ASPIRIN CAN REDUCE CANCER MORTALITY AND METASTASES RISK

Evidence from 3 new studies demonstrates that aspirin can reduce the risk for cancer-related mortality and can reduce or prevent the risk for distant metastasis.

Peter M. Rothwell, MD, PhD, professor of clinical neurology at the University of Oxford, United Kingdom, was lead author on all 3 studies.

In the first study, published online March 21 in the Lancet, comparing daily aspirin with no aspirin to prevent vascular events, aspirin use reduced the risk for nonvascular death in all 51 trials examined (1021 vs 1173 deaths; odds ratio [OR], 0.88; P = .003). When data from 34 trials were examined (n = 69,224; 89% of total cohort), there were fewer deaths from cancer in the aspirin than in the control group (562 vs 664 deaths; OR, 0.85; P = .008).

Dr. Rothwell and colleagues note that even though the decreased risk for major vascular events in these trials was initially offset by a higher risk for major bleeding, both of these effects diminished over time, leaving only the reduced risk for cancer after 3 years.

"In view of the very low rates of vascular events in recent and ongoing trials of aspirin in primary prevention, prevention of cancer could become the main justification for aspirin use in this setting," they write.

Compelling But No Recommendations Yet

In an accompanying editorial, Andrew T. Chan, MD, MPH, and Nancy R, Cook, ScD, both from Harvard Medical School in Boston, Massachusetts, note that although these results are compelling, they do have limitations.

These analyses exclude the largest randomized trials in primary prevention, the editorialists point out. The Women's Health Study (WHS) of 39,876 women treated with alternate-day aspirin 100 mg over 10 years and the Physicians' Health Study (PHS) of 22,071 men treated with alternate-day aspirin 325 mg over 5 years were not included in the current study because of possible differences in the biologic effect between alternate-day and daily aspirin intake. However, in these 2 studies, aspirin was not associated with a lower risk for colorectal cancer or overall cancer incidence or mortality.

Another limitation, say the editorialists, is that the researchers only used 6 randomized trials to analyze low-dose aspirin in the primary prevention of cancer.

In these 6 trials (n = 35,535), aspirin was shown to lower the incidence of cancer after 3 years in women (132 vs 176; OR, 0.75; P = .01), in men (192 vs 245; OR, 0.77; P = .008), and in both (324 vs 421; OR, 0.76; P = .0003).

A third limitation is that because the included studies were designed to examine cardiovascular end points, there was no information about cancer screening or surveillance.

Finally, some of the analyses were limited by the quality of available data; some estimates pooled individual-level data with published results.

But "caveats notwithstanding, Rothwell and colleagues show quite convincingly that aspirin seems to reduce cancer incidence and death across different subgroups and cancer sites, with an apparent delayed effect," they write. For most individuals, "the risk–benefit calculus of aspirin seems to favor aspirin's long-term anticancer benefit. These findings are consistent with observational findings and our understanding of the stepwise progression of carcinogenesis."

These data might not be the final word on aspirin, as far as making a population-based recommendation, the editorialists caution, because the WHS and PHS remain "significant counterbalancing trials that have not shown a cancer benefit with alternate-day aspirin up to 10 to 12 years."

Another factor to be considered is the adverse events from daily aspirin. Even though there is a "convincing case" that the vascular and anticancer benefits of aspirin outweigh the harms of major extracranial bleeding, less serious adverse effects on quality of life, such as less severe bleeding, are not accounted for in these analyses, Drs. Chan and Cook write.

Nonetheless, until data from forthcoming trials and longer-term follow-up from the WHS and PHS become available, this "impressive collection of data moves us another step closer to broadening recommendations for aspirin use," they conclude.

Metastasis in Randomized Trials

In the second study, also published online March 21 in the Lancet, Dr. Rothwell and colleagues analyzed data from 5 large randomized trials of daily aspirin (75 mg or more daily) for the prevention of vascular events in the United Kingdom. The cohort consisted of 17,285 trial participants, 987 of whom had a new solid cancer diagnosed during a mean follow-up of 6.5 years.

Aspirin use reduced the risk for cancer with distant metastasis (hazard ratio [HR] for all cancers, 0.64; P = .001). The risk for cancer with distant metastasis was reduced by 36%, and the risk for adencarcioma was reduced by 46% (P = .0007). Among patients with adenocarcinoma who did not have metastasis at their initial diagnosis and who remained on trial treatment up to or after diagnosis, the use of aspirin reduced the risk for metastasis on subsequent follow-up by about 70%.

Aspirin lowered the cancer mortality rate among patients who developed adenocarcinoma, especially in those without metastasis at diagnosis (HR, 0.50; P = .0006). Aspirin also lowered the overall risk for fatal adenocarcinoma (HR, 0.65; P = .0002), but not the risk for other fatal cancers (HR, 1.06; P = .64). These effects were independent of confounders such as age and sex, but the absolute benefit was greatest in smokers, the authors note.

Observation vs Randomized

The third study, published online March 21 in the Lancet Oncology, looked at the effect of aspirin on metastases, but with a different approach. The authors compared the effect of aspirin on the 20-year risk for cancer-specific mortality between observational studies and randomized trials.

They conducted this comparison because although randomized trials can clearly establish the risk for colorectal cancer, other solid tumors, and metastasis, such trials lack the statistical power to establish effects on less common cancers and on cancers in women.

Observational and case–control studies can provide these data if the results are shown to be reliable.

Overall, results from observational studies were similar to those from randomized trials, and showed that regular aspirin use lowered the long-term risk for several cancers and for distant metastasis.

In 6 eligible randomized trials, the aspirin group had a consistently lower 20-year risk for death from colorectal cancer than the control group (OR, 0.58; P = .0002). In the 26 case–control studies, any use of aspirin was associated with a lower risk for colorectal cancer (pooled OR, 0.67; P < .0001).

In 17 case–control studies, the regular use of aspirin was associated with a reduced risk for colorectal cancer (pooled OR, 0.62; P < .0001). In the randomized trials, there was good correlation between the effect of daily aspirin use and the 20-year risk for death from colorectal cancer (OR, 0.58; P = .0002).

The authors observed the same consistent reductions in risks for esophageal, gastric, biliary, and breast cancers, and estimates of the effect of aspirin on individual cancers in case–control studies were highly correlated with those seen in randomized trials (P = .0006). The largest effects were observed for gastrointestinal cancers.

In 5 studies, the regular use of aspirin was associated with a reduced proportion of cancers with distant metastasis (OR, 0.69; P < .0001); in 7 studies, it was not associated with a reduction in regional spread (OR, 0.98; P = .71). This was consistent with the findings from the randomized trials.

The authors note that "there is an urgent need for more data for effects on metastasis when aspirin is started after diagnosis of cancer."

More data are also needed for the effects of nonaspirin nonsteroidal anti-inflammatory drugs, they write, adding that "new case–control studies...have the potential to provide data quickly for each of these issues, with reasonable reliability and good statistical power."

All 3 studies were unfunded. Dr. Rothwell reports a financial relationship with several pharmaceutical companies with an interest in antiplatelet agents, including AstraZeneca, Bayer, Boehringer Ingelheim, sanofi-aventis, Bristol-Myers Squibb, and Servier; and being on the executive committee of the ARRIVE Trial. Coauthor F. Gerald R. Fowkes, FRCPE, from the Centre for Population Health Sciences, University of Edinburgh, United Kingdom, reports receiving research support and honoraria from AstraZeneca, Bayer, sanofi-aventis, and Bristol-Myers Squibb. Dr. Chan reports serving as a consultant to Bayer HealthCare and Millennium Pharmaceuticals. Dr. Cook reports being an investigator for the WHS.