Guest Update by Dr. Asad Umar
NCI Committed to Colorectal Cancer Prevention
Over the last several years, there has been important progress in clinical research testing the cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex) to prevent the recurrence of colon polyps in individuals who have had such polyps removed. This includes the recently published efficacy results of two phase III trials - the Adenoma Prevention with Celecoxib (APC) and PreSAP trials - both of which demonstrated a significant reduction in the recurrence of colon polyps among participants taking celecoxib compared with placebo.
These trials, however, were not entirely positive for the safety profile of celecoxib. According to an NCI-funded independent safety analysis of data from both trials, there is an increased risk of serious adverse cardiovascular events associated with the daily use of celecoxib, particularly at higher doses. Celecoxib, the analysis found, can significantly increase blood pressure, which could possibly account for the increased cardiac risk. This must be investigated further, however. (Detailed information on the results of these studies and NCI-supported studies involving celecoxib are available on the NCI Web site.)
Despite these findings of increased cardiovascular adverse event risk, celecoxib is still the only FDA-approved drug used in conjunction with surgery to reduce the number of colorectal polyps in individuals with a hereditary condition called familial adenomatous polyposis (FAP). Based on the abundance of data demonstrating its efficacy in reducing the risk of precancerous colon polyps, NCI remains committed to investigating celecoxib for the prevention of colorectal cancer in a broader population at higher risk of developing cancer.
At NCI, we believe it is a clinical imperative to make cancer prevention a reality, particularly for a cancer that is as pervasive and deadly as colorectal cancer, of which 150,000 new diagnoses are made each year.
This will require altering how the research community approaches cancer prevention. In the treatment realm, once a drug is found to be effective, rarely is it abandoned purely because of toxicity concerns. Rather, additional research is performed to understand its toxicities while striving to minimize risks and maximize effectiveness.
To make greater advances in cancer prevention research, we are moving toward "molecular prevention": identifying molecular markers that can help us discern who is most likely to benefit from the drug as a cancer prevention agent.
In NCI’s Division of Cancer Prevention, Dr. Iqbal Ali led a study published in 2004, for example, that used proteomic technologies to identify which individuals with FAP were most likely to benefit from celecoxib. Dr. Ali is continuing this research in other high-risk cohorts and preliminary results are encouraging.
More work in the laboratory and with animals should help us identify why celecoxib increases blood pressure and whether that underlies the increased cardiac risk associated with its use. In addition, more research is needed to understand the effect of different dosing regimens on cardiovascular toxicity and chemopreventive efficacy.
The challenge is to pursue the necessary science in a most efficient manner to translate the promise of cancer prevention into practice with minimum toxicity and maximum efficacy.