The association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin (ASA), celecoxib and rofecoxib and lower risk of colorectal adenoma or CRC has been studied in numerous prospective, observational studies of both healthy subjects and those with a prior history of CRC. Studies that looked at the effect of ASA use after CRC diagnosis showed ASA use was associated with a lower risk of disease recurrence and death. A question that remained unanswered was whether the use of ASA could influence the prognosis for patients with established CRC. In the August 12, 2009 issue of Journal of the American Medical Association (JAMA), Chan, Ogina & Fuchs reported on a prospective cohort study that examined the association between ASA use after CRC diagnosis.1
In this study, the investigators studied the effect of ASA use among patients with stage I, II and III CRC who were already enrolled as participants in two large observational studies: the Nurses Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Participants in the NHS and HPFS complete biennial questionnaires. It was from those questionnaires that ASA use was obtained. The Chan, et al, study was designed to measure CRC-specific and overall mortality using Kaplan-Meier curves and the log-rank test to compare the study outcomes according to ASA use.
Study Participants
- N = 1279 participants
- 840 women from NHS
- 439 men from HPFS
- Diagnosed with stage I, II or III CRC through 2002
- Provided data on ASA use before and after CRC diagnosis
ASA is thought to prevent colorectal neoplasia through inhibition of cyclooxygenase 2 (COX-2), an isoenzyme that is overexpressed in the majority of human CRC.2 Because of the association between overexpression of COX-2 and poor prognosis among CRC cancer patients in some studies, Chan and colleagues also collected tumor tissue from 459 participants (207 from NHS; 252 from HPFS) for analysis.
Table 1. Comparison of ASA use before and after CRC diagnosis
|
ASA Use |
N |
% |
|
No regular use of ASA before and after diagnosis |
536 |
42 |
|
Regular use of ASA before and after diagnosis |
366 |
29 |
|
Regular use before diagnosis but discontinued after diagnosis |
194 |
15 |
|
No regular use of ASA before diagnosis but initiated after diagnosis |
183 |
14 |
Results
Among the 1279 eligible participants, 480 total deaths were documented. Of those, 222 deaths were due to CRC. Participants still alive through the end of follow-up had a median time of follow-up from date of CRC diagnosis of 11.8 years.
Results, stratified by ASA use
- 193 total deaths (35%) and 81 CRC-specific deaths (15%) among 549 participants who regularly used ASA after CRC diagnosis, compared with 287 total deaths (39%) and 141 CRC-specific deaths (19%) among 730 participants who did not use ASA
- Compared with ASA nonusers, participants who regularly used ASA after diagnosis experienced a multivariate hazard ratio (HR) for CRC-specific mortality of 0.71 (95% confidence interval [CI], 0.53-0.95) and for overall mortality of 0.79 (95% CI, 0.65-0.97)
- Among 719 participants who did not use ASA before diagnosis, ASA use initiated after diagnosis was associated with a multivariate HR for CRC-specific mortality of 0.53 (95% CI, 0.33-0.86)
Results, stratified by COX-2
- Among 459 participants with CRC that were accessible for immunohistochemical assessment, the effect of ASA differed significantly according to cyclooxygenase 2 (COX-2) expression (P for interaction = .04)
- Regular ASA use after diagnosis was associated with a lower risk of CRC-specific mortality among participants in whom primary tumors overexpressed COX-2 (multivariate HR, 0.39; 95% CI, 0.20-0.76), whereas ASA use was not associated with lower risk among those with primary tumors with weak or absent expression (multivariate HR, 1.22; 95% CI, 0.36-4.18)
Summary
Chan and colleagues observed that use of ASA after a diagnosis of stage I, II or III CRC was associated with a decreased risk of CRC-specific mortality. This association appeared to be strongest among participants whose primary tumors overexpressed COX-2 and appeared to be independent of the intake of aspirin prior to diagnosis. They noted that their data supported the potential for using COX-2 markers to tailor ASA use among patients with newly-diagnosed CRC. However, they stress caution in recommending ASA or other NSAID use as cancer therapy due to concerns over toxicities of the NSAID class, such as GI bleeding and renal toxicity. Further studies, especially placebo-controlled trials, are required.
References
- Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302:649-659. Link to abstract http://jama.ama-assn.org/cgi/content/short/302/6/649
- Eberhart CE, Coffey RJ, Radhika A, et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994;107:1183-1188. Link to PubMed abstract http://www.ncbi.nlm.nih.gov/pubmed/7926468