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 safter 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, antioxidents, 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.