Could Aspirin Be a Viable Adjuvant Treatment for Cancer?

Epidemiological evidence as well as evidence from recent randomized trials suggest that aspirin may be of use in the adjuvant setting to treat cancer. Dr. Ruth E Langley and colleagues provide an overview of the evidence in favor of aspirin in cancer despite aspirin being “neither new nor expensive,” in a recent review in the British Journal of Cancer.[1]

Aspirin 3D model; source: Wikimedia Commons, user Rob Hooft

Despite being under the radar as a potential antineoplastic agent, the authors highlight continuing in vitro, preclinical, and in-human trials that are helping to uncover the mechanisms of aspirin in eliciting a tumor response. They highlight that aspirin affects multiple intracellular pathways and influences many physiological processes important in cancer progression, such as apoptosis and angiogenesis. 

Recent randomized trials that have aimed to show that aspirin can help to prevent cardiovascular disease have also shown a reduction in cancer incidence with long-term patient follow-up. Other traditional nonsteroidal anti-inflammatory drugs (NSAIDs) have also been shown to play a role in cancer risk reduction.

Preclinical evidence and mechanisms of aspirin's anti-cancer activity

The first evidence of a potential role for aspirin as an anti-cancer therapy was in a 1968 mouse study, which showed that a platelet reduction was associated with a 50% reduction in metastases in mice. This result was supported by further mouse studies but the findings were never followed up on in human trials.

Aspirin inhibits the two isoforms of cyclooxygenase, COX-1 and COX-2, located in blood vessels, the stomach, and the kidneys. Because cyclooxygenase is responsible for synthesis of prostaglandins, non-hormonal messenger molecules that regulate the inflammatory response, inhibition of COX-1 and 2 facilitates the reduction of inflammation. Prostaglandins also function in angiogenesis, apoptosis, cell proliferation and migration, and thrombosis.

While the authors point out that blocking prostaglandin synthesis is considered to be the main mechanism by which aspirin and other NSAIDS exert their anti-inflammatory function, it is not yet clear whether the anti-cancer properties of aspirin can be attributed only to its inhibition of the COX molecules. Because aspirin binds to the COX molecules irreversibly, despite having only a 15- to 20-minute half-life in the body, its effect of decreased platelets and a down-regulation of the high concentration of COX-2 in tumors and the tumor stromal environment may be the explanation for its anti-cancer activity.

“COX-2 over-expression is seen in a number of tumor types though it is not proven that the anti-cancer effects of aspirin are mediated through COX-2,” explains Dr. Langley.

Platelet inhibition may be important in metastasis.  It has been proposed that platelets affect the spread of metastases by allowing cancer cells to migrate more efficiently via an association with circulating white blood cells and endothelial cells and by protecting circulating cancer cells from natural killer cells.

Potential COX-indepenpendent anti-cancer activities of aspirin include the inhibition of the transcription factor nuclear factor kappa B (NFkB) and an increase in apoptotic cells in neoplastic but not normal tissues. There is also in vitro evidence that aspirin can potentially interact with other tumorigenesis pathway molecules, including B-catenin and wnt signalling, and tumor necrosis factor, as well as the DNA mismatch repair system.

The clinical evidence

According to the review authors, the first evidence that aspirin could act in chemoprevention was from a 1988 case-control colorectal cancer study that showed aspirin was associated with a significantly lower risk of the cancer after adjustment for other risk factors. Further large cohort trials showed that both duration of aspirin use and dose are important, with a maximum reduction of colorectal cancer seen with at least fourteen 325-mg tablets of aspirin a week for 6 to 10 years.[2]

A few randomized, large-scale trials with a median follow-up of 10 years have shown no reduction in risk of cancer with aspirin usage, but according to the authors, ineffective dose and scheduling, poor compliance, and longer-follows cannot be ruled out as reasons for the negative results. Two smaller randomized, 23-year median follow-up trials did show a reduced rate of colorectal cancer incidence in patients taking higher doses of aspirin (hazard ration [HR] 0.73, P = .02), and a pooled analysis of these two trials also showed an overall reduced incidence of colorectal cancer.[3] A meta-analysis of primary outcome measure trials, including seven randomized aspirin trials, with an average treatment period of at least 4 years, showed a reduction in deaths from all cancers after 5 years of follow-up.

As far as evidence for a secondary prevention effect of aspirin, a meta-analysis of four trials in patients with colorectal adenomas has suggested a reduction in the rate of reoccurrence of adenomas by 18% with daily aspirin usage. Additionally, two recent non-randomized therapeutic studies showed that those diagnosed with colorectal cancer who used aspirin regularly after their diagnosis had reduced colorectal cancer–specific and overall mortality. Additionally, those whose tumors overexpressed COX-2 had the most benefit for colorectal-specific mortality. Similar results in 2010 were seen for breast cancer, with aspirin use after a breast cancer diagnosis being associated with a decreased distant diagnosis. Small-scale trials in lung cancer patients taking aspirin in combination with chemotherapy did not show any added benefit of aspirin, and advanced renal cell cancer patients taking aspirin along with receiving interferon-alpha did not show any difference compared with interferon-alpha alone. “The most recent data from Peter Rothwell[4] shows aspirin reduces mortality from most solid common tumors, not just colorectal cancer,” says Dr. Langley.

Aspirin use is not currently recommended as a primary prevention strategy because of the risk of serious gastrointestinal bleeding, which goes up from 1% to 2%-3% with regular use over 10 years. However, with more data, the benefit-to-risk ratio will likely be different for those with a low-burden, early-stage cancer, the authors suggest. There is also the added benefit for those with cardiac disease.

They conclude that with the exception of the Thrombosis Prevention Trial and the Swedish Aspirin Low-Dose Trial, the current epidemiological and randomized trial data support the idea that anti-cancer activity will more likely be seen with long-term high-dose aspirin use; that longer than 10-year follow-ups are needed for future clinical trials; and that daily usage is more beneficial than alternate-day dosage.

“Publicly funded researchers have a responsibility to ensure that drugs for which there is no longer a financial incentive for pharmaceutical companies to develop further are assessed in light of current knowledge and evolving clinical practice,” the authors state in their discussion.

Perhaps this review will revive the interest in aspirin’s anti-neoplastic activity, as the current epidemiological evidence suggests that aspirin is certainly worthy of further investigation “particularly in the adjuvant setting, when disease burden is expected to be minimal,” according to Dr. Langley and colleagues. “Trials are clearly needed to assess daily aspirin as both a primary prevention agent in cancer and in the adjuvant setting,” stresses Dr. Langley.

References:

References:
1. Langley RE et al. Br J Cancer. 2011;105:1107-13.
2. Chan AT et al. Gastroenterology. 2008;134: 21-8.
3. Flossmann E et al. Lancet. 2007;369:1603-13.
4. Rothwell PM et al. Lancet. 2011;377:31-41.