Among the 1279 eligible participants with stage I, II, or III colorectal cancer, we documented 480 total deaths among which 222 deaths were due to colorectal cancer. For participants who were alive through the end of follow-up, the median time of follow-up from date of diagnosis was 11.8 years (interquartile range, 7.6-16.2). There were 536 participants who did not regularly use aspirin before and after diagnosis (42%), 366 regularly used aspirin before and after diagnosis (29%), 194 regularly used aspirin before diagnosis but then discontinued use after diagnosis (15%), and 183 did not regularly use aspirin before diagnosis but initiated use after diagnosis (14%). Baseline characteristics of the participants are shown in . Compared with nonusers, regular users of aspirin before diagnosis appeared to be less physically active. After diagnosis, regular users of aspirin after also appeared to be less physically active, were more likely to have previously smoked cigarettes, and were less likely to be diagnosed with stage III disease compared with nonusers.
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 (39%) total and 141 (19%) colorectal cancer–specific deaths among 730 participants who did not use aspirin. For the entire cohort, the overall 5-year survival was 88% for those participants who used aspirin compared with 83% for those who did not. The corresponding 10-year survival rates were 74% and 69%. Regular use of aspirin after diagnosis was associated with a significant reduction in risk of colorectal cancer–specific mortality (log-rank P=.02; ) and a reduction in overall mortality (log-rank P=.03; ). The relationship remained largely unchanged even after adjusting for use of aspirin before diagnosis as well as other predictors of cancer recurrence (). Compared with nonusers, the multivariate HR associated with regular aspirin use after diagnosis was 0.71 (95% CI, 0.53-0.95) for colorectal cancer–specific mortality and 0.79 (95% CI, 0.65-0.97) for overall mortality. Because the prognosis among stage I participants is generally favorable, we also examined the influence of aspirin use among those diagnosed with stage II or III disease and observed similar results (multivariate HR, 0.72; 95% CI, 0.53-0.99 for colorectal cancer–specific mortality and multivariate HR, 0.82; 95% CI, 0.66-1.04 for overall mortality).
Survival According to Aspirin Use After Diagnosis
Risk of Colorectal Cancer-Specific Mortality and Overall Mortality According to Use of Aspirin After Diagnosisa
In contrast to aspirin use after diagnosis, aspirin use prior to cancer diagnosis did not appear to be associated with either colorectal cancer–specific mortality (multivariate HR, 1.05; 95% CI, 0.80-1.37) or overall mortality (multivariate HR, 0.93; 95% CI, 0.77-1.11). This relationship was consistent after including those participants with colorectal cancer who did not return a postdiagnosis aspirin questionnaire (multivariate HR, 1.00; 95% CI, 0.81-1.25). A formal test for interaction between aspirin use before diagnosis vs aspirin use after diagnosis on colorectal cancer–specific mortality was not statistically significant (P=.09). However, simultaneous inclusion of both prediagnosis and postdiagnosis aspirin use in models confirmed that post-diagnosis aspirin use remained independently associated with colorectal cancer–specific mortality (P=.008) and overall mortality (P=.03), while pre-diagnosis aspirin use was not significantly associated with either colorectal cancer–specific mortality (P=.14) or overall mortality (P=.98).
To better characterize this relationship, we examined postdiagnosis aspirin use according to use of aspirin prior to cancer diagnosis (). Among the 719 participants who did not use aspirin before diagnosis, initiation of use postdiagnosis was associated with a multivariate HR for colorectal cancer–specific mortality of 0.53 (95% CI, 0.33-0.86) and overall mortality of 0.68 (95% CI, 0.51-0.92). In contrast, among participants who were using aspirin before diagnosis, continuation of aspirin use postdiagnosis was not associated with a significant reduction in colorectal cancer–specific survival (multivariate HR, 0.89; 95% CI, 0.59-1.35) or overall survival (multivariate HR, 0.95; 95% CI, 0.71-1.28).
We have previously shown that aspirin use is associated with a lower risk of subsequently developing colorectal COX-2–positive cancers but not colorectal COX-2–negative cancers.9
Thus, we examined whether the effect of postdiagnosis aspirin use on survival differed according to COX-2 expression status within the primary tumors. Among 459 participants for whom we had sufficient tumor tissue with adjacent normal mucosa to assay for COX-2, the benefit of aspirin use after diagnosis appeared to be confined to those with COX-2–positive primary tumors (). Among participants with COX-2–positive tumors, regular aspirin use after diagnosis was associated with a lower risk of colorectal cancer–specific (multivariate HR, 0.39; 95% CI, 0.20-0.76) and overall (HR, 0.62; 95% CI, 0.42-0.93) mortality, whereas postdiagnosis aspirin use was not associated with lower risk of either colorectal cancer–specific or overall mortality for those with COX-2–negative tumors. A test for heterogeneity of the effect of regular aspirin use after diagnosis on survival for COX-2–positive tumors vs COX-2–negative tumors was statistically significant (P
for interaction = .04).
We considered the possibility that the superior benefit of postdiagnosis aspirin use among COX-2–positive cancers reflected the observation that COX-2–positive cancers are more likely to develop among individuals who abstain from aspirin use prior to cancer diagnosis. In a post hoc analysis, we therefore examined the joint effect of prediagnosis and postdiagnosis aspirin use according to tumoral COX-2 expression. Although participants who reported aspirin use following diagnosis but not before diagnosis (postdiagnosis use only) experienced a significant reduction in colorectal cancer–specific mortality from COX-2–positive cancers (HR, 0.22; 95% CI, 0.07-0.74), COX-2–positive participants who reported aspirin use both before and after diagnosis also experienced a non-significant reduction in colorectal cancer–specific mortality (HR, 0.56; 95% CI, 0.23-1.33).
Among participants who did not use aspirin before diagnosis, the association between postdiagnosis aspirin use and survival was modestly dose-responsive (). Compared with individuals who used any aspirin, the multivariate-adjusted HR for colorectal cancer–specific mortality was 0.57 (95% CI, 0.32-0.99) for those who used 0.5 to 5 standard aspirin tablets and 0.49 (95% CI, 0.18-1.35) for individuals who used 6 or more tablets per week (P for trend = .04).
Risk of Colorectal Cancer-Specific Mortality and Overall Mortality According to Dose of Aspirin Used After Colorectal Cancer Diagnosisa
Since the decision to use or avoid aspirin could be influenced by occult cancer recurrence or impending death, we performed a secondary analysis in which we excluded participants who died within 12 months of completing the assessment of postdiagnosis aspirin use. Our results were essentially unchanged. Compared with nonusers, participants who regularly used any aspirin after diagnosis had a multivariate-adjusted HR for colorectal cancer–specific mortality of 0.71 (95% CI, 0.53-0.95) and a multivariate HR for overall mortality of 0.80 (95% CI, 0.65-0.97). Moreover, when we examined survival from the date of return of the questionnaire regarding postdiagnosis aspirin use rather than the date of diagnosis of colorectal cancer, we also observed similar results (multivariate HR, 0.71; 95% 0.53-0.95 for colorectal cancer–specific mortality and multivariate HR, 0.79; 95% CI, 0.65-0.97 for overall mortality).
Because aspirin use was not randomly assigned in this population, we also conducted a secondary analysis using a propensity score in which we computed each participant's probability to use aspirin after diagnosis of colorectal cancer without regard to outcome. Adjusting for quintile categories of this propensity score did not alter our findings (propensity-adjusted HR, 0.70; 95% CI, 0.52-0.94 for colorectal cancer–specific mortality and propensity-adjusted HR, 0.82; 95% CI, 0.67-0.99 for overall mortality).
We also evaluated potential differences in the influence of aspirin according to strata of clinical characteristics. There were no significant differences in the influence of aspirin in strata defined by sex (cohort), age, cancer stage, site of primary tumor, year of diagnosis, or BMI (). We also confirmed that the inverse association between postdiagnosis aspirin use and colorectal cancer–specific mortality was also observed among the 241 participants for whom we collected data on treatment. Although statistical power was limited, the association between postdiagnosis aspirin use and mortality did not appear to be materially changed, even after accounting for receipt of chemotherapy (multivariate HR, 0.40; 95% CI, 0.15-1.10 for colorectal cancer–specific mortality and multivariate HR, 0.53; 95% CI, 0.26-1.07 for overall mortality). Moreover, postdiagnosis aspirin use was not associated with likelihood of receiving adjuvant chemotherapy across stages of colorectal cancer. Among participants with stage I colorectal cancer, 11% of aspirin users received chemotherapy compared with 12% of nonusers (P for difference = .82). Similarly, among participants with stage II or III colorectal cancer, 73% of aspirin users received chemotherapy compared with 77% of nonusers (P for difference = .53).
Multivariate-Adjusted Stratified Analyses of Colorectal Cancer–Specific Survival According to Aspirin Use After Diagnosis