Current drug development work recognises that the growth of tumours involves cross-talk between different signalling pathways, and that resistance develops to agents that have a single target. Aspirin affects multiple intracellular pathways and influences physiological processes such as apoptosis and angiogenesis that are important in the growth and development of malignancies (). 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. Aspirin pre-dates current anti-cancer strategies such as the use of adjuvant chemotherapy after a potentially curative operation. Although significant tumour shrinkage is not seen when aspirin is administered for other clinical indications such as cardiovascular disease, epidemiological evidence and pre-clinical data suggest that aspirin is worthy of further investigation particularly in the adjuvant setting, after potentially curative surgery and chemotherapy if appropriate, when disease burden is expected to be minimal.
Regular aspirin use is not currently recommended as a primary prevention strategy against cancer for those at average risk because of the risk of toxicity, particularly serious gastrointestinal bleeding. It is estimated that regular aspirin use increases the risk of a significant bleed from 1% over 10 years to 2–3% (Cuzick et al, 2009
) and this outweighs the potential cancer benefits particularly if effective screening is available. For aspirin administered adjuvantly, the benefit:risk ratio will be different, as higher morbidity and mortality from recurrent cancer may outweigh the toxicity associated with regular aspirin use. There is also potential for wider health benefits; colorectal cancer shares similar risk factors, such as smoking and the metabolic syndrome, with coronary artery disease; thus, aspirin could potentially be beneficial from both an oncological and cardiological perspective (Chan et al, 2007
). In any future trials the challenge will be to identify and exclude those individuals most at risk of toxicity, for example, those with a previous history of gastric ulceration (Patrono et al, 2001
) and include those most likely to benefit. Commencing aspirin while conventional adjuvant cytotoxic chemotherapy is being administered could increase toxicity, particularly the risk of bleeding if thrombocytopaenia was present. Waiting until chemotherapy had finished would allow the use of a ‘run-in' period, as used in adenoma prevention trials, in which a dose of 300
mg daily appeared to be well tolerated and participants were assessed as to whether they would be able to tolerate aspirin before they were randomised (Baron et al, 2003
; Sandler et al, 2003
). This increased compliance and reduced the risk of serious adverse events particularly gastrointestinal haemorrhage.
With the exception of the recent data from the Thrombosis Prevention Trial and the Swedish Aspirin Low Dose Trial presented by Rothwell et al (2010)
, the epidemiological data and the randomised trials assessing primary prevention support the premise that the anti-cancer effects of aspirin are most likely to be seen when higher doses are administered, there is long-term use (many years), longer follow-up (>10 years in some instances) and daily usage rather than alternate day scheduling. At higher doses, aspirin is a more potent inhibitor of Cox-2 providing a potential mechanistic explanation for these findings. The observation that the benefit of aspirin after colorectal diagnosis was greatest in those whose tumours overexpressed Cox-2, and that those who had taken aspirin before diagnosis did not appear to benefit from taking aspirin adjuvantly (Rothwell et al, 2010
) gives an indication as to who may benefit from aspirin after a cancer diagnosis and emphasises the need for pathological assessment of tumour samples to be built into any randomised trials.
The current limited testing of aspirin (http://clinicaltrials.gov
) as a therapeutic agent either in the adjuvant setting (ASCOLT and Big A trial) or in combination with other anti-cancer agents is in marked contrast to the number of studies that were initiated using selective Cox-2 inhibitors before 2004. There were numerous phase II studies and at least 12 randomised phase III trials that were ongoing in 2004, before the concerns about cardiovascular toxicity were raised, with >9000 planned participants including those with breast, colorectal, oesophageal, prostate and lung malignancies. A number of these studies involved rofecoxib and had to be discontinued when the product was withdrawn. Others were stopped early although the investigational agent (usually celecoxib) was not withdrawn.
Aspirin continues to be evaluated in vitro and in pre-clinical models to help elucidate mechanisms involved in carcinogenesis and the response of tumours to anti-neoplastic agents. Recent randomised evidence from trials primarily designed to prevent cardiovascular disease show a reduction in cancer incidence with long-term follow-up and epidemiological evidence from colorectal and breast cancer studies evaluating the effects of aspirin use after diagnosis suggests that aspirin may have a role in the adjuvant setting. The clinical management of patients is also continually evolving, with new combinations of agents or strategies being assessed; aspirin should not be overlooked in this process because it is neither new nor expensive.