WASHINGTON, DC—Statins do not appear to protect against the development of colorectal adenomas, and use of the drugs for three years or more may even raise the risk of precancerous lesions in high-risk persons. That was the conclusion of a subset analysis of the Adenoma Prevention with Celecoxib (APC) trial reported here at the American Association for Cancer Research Annual Meeting.
The findings were simultaneously published online on April 19 in the AACR journal Cancer Prevention Research.
“Statins definitely did not prevent adenomas,” said Monica M. Bertagnolli, MD, Professor of Surgery at Harvard Medical School. However, she emphasized, “Statins save lives in patients with cardiovascular disease, and people taking statins to protect against heart disease and stroke should absolutely not consider changing drugs.”
Preclinical studies had suggested that statins inhibit the growth of colon tumors, but observational studies and meta-analyses produced conflicting results, Dr. Bertagnolli explained.
The new results are from a planned secondary analysis of the APC trial, which was primarily designed to evaluate whether the anti-inflammatory drug celecoxib could be used to prevent colon cancer (Bertagnolli M et al: NEJM 2006;355: 873-884).
APC involved 2,035 patients with an increased risk for colorectal adenomas, randomized to one of two doses of celecoxib or placebo.
The trial was ended prematurely after three years when an interim analysis showed celecoxib to be associated with an increased risk of cardiovascular events. However, celecoxib was also associated with a 40% reduced risk of sporadic adenomas and a 63% reduced risk of advanced adenomas.
Planned Secondary Analysis
“Statins were examined as a prospective, planned endpoint of the study because of our hypothesis at the beginning that statins could be chemopreventive,” Dr. Bertagnolli said.
The new analysis involved only the 679 people who received placebo in the original study. “Celecoxib has a beneficial effect that would impact the results,” she said.
About a third (221) of the people in the placebo group reported taking statins. Medication use was updated every six months.
All participants underwent colonoscopic surveillance for five years after study enrollment.
After adjustment for cardioprotective aspirin use, age, and sex, participants in the placebo arm who used statins at any time had a nonsignficant 24% increase in risk of adenoma recurrence at five years compared with participants who had never used statins.
Participants who took statins for more than three years, however, had a significant 39% higher odds of developing adenomas over the five-year study period than those who didn't take statins.
“More clinical data are needed to determine whether statins can actually increase adenoma risk, as this observational result was only significant in the subset of patients who were using statins for more than three years and who were also taking placebo,” Dr. Bertagnolli said.
Discussant: Results Put Another Nail in the Statin Coffin
Study discussant John A. Baron, MD, Professor of Medicine and Community and Family Medicine at Dartmouth University, said that the results “put another nail in the statin coffin.”
“The negative data add to accumulating evidence that, at least overall, statins probably do not prevent colorectal neoplasia,” he said.
However, he did not rule out the possibility that statins may have some potential as a chemopreventive, since it takes years for colorectal cancer to develop and statins have been available only since 1987.
“Early data regarding statins and cancer are essentially noninformative. It's really only now that we can even begin to get cancer data about statins,” he said.
But, Dr. Baron continued, “adenomas are a different story…as they are an earlier stage in the carcinogenesis pathway. So you can expect to see effects sooner,” and none were seen here.
Dr. Baron said that statins may provide benefits against colon cancer “with high cumulative doses or in genetically defined subgroups.”
He noted that another study, also published online April 19 in Cancer Prevention (Lipkin SM et al), showed that the genotype of the HMG-CoA reductase gene affected the association between colorectal cancer and statins.
“It is theoretically possible that the variants might differ from population to population, and so explain the varying observational findings,” Dr. Baron said.
Louis M. Weiner, MD, Director of the Georgetown Lombardi Comprehensive Cancer Center, stressed that patients taking statins for cardiovascular prevention should be told to stay on statins.
“This is a small, preliminary, hypothesis-generating study,” he said.
Also, only people already at high risk of colon cancer were involved, so the question of whether statins can help prevent colon cancer in the general population is still unanswered, Dr. Weiner said.
Dr. Bertagnolli received funding from Pfizer and the NCI for the study.