Background
Colorectal cancer (CRC) is common, with an incidence of 20.1/100,000/year in men and 14.6/100,000/year in women. Worldwide, the incidence of CRC ranks fourth in frequency in men and third in women. CRC accounts for over 1 million new cases of cancer each year, 9.4% of the world's total. The prevalence is second only to that of breast cancer worldwide, with an estimated 2.8 million people alive with bowel cancer within 5 years of diagnosis. The disease causes over 592,000 deaths each year. Treatment involves surgical resection of the bowel in over 80% of patients. Adjuvant chemotherapy may reduce local recurrence and mortality but is dependent on the stage of the cancer. Fewer than 50% of patients survive more than 5 years after diagnosis. Although improved surgical and oncological techniques and population-wide screening programmes have certainly had a positive impact on the incidence and outcomes from CRC, further benefits in outcomes should be possible with chemopreventative strategies. At present there are no widely accepted chemo-preventative interventions. Inhibition of cyclooxygenase-2 (COX-2) has been associated with a reduced incidence of CRC in case control studies and experimental animal studies have given encouraging results. However although COX-2 inhibitors do reduce adenomatous polyp formation, the adverse cardiovascular profile of these drugs, will undoubtably prevent their use in a wide chemopreventative strategy. The potential for cardiovascular safety needs to be considered in a prevention strategy, especially as many of the risk factors such as obesity and hyperinsulinaemia are common to both vascular disease and CRC. Although long-term use of aspirin does seem to reduce the incidence of CRC, it is not currently recommended because of the increased risk of bleeding.
Against this background, the effects of HMG-CoA reductase inhibitors (statins) are particularly pertinent. On one hand they could be expected to be commonly prescribed to patients at risk of colon cancer, hence any effects on increasing CRC risk may be clinically important and on the other, there are data suggesting a potentially important protective effect of statins against CRC. Laboratory studies have shown that statins induce apoptosis, inhibit proliferation and reduce invasion in multiple colon cancer cell lines. This effect seems to be a class effect and has been documented with lovastatin, simvastatin, pravastatin and atorvastatin and is most plausibly due to the inhibition of the mevalonate synthetic pathway reducing the cellular availability of substrates required for the isoprenylation of small signaling G-proteins and the resultant inhibition of pro-carcinogenic and pro-survival pathways. Other protective mechanisms have been suggested, including anti-inflammatory actions, reduction in circulating lipids and a beneficial effect on adipokine secretion profiles.
Clinical studies with statins and CRC have given variable results. Two separate studies showed a highly significant 50% reduction in CRC incidence in statin users. A more recent observational study showed a 38% reduction in CRC incidence only in lovastatin users with a non-significant trend for greater protection with more than 3 years therapy and two separate meta-analyses suggested a protective effect of statins Bardou at al confirmed that randomized controlled trials tended to show a small a non-significant-reduction in CRC incidence in statin users, whilst observational and case–control studies suggested a persistent but modest protective effect of statins. These differences are thought to arise from the low absolute incidence of CRC in the randomized trials and relatively limited short term nature of statin trials, which were not primarily designed to examine cancer incidence. In addition to lovastatin protective effects have been reported with simvastatin and pravastatin. However other studies, often with different methodologies have shown no effects. The reasons for these discrepancies are not clear but probably involve differences in the study design, populations, specific statin use in different populations, age at initiation of statin use and the controls examined, duration of statin exposure and exposure to confounding factors. However, many of the recent observational studies had significant limitations with statin use being measured from prescriptions and an uninvestigated control group recruited from general practice databases. In several of the studies statin exposure was regarded as positive if as little as one prescription or 3 months therapy was taken. The maximal duration of follow up in cohort studies was usually less than 5 years and this may not have been sufficient time for the effects of statins to become apparent as other studies with over 5 years, or a mean of 9 years follow up showed more protective effects. A recent longer-term study showed that > years statin exposure, assessed using a questionnaire, was not associated with a reduced incidence of colon cancer. Statins and other medications purchased over the counter were not included in many of the studies and neither BMI nor smoking data were available in all studies. The controls were not investigated with endoscopy so there was no certainty over these diagnoses and no information available to assess early CRC. One major review confirmed that the data on statins and colon cancer were conflicting and inconsistent and although a number of studies have provided no evidence of protection, the situation was sufficiently unclear that further clinical studies were warranted.
Therefore, given this uncertainty we have examined the effect of statin use on the incidence of CRC in an average risk United Kingdom population.