# 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.