Associations of Aspirin and Non-Aspirin Non-Steroidal Anti-Inflammatory Drugs With Colorectal Cancer Mortality After Diagnosis

Jane C. Figueiredo, PhD; Eric J. Jacobs, PhD; Christina C. Newton, MSPH; Mark A. Guinter, PhD; William G. Cance, MD; Peter T. Campbell, PhD

Disclosures

J Natl Cancer Inst. 2021;113(7):833-840. 

In This Article

Abstract and Introduction

Abstract

Background: Aspirin use reduces colorectal cancer (CRC) incidence, but there is limited evidence regarding associations of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) with CRC-specific survival.

Methods: This prospective analysis includes women and men from the Cancer Prevention Study-II Nutrition Cohort who were cancer free at baseline (1992 or 1993) and diagnosed with CRC during incidence follow-up through 2015. Detailed information on aspirin and non-aspirin NSAID use was self-reported on questionnaires at baseline, in 1997, and every 2 years thereafter. Pre- and postdiagnosis data were available for 2686 and 1931 participants without distant metastases, respectively, among whom 512 and 251 died from CRC during mortality follow-up through 2016. Secondary analyses examined associations between prediagnosis aspirin use and stage at diagnosis (distant metastatic vs localized or regional). All statistical tests were 2-sided.

Results: Long-term regular use of aspirin (>15 times per month) before diagnosis was associated with lower CRC-specific mortality (multivariable-adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.52 to 0.92). Postdiagnosis regular aspirin use was not statistically significantly associated with risk of CRC-specific mortality overall (HR = 0.82, 95% CI = 0.62 to 1.09), although participants who began regular aspirin use only after their diagnosis were at lower risk than participants who did not use aspirin at both the pre- and postdiagnosis periods (HR = 0.60, 95% CI = 0.36 to 0.98). Long-term aspirin use before diagnosis was also associated with lower odds of diagnosis with distant metastases (multivariable-adjusted odds ratio = 0.73, 95% CI = 0.53 to 0.99).

Conclusions: Our results suggest that long-term aspirin use before a diagnosis of nonmetastatic colorectal cancer may be associated with lower CRC-specific mortality after diagnosis, consistent with possible inhibition of micrometastases before diagnosis.

Introduction

Colorectal cancer (CRC) patients seek guidance on lifestyle factors to improve their prognoses.[1] Evidence from randomized trials and observational studies convincingly demonstrate that relatively long-term regular aspirin use lowers risk of CRC incidence, even at low doses.[2] Recently, however, the Aspirin in Reducing Events in the Elderly (ASPREE) study, a randomized trial of aspirin compared with placebo in people age 70 years or older, followed for an average of 4.7 years, reported an unexpected but statistically significant increase in CRC-specific mortality (hazard ratio [HR] = 1.77, 95% confidence interval [CI] = 1.02 to 3.06) with the low-dose intervention.[3,4] This result may be because of chance[5] but nonetheless raises potential concerns about the relatively short-term effects of aspirin initiation on CRC mortality risk in the elderly.

There is currently no evidence from randomized trials on aspirin use and mortality outcomes specifically from studies of CRC survivors. Several observational studies, however, have examined the association between postdiagnosis aspirin use and CRC-specific mortality.[6–15] Some of these studies observed a reduction in mortality associated with postdiagnosis aspirin use;[8–12,14] others did not.[6,7,13,15] The association between prediagnosis aspirin use and CRC mortality is also inconsistent across studies.[6,8,11,16–21] Most of these studies did not adjust their aspirin and CRC mortality estimates for potential confounding from non-aspirin non-steroidal anti-inflammatory drug (NSAID) use, an important limitation that bears consideration.

There is evidence that non-aspirin NSAIDs may inhibit colorectal carcinogenesis.[22,23] Randomized clinical trials support the hypothesis that cyclooxygenase (COX)-2 selective inhibitors (ie, celecoxib and rofecoxib) are effective in preventing colorectal adenomas.[24–27] In a systematic review and meta-analysis, non-aspirin NSAIDS were associated with a reduced risk of incident CRC,[28] but their association with CRC-specific mortality has been investigated in only a handful of studies with conflicting findings.[14,16,17,20,21]

Both aspirin and non-aspirin NSAIDs block the metabolism of arachidonic acid through the prostaglandin H synthase or Cox pathways.[29] Aspirin irreversibly inactivates COX-1 and COX-2 through acetylation, whereas non-aspirin NSAIDs reversibly inhibit the activity of these enzymes through competitive binding.[30,31] Non-aspirin NSAIDs may inhibit colorectal carcinogenesis by inhibiting COX-2.[22,23] Aspirin, however, appears unlikely to inhibit carcinogenesis by inactivating COX-2; instead, it appears to inhibit carcinogenesis by inhibiting platelet activation through COX-1 and reducing thromboxane A expression.[31] Mature platelets lack a nucleus and cannot replace inactivated COX-1, so even low-dose aspirin effectively inhibits platelet activation.[31] Inhibition of platelet activation is thought to inhibit metastases[32,33] and may mediate the cancer-preventive properties of aspirin.[31]

It is important to inform clinicians and CRC survivors about the potential benefits and harms of aspirin and non-aspirin NSAIDs. We used data from the Cancer Prevention Study-II Nutrition cohort (CPS-II) to examine the associations of pre- and postdiagnosis use of aspirin and non-aspirin NSAIDs with CRC-specific mortality among CRC survivors. Because inhibition of distant metastases is a potential mechanism of action for aspirin, we also explored associations of long-term aspirin use among case patients with and without distant metastases.

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