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)
Discontinued
 * 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
 * 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