Prevention of cancer requires a multi-pronged approach consisting of early detection through screening, lifestyle choices and pharmacological interventions. Chemoprevention, as defined by the International Agency for Research on Cancer, refers to interventions with pharmaceuticals, vitamins, minerals or other chemicals (natural or synthetic) at any of the multiple stages of carcinogenesis to reduce cancer incidence.
Colorectal cancer evolves over 10-25 years, via a sequence of genetic alterations. Studies in colorectal cancer chemoprevention frequently use adenoma (precursor of cancer) recurrence as a surrogate end point.
Individuals with history of adenomas, colorectal cancers, or inflammatory bowel disease have a higher risk of developing colorectal cancer. The highest risk group consists of two familial syndromes - familial adenomatous polyposis (FAP) and hereditary non-polyposis coli (HNPCC). FAP is caused by mutations in the APC (adenomatous polyposis coli) gene, and without colectomy, 90% of patients will develop colonic cancer by age 45. In HNPCC inherited mutations in DNA mismatch repair genes lead to a 70-80% lifetime risk of early-onset colorectal cancer.
NSAIDS (non-steroidal anti-inflammatory drugs) are a diverse group of drugs that act predominantly to inhibit cyclooxygenase (COX) enzymes.- COX-1 is regarded as a housekeeping enzyme, involved in maintenance of normal tissue homeostasis, whereas COX-2 is an inducible enzyme upregulated at sites of inflammation. It is over-expressed in 90% of colorectal cancers and 40% of colorectal adenomas. Experimental data suggests that COX-2 may contribute to tumor formation via stimulation of blood vessel growth, inhibition of apoptosis (cell death) and increased tumor cell invasiveness.
Large epidemiological studies (Cancer Prevention Trial, the Nurses Health Study and the Health Professionals Follow-up Study) have demonstrated a 40% to 50% reduction in colorectal cancer incidence with chronic NSAID use.
Clinical trials of sulindac and the COX2 selective inhibitor celecoxib in FAP patients showed a significant decrease in polyp numbers after 6 or more months of treatment.However, polyp regrowth was observed within 3 months of stopping sulindac. In addition, treatment with sulindac in FAP patients who have yet to develop adenomas did not prevent their development. Therefore at present, colectomy remains the primary therapy for FAP.
In trials with lower risk subjects, aspirin 325mg per day decreased recurrence of adenomas in patients with previous colorectal cancer by 35%. In a separate study of patients with a past history of adenomas, treatment with aspirin 81mg daily was associated with a 19% risk reduction in adenoma recurrence, but there was no beneficial effect with 325mg aspirin per day.
Trials of selective COX2 inhibitors have shown benefit, but unfortunately, also show increased cardiovascular toxicity. Extended use of 25mg daily rofecoxib in a colorectal adenoma chemoprevention trial (Adenomatous Polyp Prevention of Vioxx- APPROVe) showed increased relative risk of thrombotic events and led to subsequent withdrawal from the market. The Adenoma Prevention with Celecoxib (APC) and Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trials investigated a treatment with celecoxib or placebo in populations with previous adenomas. Both showed reduction in colorectal adenoma incidence with celecoxib treatment (43.2% and 37.5% for 200mg and 400mg celecoxib twice daily respectively vs 60.7% with placebo in the APC study; and 33.6% vs 49.3% with placebo in PreSAP study). However they also demonstrated increased risk of cardiovascular events leading to early discontinuation of both trials.
To enhance the effects of NSAIDs, adding D,L-alpha-difluromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), has been tested, and found to have synergistic inhibitory effects in animal models of colon cancer. Ornithine decarboxylase activity and polyamine levels are elevated in colonic polyps and cancers relative to normal adjacent mucosa. In patients with history of adenomas, DFMO suppressed rectal polyamine content for one year at low doses with few side effects. There is an ongoing trial of DFMO and celecoxib vs celecoxib alone in FAP patients. DFMO is also being evaluated in combination with sulindac in a phase III trial in patients with sporadic adenomatous polyps and in a phase II trial in FAP patients.
Ursodeoxycholic acid (UDCA) suppresses the effects of secondary bile acids, thereby preventing colon carcinogeneis in experimental models. In patients with ulcerative colitis and primary sclerosing cholangitis, treatment with UDCA showed 74% risk reduction of colorectal neoplasia over 6 years compared to placebo. In a phase III placebo-controlled randomized study, UDCA treatment for 3 years in patients with prior colonic adenomas was associated with a non-significant reduction in total adenoma recurrence rate, and a significant reduction in adenomas with high-grade dysplasia.
Further studies exploring a longer treatment duration, longer follow-up period, usage in higher risk groups such as ulcerative colitis, FAP and in combination with other drugs are needed to define the utility of UDCA.
Epidemiological data suggest a protective effect of calcium for colorectal cancer. Data from the Nurses Health Study and Health Professionals Follow-up study showed higher calcium intake was associated with 35% risk reduction for distal colon cancers. Meta-analyses of several previous studies have also showed reduced cancer risk with higher calcium intake as did a randomized placebo-controlled study of calcium supplementation. Based on this, calcium supplementation has been approved for primary or secondary prevention of colonic adenomas by the American College of Gastroenterology. However, more recently, a large study of calcium and vitamin D supplementation in postmenopausal women for 7 years showed no difference in the rate of invasive colorectal cancer at mean follow-up of seven years although longer follow-up and data is still expected.
Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors , or “statins”, are widely used as treatment for hypercholesterolaemia. In two large cardiovascular trials, simvastatin and pravastatin were associated with reduced incidence of colorectal cancer, although a large proportion of patients were also taking aspirin in these studies which may have confounded the results. Statins reduce carcinogen-induced colon cancer in experimental animal models and induce apoptosis in colorectal cancer cell lines. A number of epidemiologic studies have been published on the effects of statins on cancer risk. A population-based case control study (Molecular Epidemiology of Colorectal Cancer) showed a 47% reduction in risk of colorectal cancer with statin use over 5 years, however several other studies showed no or even detrimental outcomes. Even meta-analyses at present have showed no effect on cancer incidence with the use of statins. Hence the association of statin use and cancer is inconclusive and further trials are pending.
Unfortunately, despite perceived benefits of NSAIDs and COX2 inhibitors, we do not yet know how to incorporate their use into an effective clinical strategy. For FAP patients, surgery remains the mainstay of care. For patients with sporadic adenomas, chemoprevention with either cannot be recommended.
Further research is needed into the molecular targets, cell signalling pathways, mechanisms of carcinogenesis. In addition, research on the ideal chemoprevention strategy also has to go hand-in-hand with research on pharmacogenetics, inter-individual genetic variability which affects drug efficacy, toxicities and drug clearance. For example, differences in NSAID metabolism and prostaglandin synthesis have been found, this suggests that only a genetically defined subset of the population may benefit from NSAIDs.
With more knowledge comes better understanding of what the risk-benefit ratio of each chemopreventive strategy is for the individual patient. This will enable rational tailored therapy that will hopefully yield maximal efficacy and benefit at minimal toxicity.
Ang Mei-Kim
Registrar
Dept of Medical Oncology
National Cancer Centre
