Could progressive iron loss from mucosal microbleeding represent a mechanism of cancer prevention from prolonged aspirin use?

Authors


Dear Editor,

Accumulating evidence has found that daily aspirin might prevent several common cancers, with both case-control and cohort studies suggesting an association between daily aspirin use and reduced risk of cancer, particularly of the gastrointestinal tract.1

A recent pooled analysis of 51 randomized trials of daily aspirin for prevention of vascular events reported a statistically significant 15% reduction in overall cancer mortality during an intervention period of up to 10 years.2 The overall reduction in cancer mortality was mostly attributable to an estimated 37% reduction in cancer mortality during follow-up occurring after 5 years on aspirin. On the other hand, examining the association between daily aspirin use and overall cancer mortality among 100,139 men and women with no history of cancer in the US Cancer Prevention Study II Nutrition Cohort, it has been shown that daily aspirin use was associated with modestly lower overall cancer mortality.3 Interestingly, the association between aspirin use and lower overall cancer mortality was somewhat stronger in analyses of maintained long-term aspirin use than in analyses of aspirin use at baseline. However, the estimated lower overall cancer mortality associated with 5 or more years of daily aspirin use in this study3 was only 16%. Furthermore, two very large randomized trials of alternate-day aspirin observed no effect on overall cancer mortality.4,5 We propose that a plausible explanation of these contradictory findings may be related to the mechanisms related to aspirin-induced anticancer effects.

It has been suggested that an important mechanism for the beneficial action of aspirin in cancer prevention may be related to aspirin-associated iron loss.6 There is no argument that aspirin causes gastrointestinal bleeding that may be occult or life-threatening. Small unapparent blood losses from gastrointestinal mucosa appear to be enough to cumulatively result in negative iron balance without necessarily causing anemia.

Observational studies suggest the magnitude of aspirin-mediated iron loss. The Framingham Study7 found that the mean serum ferritin was lower among categories of regular aspirin users by 21–50%. In a Danish population,8 aspirin use was associated with serum ferritin values 20% lower than nonusers. Postmenopausal women in the Nurses' Health Study9 who used aspirin 15–30 times per month had a 19% lower mean serum ferritin than nonusers.

So far, studies of the anticancer effects of aspirin have not assessed the potential role of iron loss from aspirin use. Moreover, the effects on iron losses of measures to suppress bleeding cannot be determined from the published results. If iron loss is a significant mechanism, any action that sought to minimize aspirin-induced bleeding, such as the use of proton-pump inhibitors or an alternate-day aspirin regimen, may have inadvertently minimized efficacy. In iron depletion, less iron may be available for carcinogenesis through free radical mediated mechanisms and for promotion of tumor growth.

A protective effect of iron loss against cancer mortality has been confirmed in a recent randomized trial with subjects randomized to reduction in iron stores through calibrated phlebotomies or observation.10 In the iron reduction group, mean serum ferritin declined from 122.5 to 79.7 ng/ml, a 35% decrease, which is the same order of magnitude reported with aspirin use.7–9 Over 4.5 years, risk of new visceral malignancy was significantly lower in the iron reduction group than in controls; among patients with new cancers, those with iron reduction had highly significantly lower cancer-specific and all-cause mortality.10

Therefore, progressive iron loss from mucosal microbleeding, usually considered an undesirable side effect, could be a mechanism of cancer prevention from prolonged aspirin use.

Yours sincerely,

Luca Mascitelli*, Mark R. Goldstein†, * Comando Brigata alpina “Julia,” Medical Service, Udine, Italy, † NCH Healthcare Group, Naples, FL

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