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Genetic counseling: Colorectal Cancer Chemoprevention

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Colorectal Cancer Chemoprevention

BackgroundEdit

  • 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)Edit

  • 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 AgentsEdit

  • 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 vomitting
        • 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

NotesEdit

The information in this outline was last updated in 2002.


Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling

Heckert GNU white Permission is granted to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1.2 or any later version published by the Free Software Foundation; with no Invariant Sections, no Front-Cover Texts, and no Back-Cover Texts. A copy of the license is included in the section entitled "GNU Free Documentation License."

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