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.