Aspirin against Cancer – colorectal and elsewhere

Dr Sheehan has an interest in colorectal cancer, the second most common cancer in Ireland. aspirin is of interest to her because it is a cyclo-oxygenase (COX) inhibitor.

COX (which has two forms, COX-1 and COX-2) is one step in the conversion of arachidonic acid to prostaglandins. COX-2 is highly inducible and upregulated in colorectal cancer, 70-80% of which exhibit a 2-50 fold increase in COX-2 expression. It is also expressed in stomach, oesophageal, breast, ovary and skin cancers.

More than 30 published studies provide data on aspirin use in colorectal cancer. Among them are reports of a 40% lower risk of colorectal cancer among regular users of aspirin. In a prospective study, aspirin use 16 times per month reduced the risk of fatal colon cancer by 42%. Giovannucci et al found that 5-9 years of regular use could prevent colorectal cancer in women. Sulindac treatment of patients with familial polyposis (FAP) reduced the number and size of polyps within 9 months. In a familial polyposis mouse model, knock out of the COX-2 gene resulted in significant inhibition in colonic polyp growth. Furthermore, more than 25 animal studies have shown prevention or inhibition of chemically induced adenomas and carcinomas in the colon following treatment with aspirin or NSAIDs.

Several clinical trials are underway to investigate the effects of treating colorectal cancer patients with aspirin. One of the larger studies, funded by the National Cancer Institute in the US, has recruited 900 patients over 4 years. They will investigate whether or not treating patients with 325mgs of aspirin will improve disease free survival. Others are investigating the effects of aspirin and NSAIDs on oesophageal, gastric and lung cancers. The effect of aspirin may be multifactorial, on various growth and pro-angiogenic factors, rather than just on COX.

Dr Sheehan investigated tumours from 76 patients with colorectal cancer diagnosed between 1988 and 1990, were graded for the percentage of cells staining for COX-2. They were subdivided into four subsets - <1%, 1-19%, 20-50%, >50%.

There was a significant association between advanced Dukes stage (a clinical measure of severity of the cancer), lymph node involvement and maximum tumour diameter and COX-2 expression. Patients with tumours in which there was <1% COX-2 staining had much better survival than those with more COX-2 staining.

Dr Sheehan concluded that there was ample evidence to suggest that aspirin reduces the risk of developing colorectal cancer. Selective COX-2 inhibitors are on trial, but it is not known whether they are better than aspirin. It is also possible that aspirin or NSAIDs may be used to treat patients who develop this cancer. The dose and duration of aspirin that is required for treatment remains unclear but the results of clinical trials now underway should provide these answers in the near future.