Long-term, regular aspirin use linked to lower colorectal cancer mortality
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Long-term, regular use of aspirin before diagnosis appeared associated with lower colorectal cancer-specific mortality, according to results of an observational study published in Journal of the National Cancer Institute.
Peter Campbell, MSc, PhD, scientific director in the department of population science at American Cancer Society, and colleagues pursued the research, in part, because one study published last year suggested increased colorectal cancer mortality with aspirin use. Additionally, they wanted to help health care providers and colorectal cancer survivors make educated decisions regarding lifestyle and behavior that could affect long-term prognosis.
“We were interested in seeing if we’d observe harm or benefit in a much larger, observational study [and we had] been broadly interested in lifestyle and behavioral factors that may influence prognosis among [colorectal cancer] survivors for about a decade,” Campbell told Healio. “It’s important to provide additional information for clinicians and [colorectal cancer] survivors to help make informed decisions.”
The analysis included 4,071 adults from the Cancer Prevention Study-II Nutrition cohort who were cancer-free at baseline (1992 or 1993) and subsequently diagnosed with invasive colon or rectal cancer by end of follow-up (June 30, 2015). The mean age at colorectal cancer diagnosis was 73.5 years.
After excluding those without data on aspirin use, Campbell and colleagues followed 2,686 adults with data on pre-diagnosis aspirin use and 1,231 adults with data on post-diagnosis aspirin use for mortality outcomes through December 2016. Overall, 512 of the former group and 251 of the latter group died of colorectal cancer.
Results showed long-term regular use of aspirin, defined as taking it at least 15 times per month, before diagnosis was associated with lower colorectal cancer-specific mortality (HR = 0.69; 95% CI, 0.52-0.92).
Although results suggested post-diagnosis regular aspirin use was not statistically significantly associated with risk for colorectal cancer-specific mortality overall (HR = 0.82; 95% CI, 0.62-1.09), participants who began regular aspirin use only after their diagnosis exhibited lower risk than participants who did not use aspirin during both the pre-and post-diagnosis periods (HR = 0.6; 95% CI, 0.36-0.98).
In a secondary analysis, Campbell and colleagues evaluated pre-diagnosis aspirin use and stage at diagnosis (distant metastatic vs. localized or regional). Results showed long-term aspirin use prior to diagnosis was associated with lower odds of diagnosis with distant metastases (OR = 0.73; 95% CI, 0.53-0.99).
“We thought it was really interesting that pre-diagnosis aspirin use was associated with lower odds of distant metastatic disease,” Campbell said. “It’s exactly part of the story for what we hypothesized would explain the lower mortality, but it’s always exciting when a hypothesis is supported by empirical data.”
Although the observational study would need additional research to confirm the findings, “we think some of this benefit in terms of survival comes from aspirin’s ability to inhibit micrometastases, likely through aspirin’s effect on platelet inhibition,” Campbell said.
“Cancer guidelines aren’t formulated from any singular study, this one included, [but] in the absence of contraindications to taking aspirin, this study at least does not suggest it’s potentially harmful to take aspirin post-diagnosis,” Campbell added.
Campbell and colleagues acknowledged that their analysis was limited by the inability to examine associations stratified by tumor molecular features, as previous studies suggested an association of aspirin use with colorectal cancer risk and mortality could be modified by various molecular features of the tumor. Additionally, the researchers noted they had incomplete information on medication usage, and the results may be confounded by unaccounted risk factors.
“In terms of future research on this topic, there are a few randomized, clinical trials that should be finishing up in the next 2 or 3 years,” Campbell said. “It’ll be curious to see if those results show a bona fide impact of aspirin on [colorectal cancer] survival.”
For more information:
Peter T. Campbell, MsC, PhD, can be reached at 250 Williams St. NW, Atlanta, GA 30303; email: peter.campbell@cancer.org.
Perspective
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Andrew T. Chan, MD, MPH
Considerable evidence from well-conducted cohort studies and secondary analyses of randomized controlled trials (RCTs) has established that aspirin reduces the risk for incident colorectal cancer (CRC). Initial data from the Nurses’ Health Study and Health Professionals Follow-up Study demonstrated that aspirin use after the diagnosis of an established CRC was associated with improved CRC-specific survival and OS. This finding has been confirmed by other population-based cohorts, motivating the launch of several phase 3 RCTs of aspirin among patients with CRC after curative resection.
Figueiredo and colleagues complement this evidence base with a large prospective analysis of the Cancer Prevention Study-II Nutrition cohort. They found that long-term regular use of aspirin before diagnosis was significantly associated with lower CRC-specific mortality; aspirin use after diagnosis was nonsignificantly associated with lower CRC-specific mortality. Notably, individuals who initiated aspirin use after diagnosis had a 40% reduction in CRC-specific mortality compared with those who did not use aspirin either before or after diagnosis.
Taken together with the prior observational studies, as well as an RCT showing aspirin reduces risk for colorectal adenoma among patients with previous early-stage CRC, this evidence supports a role for aspirin in inhibiting micrometastatic lesions.
Nonetheless, these results should be considered in the context of the recent ASPREE RCT, which found no reduction in incident CRC and a surprising increase in CRC mortality associated with aspirin use. However, ASPREE was limited to adults aged older than 65 to 70 years, the vast majority of whom had not previously taken aspirin. This suggests that aspirin’s biological effects may vary according to the timing of exposure over the life course. Among younger adults, aspirin may prevent the initial formation of tumors or the spread of micrometastases. In contrast, among older adults, initiation of aspirin could paradoxically accelerate development or spread of in situ tumors or micrometastases if aspirin’s anti-inflammatory effects blunt antitumor immune responses that may be more impaired with increasing age.
The results of several ongoing RCTs of postdiagnosis aspirin use, some of which select patients according to tumor molecular profile that predicted aspirin response in observational studies, may shed light on this possibility. Of course, this will require enrollment of a sufficient number of older adults to conduct meaningful subgroup analyses. The future of successful prevention strategies with aspirin will likely depend on a more precise, perhaps molecularly targeted approach that optimizes the timing of intervention to account for heterogeneity in underlying biology to maximize benefits and minimize risks.
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