Handbook of Genetic Counseling/Colorectal Cancer Chemoprevention

Colorectal Cancer Chemoprevention Background Colorectal Cancer Second leading cause of cancer-related deaths in US Estimated 56,000 people die annually Surgical resection and chemotherapy or radiation are standard treatment procedures Lifetime risks for colorectal cancer General population 5% Family history of adenoma or CRC 15-20% HNPCC 80% FAP approaches 100% Annual incidence 130,000 When detected and treated while still localized 5 year survival exceeds 90% Only 40% of cancers diagnosed while still localized Current screening recommendations include: Annual fecal occult blood testing Flexible sigmoidoscopy every five years Colonoscopy every 10 years or double contrast barium enema every 5-10 years Chemoprevention Use of natural or pharmacologic agents to halt, reverse, or delay carcinogenesis Mechanisms to protect against mutagens Inhibit uptake or activation Enhance DNA repair of apoptosis Modulate cellular activities Signal transduction Growth factor activity Hormonal activity Immune response DNA methylation Development of chemotherapeutics Goal is to achieve an acceptable therapeutic index Therapeutic index is risk to benefit ratio Want benefits of chemoprevention to greatly outweigh risks Important for all therapeutic agents, but particularly those used for prevention Prevention of cancer may require years of therapy Four considerations in development Therapeutic regimen Dose Duration Route of administration Side effects Mechanistic specificity Agents ability to provide therapeutic development without affecting other pathways in body Reduces number of side effects Combinations with other chemotherapeutics Chemoprevention in colon cancer Alternative approach to screening to reduce mortality from colorectal cancer Directed at preventing development of polyps that have potential to progress to colon cancer Agents interfere with genetic alterations that lead to development of adenomas or their progression to cancer Evaluation of chemotherapeutic effectiveness Enhanced by increasing understanding of molecular events in carcinogenesis Rely on different types of studies Epiemiological Animal studies Mechanisms of action of agents Controlled clinical trials Measures of efficacy Difficult to determine what intermediate clinical events correlate with long term benefits Long term benefits Reduction in cancer incidence Reduction in cancer mortality Fewer or less invasive surveillance Clinical measurements Regression, suppression, and prevention of adenomas Examine adenoma number, size, burden, histopathology, cellular/molecular characteristics Trials usually are performed on only one risk cohort and may not apply to other cohorts or general population FAP HNPCC Inflammatory bowel disease Personal or family history of colorectal cancer General population Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) Catalytic enzymes that convert arachidonic acid into prostanoids Non-selective inhibitors inhibit both COX-1 and COX-2 Selective inhibitors inhibit only COX-2 Inhibiting COX enzymes causes increase in arachidonic acid Stimulates conversion of sphingomyelin to ceramide Ceramide induces apoptosis Apoptosis may also occur due to alterations in prostaglandin production and a decrease in angiogenic factors May also have COX-independent chemopreventive activities Inhibit COX-1 by irreversible acetylation Constitutively expressed in most epithelial cell types Plays role in cytoprotection Inhibition of COX-1 in GI tract can cause ulceration and bleeding Not involved in colon carcinogenesis Inhibit COX-2 by competitive inhibition Little basal expression in cells Induced by cytokines, mitogens, and growth factors Expression induced by cytokines, mitogens, and growth factors Overexpression may promote proliferation, inhibit apoptosis, and promote angiogenesis Includes aspirin, sulindac, celecoxib, and rofecoxib Aspirin Case-control studies Show 40-50% reduction in risk of colonic adenomas or colorectal cancer Studies done on members of general population Randomized controlled trial Only one has been completed Analyzed men in cohort examining the effects of aspirin on coronary artery disease Found no significant difference in risk of developing adenomas or cancer with use or aspirin Men were taking very low dose - may be a threshold dose that was not achieved in this study Benefit seems to be greatest in people taking aspirin consistently for many years Sulindac Non-specific COX inhibitor Observational and randomized trials Studied patients with FAP Showed substantial reduction in size and number of polyps Increase in number and size of polyps noted three months after sulindac Discontinued Development of new colorectal carcinoma reported in patient with FAP while taking sulindac Randomized trial of primary chemoprevention Double-blind, placebo controlled Found sulindac did not slow development of adenomas in patients with FAP Found no significant difference in number of polyps between groups Celecoxib Selective COX-2 inhibitor Randomized controlled trial Showed regression of polyps in patients with FAP by 28% Insufficient information about long-term effects Only agent approved by FDA for treatment of adenomatous polyps Risks of NSAIDs Non-selective NSAIDs can cause ulceration and bleeding in GI tract Concern about risk of cardiovascular effects of COX-2 inhibitors Possible prothrombotic potential of COX-2 inhibitors Important to assess long term effects because may require years of treatment Future of NSAIDs Current studies looking at celecoxib and related COX-2 inhibitor rofecoxib Studies comparing effects of aspirin with selective COX-2 inhibitors Development and testing of NO-releasing NSAIDs that may be safer and more effective than traditional NSAIDs Other Chemopreventive Agents DFMO (a-difluoromethylornithine) Irreversible inhibitor of enzyme ornithine decarboxylase (ODC) ODC is enzyme involved in biosynthesis of polyamines Polyamines are promoters of cell proliferation ODC activity and polyamine levels significantly elevated in colorectal adenomas and cancers compared to normal tissues Phase II clinical trials in 1980's Pulled due to limited efficacy Severe side effects noted Thrombocytopenia Nausea and vomiting Abdominal pain Diarrhea Reversible hearing loss Recent early trials show DFMO may be effective at low doses Dose-limiting ototoxicity only side effect Now being tested in Phase II/III trials in those at risk for colorectal, bladder, or skin cancer May have additive effect when used with COX inhibitors Folate Individuals with high dietary folate intake have lower incidence of colorectal cancer Greatest benefit if using supplements May require years of use for benefit to be seen Mechanism of action unknown Calcium Some studies show supplements decrease proliferation of colorectal epithelium Within one year of use Dose required to see effect still unknown May inhibit carcinogenesis by binding bile acids and fatty acids in bowel lumen Hormone Replacement Therapy (HRT) May provide 20% reduction in risk for colorectal cancer Estrogens may decrease production of secondary bile acids by decreasing insulin-like growth factor I Vitamins, antioxidants, fiber Data from prospective studies show no effect in rate of adenoma formation with vitamin or antioxidant supplements Studies show very weak protective effect of increased dietary fiber Notes The information in this outline was last updated in 2002.