Colorectal Cancer Prevention

1
Colorectal Cancer Prevention Early Detection
Update 2008

• American Cancer Society

2
Colorectal Cancer

• The third most common cancer in U.S.
• 148,810 new cases expected in 2008
• The second deadliest cancer
• 49,960 deaths nationwide
• More than 1 million Americans living with
  colorectal cancer

3
Colorectal Cancer Risk Factors

• Age
• 90 of cases occur in people 50 and older
• Gender
• slight male predominance, but common in both men
  and women
• Race/Ethnicity
• African Americans have highest incidence and
  mortality rate of all groups in U.S., Hispanics
  the lowest (with considerable variation depending
  on country of origin)
• Increased rates also documented in Alaska
  Natives, some American Indian tribes, Ashkenazi
  Jews

4
Risk Factors (continued)

• Increased risk with
• Personal history of inflammatory bowel disease,
  adenomatous polyps or colon ca
• Family history of adenomatous polyps, colon
  cancer, other conditions

Individuals with these risk factors may require
earlier and more intensive screening
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Colorectal Cancer
Sporadic (average risk) (6585)
Family history(1030)
Rare syndromes (lt0.1)
Hereditary nonpolyposis colorectal cancer (HNPCC)
(5)
Familial adenomatous polyposis (FAP) (1)
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Risk Factor - Polyps

• Different types
• Hyperplastic
• minimal cancer potential
• Adenomatous
• approximately 90 of colon and rectal cancers
  arise from adenomas

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Normal to Adenoma to Carcinoma
Human colon carcinogenesis progresses by the
dysplasia/adenoma to carcinoma pathway
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Benefits of Screening

• Cancer Prevention
• Removal of pre-cancerous polyps prevent cancer
  (unique aspect of colon cancer screening)
• Improved survival
• Early detection markedly improves chances of
  long term survival

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Benefits of Screening
1996 - 2003
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Colorectal Screening Rates

• Just 40 of colorectal cancers are detected at
  the earliest stage.
• A little more than half of Americans over age
  50 report having had a recent colorectal cancer
  screening test
• Slow but steady improvement in these numbers
  over the past decade (but all are not benefiting
  to the same degree)

varies based on data source
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Colorectal Screening Rates
Source MMWR March 2008
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Trends in Recent Endoscopy Prevalence (), by
Educational Attainment and Health Insurance
Status, Adults 50 Years and Older, US, 1997-2004
A flexible sigmoidoscopy or colonoscopy within
the past five years. Note Data from
participating states and the District of Columbia
were aggregated to represent the United States.
Source Behavioral Risk Factor Surveillance
System CD-ROM (1996-1997, 1999) and Public Use
Data Tape (2001, 2002, 2004), National Center for
Chronic Disease Prevention and Health Promotion,
Centers for Disease Control and Prevention and
Prevention, 1999, 2000, 2002, 2003, 2005.
13
Trends in Recent Fecal Occult Blood Test
Prevalence (), by Educational Attainment and
Health Insurance Status, Adults 50 Years and
Older, US, 1997-2004
A fecal occult blood test within the past year.
Note Data from participating states and the
District of Columbia were aggregated to represent
the United States. Source Behavioral Risk
Factor Surveillance System CD-ROM (1996-1997,
1999) and Public Use Data Tape (2001, 2002,
2004), National Center for Chronic Disease
Prevention and Health Promotion, Centers for
Disease Control and Prevention and Prevention,
1999, 2000, 2002, 2003, 2005.
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Colorectal Stage vs. Insurance
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Colorectal Screening Rates LowReasons
(according to Patients)

• Low awareness of CRC as a personal health threat
• Lack of knowledge of screening benefits
• Fear, embarrassment, discomfort
• Time
• Cost
• Access
• My doctor never talked to me about it!

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Colorectal Cancer Screening 2008
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ACS 2003 CRC Prevention and Early Detection
Recommendations

• Fecal Occult Blood Testing (FOBT)
• Guaiac
• Immunochemical
• Flexible Sigmoidoscopy (FSIG)
• FSIG FOBT
• Colonoscopy
• Double Contrast Barium Enema (DCBE)

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The 2008 CRC Guidelines Update was a Joint
Effort of 5 Organizations

• American Cancer Society
• U. S. Multi-Society Task Force on Colorectal
  Cancer
• American Gastroenterological Association
• American College of Gastroenterology
• American Society of Gastrointestinal Endoscopists
• American College of Radiology

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2008 CRC Screening Guidelines Process

• Expert panel reviewed and deliberated on
  available evidence during two face-to-face
  meetings and a series of conference calls
• Literature published between January 2002 and
  January 2008, as well as unpublished abstracts
  and manuscripts, were reviewed by panel

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2008 CRC Guidelines Update Evidence Criteria
and Limitations

• Current evidence has a number of limitations
• Prospective studies are uncommon
• Sample sizes tend to be small
• Study participants often include higher risk,
  symptomatic patients and/or screening populations
  (magnitude of bias uncertain)
• Priority placed on prospective studies of
  asymptomatic adults, with all subjects
  undergoing colonoscopy
• Because adherence to regular screening is low,
  we are considering setting a test sensitivity
  threshold for test acceptance

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2008 CRC Guidelines Update Concerns and
Limitations

• Variations in
• Performance outside of research/expert settings
• Performance within gFOBT and FIT test groups
• Test costs
• Demands for patient adherence
• Quality of the supporting evidence for new
  technologies (typically non-experimental)

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CRC Screening Guidelines Whats New?

• CRC screening tests are grouped into two
  categories
• Tests that detect cancer and precancerous polyps
• Tests that primarily detect cancer
• It is the strong opinion of the consensus
  guidelines group that colon cancer prevention
  should be the primary goal of CRC screening.
• Exams that are designed to detect both early
  cancer and precancerous polyps should be
  encouraged if resources are available and
  patients are willing to undergo an invasive test
• If the full range of screening tests are not
  available, physicians should make every effort to
  offer at least one test from each category

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CRC Screening Guidelines What Else is New?

• Two new tests recommended
• stool DNA (sDNA) and
• computerized tomographic colonography (CTC)
  sometimes referred to as virtual colonoscopy
• The guidelines establish a sensitivity threshold
  for recommended tests
• The guidelines delineate important
  quality-related factors for each form of testing

The full article can be accessed
at http//caonline.amcancersoc.org/cgi/content/fu
ll/CA.2007.0018v1
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2008 CRC Screening GuidelinesBeginning at age
50, both men and women at average risk for
developing colorectal cancer should use one of
the screening tests below
Colonoscopy should be done if test results
are positive. For gFOBT or FIT used as a
screening test, the take-home multiple sample
method should be used. gFOBT or FIT done during
a digital rectal exam in the doctor's office is
not adequate for screening.
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CRC Screening Guidelines

• New recommendations provide information on
  performance and quality issues related to each
  form of testing.
• An overriding goal of this update is to provide
  a practical guideline for physicians and the
  public
• Guidelines continue to emphasize options for
  testing

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2008 CRC Guidelines Continue to Emphasize Options
Because

• Evidence does not yet support any single test as
  best
• Uptake of screening remains disappointingly low
• Individuals differ in their preferences for one
  test or another
• Primary care physicians differ in their ability
  to offer, explain, or refer patients to all
  options equally
• Access is uneven geographically, and in terms of
  test charges and insurance coverage
• Uncertainty exists about performance of different
  screening methods with regard to benefits, harms,
  and costs (especially on programmatic basis)

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If tests that can prevent CRC are preferred, why
not recommend them alone?

• Greater patient requirements for successful
  completion
• Endoscopic and radiologic exams require a bowel
  prep and an office or facility visit
• No true gold standard
• Colonoscopy misses 5 10 of significant lesions
  in expert settings
• Higher potential for patient injury than fecal
  testing
• Risk levels vary between tests, facilities,
  practitioners
• Patient preference
• Many individuals dont want an invasive test or a
  test that requires a bowel prep
• Some prefer to have screening in the privacy of
  their home
• Some may not have access to the invasive tests
  due to lack of coverage or local resources

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• Quality Issues

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2008 CRC Screening Guidelines

• The medical literature reflects quality concerns
  related to essentially all forms of testing
• Examples include
• Inadequate flex sig insertion depth
• Abbreviated colonoscopy withdrawal times
• Poor sensitivity of in-office FOBT

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FOBT Sensitivity Take Home vs. In-Office

• Sensitivity of Take Home vs. In-Office FOBT

Collins et al, Annals of Int Med Jan 2005
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In-Office FOBT should be abandoned

• Conclusion
• In-office FOBT is essentially worthless as a
  screening tool for CRC and must be strongly
  discouraged
• However
• In a recent national survey, nearly 30 of
  physicians reported using single-sample,
  in-office FOBT as their primary method of
  screening for colorectal cancer.

Nadel et al, Annals of Int Med Jan 2005
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2008 CRC Screening GuidelinesNew Tests
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Stool DNA
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Stool DNA Test (sDNA)

• Rationale
• Fecal occult blood tests detect blood in the
  stool which is intermittent and non-specific
• Colon cells are shed continuously
• Polyps and cancer cells contain abnormal DNA
• Stool DNA tests look for abnormal DNA from cells
  that are passed in the stool

All positive tests should be followed with
colonoscopy
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Genetic Model of Colorectal Cancer
Bat-26 (Sporadic) p53
Bat-26 (HNPCC)
K-ras
APC
Mutation
Many decades
Dwell Time
2-5 years
2-5 years
Optimum phase for early detection
Courtesy of Barry M. Berger. MD, FCAP EXACT
Sciences
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sDNA - Sample Collection
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sDNA - Sample Collection
Collection bucket inserted into bracket and
installed under toilet seat
Patient supplies whole stool sample no diet or
medication restrictions
Patient seals sample in outer container and
freezer pack
Patient seals container and ships back to
designated lab (all packing materials and labels
supplied)
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Performance Characteristics of Stool DNA in the
Detection of CRC

• Three versions of the previously marketed sDNA
  test have been evaluated
• Version 1 (K-ras, APC, p53,BAT-26, DIA) was
  evaluated in the Imperiale trial
• Version 1.1 (K-ras, APC, P53), PreGen-Plus is the
  currently marketed test
• Version 2 (Vimentin only, or Vimentin DIA) is
  currently under evaluation and is expected to
  enter the market in Fall 2008
• Earlier and more recent tests were evaluated in
  smaller, mixed populations

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Performance Characteristics of Stool DNA in the
Detection of CRC

• Testing evaluates stool for the presence of
  altered DNA in the adenoma-carcinoma sequence
• No dietary restrictions
• No stool sampling (utilizes the entire stool)
• Several studies suggesting strong patient
  acceptance
• Testing interval uncertain
• Uncertainty about the meaning of false positives

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Stool DNA

• Limitations
• Misses some cancers
• Sensitivity for adenomas with current commercial
  version of test is low
• Technology (and test versions) are in transition
• Costs much more than other forms of stool testing
  (approximately 300 - 400 per test)
• Not covered by most insurers

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Stool DNA

• Limitations (cont.)
• Appropriate re-screening interval is not known
• Not clear how to manage positive stool DNA test
  if colonoscopy is negative
• FDA issues
• Test availability

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CT Colonography (CTC)
Courtesy of Beth McFarland, MD
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CT Colonography

• Rationale
• Allows detailed evaluation of the entire colon
• A number of studies have demonstrated a high
  level of sensitivity for cancer and large polyps
• Minimally invasive (rectal tube for air
  insufflation)
• No sedation required

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CT Colonography
Polyp
Courtesy of Beth McFarland, MD
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CTC Virtual Fly Through
Courtesy of Beth McFarland, MD
46
CTC vs. Optical Colonoscopy Sensitivities for
Polyps gt 5 mm


Adapted from AmJRad 2002
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CTC vs. Optical Colonoscopy Meta-Analyses
Halligan 2005, Mulhall 2005
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CTC vs. Optical Colonoscopy Sensitivities for
All Polyps
Pickhardt et al, NEJM 2003
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The ACRIN CT Study

• The ACRIN study is a multi-center study with each
  site using state-of-the-art technology
• 15 participating sites
• Patients underwent both CTC and colonoscopy
• 2,531 asymptomatic patients studied
• Findings published Sept 2008 in New England
  Journal

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ACRIN Results
Johnson et al, NEJM 2008
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CTC - Extra-Colonic Findings

• Most have limited clinical impact, but some are
  important
• Asymptomatic cancers outside of colon and rectum
• Aortic aneurysms
• Renal and gall bladder calculi

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CT Colonography

• Limitations
• Requires full bowel prep (which most patients
  find to be the most distressing element of
  colonoscopy)
• Colonoscopy is required if abnormalities
  detected, sometimes necessitating a second bowel
  prep
• Steep learning curve for radiologists
• Limited availability to high quality exams in
  many parts of the country
• Most insurers do not currently cover CTC as a
  screening modality

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CT Colonography

• Limitations
• Extra-colonic findings can lead to additional
  testing (may have both positive and negative
  connotations)
• Questions regarding
• Significance of radiation exposure
• Management of small polyps

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2008 USPSTF Guidelines

• U.S. Preventive Services Task Force, Ann Intern
  Med 2008

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Comparison of Recommendations
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Comparison of Recommendations
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Flat Lesions

• Background
• Described in Japanese patients since 1980s.
  Thought to be uncommon in the U.S.
• Study published in March 2008 detected flat
  lesions at much higher rate than any previous
  U.S. reports
• Colonoscopies in over 1800 veterans found
• Polyps in 37
• Flat lesions in 9.35
• 0.8 of flat lesions cancerous or pre-cancerous

Soetikno, JAMA 2008
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Flat Lesions

• Caveats
• Most lesions not truly flat

Soetikno, JAMA 2008
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Flat Lesions

• Caveats (cont.)
• Only about 1/3 of patients in Soetikno study were
  average risk screening population
• 1/3 were high risk based on personal or family
  history
• 1/3 were symptomatic
• Flat lesions findings were different among
  average risk patients
• Flat lesions found in only 6
• Cancer or pre-cancerous findings in only 0.3

Soetikno, JAMA 2008
60
Flat Lesions

• Implications for screening
• JAMA study led some to question the ability of
  CTC to detect flat lesions (although CTC was not
  utilized in the study)
• Results from early CTC/flat lesion studies were
  extremely variable (sensitivity 13 - 65)
• Recent study of experienced radiologist using
  advanced technology and protocols found 80
  sensitivity for flat lesions

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Flat Lesions Conclusions

• Flat Lesions
• May be more common in the U.S. than previously
  believed
• Occur less frequently than protuberant polyps,
  but are more likely to harbor cancer or
  pre-cancerous cells
• Appear to occur more frequently in symptomatic
  patients and in patients with identified CRC risk
  factors
• New symptoms should not be ignored because
  patient has history of normal colonoscopy
• More research needed on ways to enhance detection
  of flat lesions by colonoscopy, CTC and other
  methods

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Thank You!