular aspirin use on survival for patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803. J Clin Oncol 23(suppl 16):3530, 2005.
13. Ali R, Toh HC, Chia WK: The utility of aspirin in Dukes C and high risk Dukes B colorectal cancer—the ASCOLT study: Study protocol for a randomized controlled trial. Trials 12:261, 2011.
14. Langley RE, Wilson RH, Ring AE, et al: Add-Aspirin trial: A phase III, double-blind, placebo-controlled, randomized trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common nonmetastatic solid tumors. J Clin Oncol 32(15 suppl):TPS1617, 2014.
15. Oxaliplatin, leucovorin calcium, and fluorouracil with or without celecoxib in treating patients with stage III colon cancer previously treated with surgery. Available at clinicaltrials.gov/show/NCT01150045. Accessed March 16, 2015.
16. Neugut AI: Aspirin as adjuvant therapy for stage III colon cancer: Standard of care? JAMA Intern Med 174:739-741, 2014.
Dr. Neugut is Myron M. Studner Professor of Cancer Research, Professor of Medicine and Epidemiology, Associate Director of Population Sciences for the Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York.
