Aspirin use and survival after diagnosis of colorectal cancer

Abstract

Context: Aspirin reduces risk of colorectal neoplasia in randomized trials and inhibits tumor growth and metastases in animal models. However, the influence of aspirin on survival after diagnosis of colorectal cancer is unknown.

Objective: To examine the association between aspirin use after colorectal cancer diagnosis on colorectal cancer-specific and overall survival.

Design, setting, and participants: Prospective cohort study of 1279 men and women diagnosed with stage I, II, or III colorectal cancer. Participants were enrolled in 2 nationwide health professional cohorts in 1980 and 1986 prior to diagnosis and followed up through June 1, 2008.

Main outcome measure: Colorectal cancer-specific and overall mortality.

Results: After a median follow-up of 11.8 years, there were 193 total deaths (35%) and 81 colorectal cancer-specific deaths (15%) among 549 participants who regularly used aspirin after colorectal cancer diagnosis, compared with 287 total deaths (39%) and 141 colorectal cancer-specific deaths (19%) among 730 participants who did not use aspirin. Compared with nonusers, participants who regularly used aspirin after diagnosis experienced a multivariate hazard ratio (HR) for colorectal cancer-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 aspirin before diagnosis, aspirin use initiated after diagnosis was associated with a multivariate HR for colorectal cancer-specific mortality of 0.53 (95% CI, 0.33-0.86). Among 459 participants with colorectal cancers that were accessible for immunohistochemical assessment, the effect of aspirin differed significantly according to cyclooxygenase 2 (COX-2) expression (P for interaction = .04). Regular aspirin use after diagnosis was associated with a lower risk of colorectal cancer-specific mortality among participants in whom primary tumors overexpressed COX-2 (multivariate HR, 0.39; 95% CI, 0.20-0.76), whereas aspirin 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).

Conclusion: Regular aspirin use after the diagnosis of colorectal cancer is associated with lower risk of colorectal cancer-specific and overall mortality, especially among individuals with tumors that overexpress COX-2.

Figure 1. COX-2 Immunohistochemistry in Colorectal Cancer

Primary anti–cyclooxygenase 2 (COX-2) antibody diluted 1:300 in phosphate-buffered saline was applied overnight at 4°C. We then applied secondary anti–mouse antibody for 20 minutes followed by avidin-biotin complex conjugate. Sections were visualized by diaminobenzidine and methyl-green counterstain. A, Representative section from a COX-2–negative tumor (original magnification ×400). The gray arrowheads indicate colorectal cancer cells without COX-2 overexpression. B, Representative section from a COX-2–positive tumor (original magnification ×400). Black arrowheads indicate colorectal cancer cells with strong COX-2 expression (dark brown color) compared with normal colonic epithelium indicated by white arrowheads.

Figure 2. Survival According to Aspirin Use After Diagnosis

Figure 3. Multivariate-Adjusted Stratified Analyses of Colorectal Cancer–Specific Survival According to Aspirin Use After Diagnosis

Multivariate hazard ratios are adjusted for age at diagnosis (years), sex, date of cancer diagnosis (years), stage of cancer (I, II, or III), site of primary cancer (colon or rectum), histological grade of cancer (well, moderate, or poor/unknown), time from diagnosis to first measurement of postdiagnosis aspirin use (months), smoking (never vs current/past), metabolic equivalent tasks per week after diagnosis, body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), and colorectal cancer in a parent or sibling (yes or no). For each stratified analysis, the stratification variable was omitted from the model.