Long-term regular use of aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) prior to being diagnosed with colorectal cancer (CRC) reduced CRC-specific mortality in men and women with CRC, although regular use following a CRC diagnosis had no impact on cancer-specific death for the majority of patients, a large, prospective cohort study has shown.
Over mean follow-up of 8.4 years, regular use of aspirin/NSAIDs prior to a CRC diagnosis was associated with a significant, 31% lower risk of CRC-specific mortality at a Hazard Ratio (HR) of 0.69 (95% CI, 0.52-0.92 P value), Peter Campbell, PhD, American Cancer Society, Atlanta, Georgia and colleagues reported in the JNCI: The Journal of the National Cancer Institute.
In contrast, regular aspirin/NSAID use following a diagnosis of CRC was not significantly associated with a lower risk of CRC-specific mortality at a HR of 0.82 (95% CI, 0.62-1.09) except among “de novo” users who began to take aspirin/NSAIDs regularly after being diagnosed with CRC.
In this subgroup of participants, the risk of CRC-specific mortality was 40% lower (HR=0.60; 95% CI, 0.36-0.98) compared to participants who did not take aspirin or NSAIDs either before their diagnosis or after, investigators added.
Analyses also showed that long-term aspirin/NSAID use prior to a CRC diagnosis lowered the risk of distant metastases by 27% at an odds ratio (OR) of 0.73 (95% CI, 0.53-0.99), they noted.
“Our finding that long-term pre-diagnosis aspirin use was associated with lower CRC-specific mortality in participants with non-distant metastatic cancer motivated us to test the hypothesis that pre-diagnosis aspirin use might inhibit the development of distant metastases that are detectable at diagnosis,” Campbell and colleagues wrote. “Our results suggest that long-term aspirin use before a diagnosis of non-metastatic colorectal cancer may be associated with lower CRC-specific mortality after diagnosis, consistent with possible inhibition of micro-metastases before diagnosis.”
CPS-II Nutrition Cohort
The initial cohort consisted of 4,701 participants enrolled in the Cancer Prevention Study (CPS)-II Nutrition Cohort who were subsequently diagnosed with either invasive colon or rectal cancer following study entry.
Mean age at the time of CRC diagnosis was 73.5 years. Some 2,686 participants were included in the pre-diagnosis analysis while 1,931 others were included in the post-diagnosis analyses. Regular use of aspirin/NSAIDs was defined as 15 or more pills per month and over 70% of regular aspirin users reporting taking one tablet per day every day of the month.
Not surprisingly, regular aspirin users were more likely to have a history of cardiovascular disease (CVD) or diabetes or both and to be taking a cholesterol-lowering medication as well (P<0.001), as researchers pointed out.
“[O]nly personal history of CVD statistically significantly modified the association between regular aspirin use and CRC-specific mortality,” Campbell and colleagues noted. Interestingly, regular post-diagnosis aspirin/NSAID use was associated with a lower risk of CRC mortality among participants with no history of CVD but not, surprisingly, among participants with a history of CVD (P=0.04). As the authors explained, the fact that aspirin/NSAID use prior to a CRC diagnosis lowered CRC mortality risk might be linked to the fact that aspirin suppresses clinically occult micrometastases around the time of diagnosis.
“[A]spirin inhibits platelet activation and… activated platelets may play an important role in promoting metastases,” they wrote. “[The fact that l]ong-term regular aspirin use before diagnosis was associated with lower odds of clinically apparent distant metastases at the time of diagnosis in this study… [supports] our hypothesis.”
One limitation of the analysis included the authors’ inability to examine associations between aspirin/NSAID use stratified by tumor molecular features as some studies have suggested that the association between aspirin use and CRC risk or mortality or both may be modified by various molecular features of the tumor.
“Given that this is an observational study, we cannot rule out the possibility that the observed associations are confounded by unaccounted risk factors,” Campbell and colleagues noted. Nor could they rule out the possibility that upon disease progression, some participants either stopped or didn’t start using aspirin/NSAIDS following the diagnosis of CRC, a confounder known as “reverse causation.”
However, it’s important to point out that not all studies are in line with the generally negative findings observed in the current CPS-II Nutrition Cohort study.
For example, participants in one study who regularly used aspirin after being diagnosed with CRC had a 29% lower risk of CRC-specific mortality and a 21% lower risk of overall mortality compared with non-aspirin users.
In the same study, de novo aspirin use following a CRC diagnosis among patients who did not take aspirin prior to their diagnosis reduced CRC-specific mortality by almost half.
After adjusting for prognostic factors, another study found that the risk of CRC relapse or death from CRC was approximately 60% lower in patients who took aspirin postoperatively compared to patients who were not postoperative aspirin users.
Interestingly, no benefit was observed for preoperative use of aspirin and the risk of CRC relapse or CRC-death in the same study.
Among patients with colon or rectal cancer enrolled in the Nurses’ Health study, regular use of aspirin after being diagnosed with CRC was associated with an 82% superior CRC-specific survival compared with nonusers but only among patients with mutated PIK3CA CRC cancers, with no advantage seen from aspirin use among patients with wild-type PIK3CA tumors.
And in a fourth study, aspirin use following a diagnosis of CRC was associated with a 33% lower risk of all-cause and CRC-specific mortality compared with non-aspirin use.
“It is important to inform clinicians and CRC survivors about the potential benefits and harms of aspirin and non-aspirin NSAIDs,” Campbell and colleagues emphasized. “While more evidence is needed, preferably from randomized, controlled trials, findings from this study are an important resource to inform clinicians and CRC survivors about the potential benefits and harms of aspirin and non-aspirin NSAIDs use.”
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Long-term regular use of aspirin/NSAIDS reduced colorectal cancer-specific mortality, but only if taken prior to the diagnosis of CRC and, for most part, not after.
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The fact that upfront aspirin/NSAID use reduced CRC-specific mortality suggests that aspirin/NSAIDS may suppress clinically occult micrometastases around the time of diagnosis.
Pam Harrison, Contributing Writer, BreakingMED™
Campbell declared no conflicts of interest.
Cat ID: 23
Topic ID: 78,23,730,16,23,142,192,925
