Colorectal Cancer:Update 2008

Durado Brooks, MD, MPH

Director, Prostate and Colorectal Cancer

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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

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Colorectal Cancer

Sporadic (average risk) Sporadic (average risk) (65%–85%)(65%–85%)

FamilyFamilyhistoryhistory(10%–30%)(10%–30%)

Hereditary nonpolyposis Hereditary nonpolyposis colorectal cancer colorectal cancer

(HNPCC) (5%)(HNPCC) (5%)Familial adenomatous Familial adenomatous polyposis (FAP) (1%)polyposis (FAP) (1%)

Rare Rare syndromes syndromes

(<0.1%)(<0.1%)

CENTERS FOR DISEASE CONTROLAND PREVENTION

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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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Risk Factor - Polyps

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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

91.4%

66.1%

8.5%

0

20

40

60

80

100

5-yrSurvival

Local Regional Distant

Stage of Detection

Survival Rates by Disease Stage

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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

9

3128

16

34

29

16

39

32

17

41

33

18

45

36

19

0

5

10

15

20

25

30

35

40

45

50

Total Less than a high schooleducation

No health insurance

Pre

vale

nce

(%

)

1997 1999 2001 2002 2004

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.

10

20

16

8

21

16

9

18

12

22

16

9

19

14

9

24

0

5

10

15

20

25

30

Total Less than a high schooleducation

No health insurance

Pre

va

len

ce

(%

)

1997 1999 2001 2002 2004

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 Screening Rates Low:Reasons (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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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)

Colorectal Cancer Screening 2008

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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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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 ACS CRC Advisory 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

CRC Screening Guidelines: What’s New?

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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• delineate important quality-related factors for each

form of testing • continue to emphasize options for testing

• An overriding goal of this update is to provide a practical guideline for physicians and the public

The full article can be accessed at:http://caonline.amcancersoc.org/cgi/content/full/CA.2007.0018v1

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2008 CRC Screening Guidelines

5 0 A v e r a g e r is k a d u lt s a g e a n do ld e r

• T e s t s t h a t d e t e c t a d e n o m a t o u s

p o ly p s a n d c a n c e r – Flexible sigmoidoscopy (FSIG) every 5 years*, or – Colonoscopy every 10 years, or – Double contrast barium enema (DCBE) every 5 years*, or – CT colonography (CTC) every 5 years*

• T e s t s t h a t p r im a r ily d e t e c t c a n c e r

– Annual guaiac-based fecal occult blood test (gFOBT)* with high test sensitivity for cancer, or

– Annual fecal immunochemical test (FIT)* with high test sensitivity for cancer, or

– Stool DNA test (sDNA)*, with high sensitivity for cancer, interval uncertain

*Note: All positive screening tests should be followed up with colonoscopy

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2008 CRC Screening Guidelines

New Tests

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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 detect 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

Optimum phase for early detection

Dwell Time: Many decades 2-5 years 2-5 years

APC K-ras

Bat-26 (Sporadic)

p53Mutation

NormalEpithelium Adenoma Late

AdenomaEarly Cancer

Late Cancer

Bat-26 (HNPCC

)

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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sDNA: Evidence

Three versions of the Exact Sciences test have been evaluated

• Version 1 (K-ras, APC, p53,BAT-26, DIA) was evaluated in the Imperiale trial

• 1 .1 ( -V e r s io n K, , 5 3 ), r a s A P C P

PreGen-Plus is t h e c u r r e n t ly m a r k e t e d t e s t

• Version 2 (Vimentin only, or Vimentin + DIA) is currently under evaluation

• Earlier and more recent versions were evaluated in smaller, mixed populations

Study with One-Time Testing (v)

Sensitivity for Cancer

Ahlquist, et alGastro, 2000 (1)

91%

Imperiale, et alNEJM, 2004 (1)

51.6%

Syngal, et. alCancer, 2006 (1)

63%

, W h it n e y e t a l

, J M o l D ia g n2 0 0 4 (1 .1 )

7 0 %

Chen, et alJNCI, 2005 (2)

46%

Itzkowitz, et alDDW-AB, 2006 (2)

88%

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Stool DNA: Potential Advantages

• No dietary restrictions needed• Specificity for cancer may be significantly higher

than other forms of stool testing• No stool sampling required (entire bowel

movement collected)• Company-sponsored studies report high levels of

patient acceptance

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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• Appropriate re-screening interval is not known• Costs much more than other forms of stool testing

(approximately $300 - $400 per test)• Not covered by most insurers• Not clear how to manage positive stool DNA test if

colonoscopy is negative • FDA approval concerns

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CT Colonography (CTC)

CTC Image Optical Colonoscopy

Courtesy of Beth McFarland, MD

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CT Colonography

3 - D v ie w

Polyp

2 - Dv ie w

Courtesy of Beth McFarland, MD

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CT Colonography: Rationale

• Allows detailed evaluation of the entire colon

• Minimally invasive (rectal tube for air insufflation)

• No sedation required • A number of studies have demonstrated

a high level of sensitivity for cancer and large polyps

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CTC vs. Optical Colonoscopy: Sensitivities for All Polyps

P o ly p S iz e

>10mm >8mm>6mm

CTC 92.2% 92.6%85.7%

Colonoscopy 88.2% 89.5%90.0%

Pickhardt et al, NEJM 2003

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CTC: Additional Findings

• CTC identified 55 polyps not seen on initial colonoscopy – 21 adenomas– One 11 mm malignant polyp

• Extra-colonic findings– 5 asymptomatic cancers– Aortic aneurysms– Renal and gall bladder calculi

Pickhardt et al, NEJM 2003

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CTC: Follow-up colonoscopy

• Indication for diagnostic/therapeutic colonoscopy varies markedly based on selected polyp size threshold

• Important implications for cost-effectiveness of CTC

P o ly p S iz eT h r e s h o ld

% R e q u ir in gc o lo n o s c o p y

10mm 7.5

8mm 13.5

6mm 29.7

Pickhardt et al, NEJM 2003

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CT Colonography: Additional Evidence

• A number of other studies have demonstrated a high level of sensitivity for cancer and large polyps

• Findings from the recently completed multi-center ACRIN trial reportedly are similar to those of Pickhardt et al• Some results from this trial have been

reported at medical meetings, but have not yet been published

• Manuscript has been prepared and is currently under review

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CT Colonography: Limitations

• Requires full bowel prep (which most patients find to be the most unpleasant aspect of colonoscopy)

• Colonoscopy is required if abnormalities detected, sometimes necessitating a second bowel prep

• Extra-colonic findings can lead to additional testing (may have both positive and negative implications)

• Controversy regarding management of small polyps, sensitivity for “flat polyps”

• Radiation exposure• 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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2008 CRC Guidelines continue to emphasize options because:

• Evidence does not yet support any single test as “best”• Uncertainty exists about performance of different

screening methods with regard to benefits, harms, and costs (especially on programmatic basis)

• 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

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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

• Higher potential for patient injury than fecal testing• Risk levels vary between tests, facilities, practitioners

• Patient preference • Many individuals don’t 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

Thank You!