COLORECTAL CANCER SCREENING in December of 2002 Jeffrey W. Frank, MD.

COLORECTAL CANCER COLORECTAL CANCER SCREENING SCREENING

in December of 2002in December of 2002

COLORECTAL CANCER COLORECTAL CANCER SCREENING SCREENING

in December of 2002in December of 2002

Jeffrey W. Frank, MD

Colon Cancer ScreeningColon Cancer ScreeningWhy Screen?Why Screen?

Colon Cancer ScreeningColon Cancer ScreeningWhy Screen?Why Screen?

•2nd leading cause of cancer deaths in the USA

•1 in 20 over the age of 50 will develop colorectal cancer in lifetime

•Pre-malignant lesion - the adenomatous polyp

•Removal of adenomas prevents cancer•Established cancer generally

progresses slowly and early stages are curable

COLORECTAL NEOPLASIACOLORECTAL NEOPLASIAAdenoma/Carcinoma SequenceAdenoma/Carcinoma Sequence

COLORECTAL NEOPLASIACOLORECTAL NEOPLASIAAdenoma/Carcinoma SequenceAdenoma/Carcinoma Sequence

NormalEpithelium

HyperproliferativeEpithelium ADENOMA

CARCINOMA

2. APC (both alleles)KrasDCC

p53 (17p)

METASTASIS

other factors

1. Mismatch repair genes (HNPCC)

COLORECTAL NEOPLASIACOLORECTAL NEOPLASIADistributionDistribution

COLORECTAL NEOPLASIACOLORECTAL NEOPLASIADistributionDistribution

50%

15%

35%

50%

10%

15%

25%

ADENOMAS CARCINOMAS

Colorectal Cancer ScreeningColorectal Cancer ScreeningWho should be screened?Who should be screened?

Colorectal Cancer ScreeningColorectal Cancer ScreeningWho should be screened?Who should be screened?

Symptomatic AsymptomaticAsymptomatic

Race

High risk groups

Gender

Distal adenomasAGEAGEmost importantmost important

Colorectal Cancer ScreeningColorectal Cancer ScreeningAge - the most important factorAge - the most important factor

Colorectal Cancer ScreeningColorectal Cancer ScreeningAge - the most important factorAge - the most important factor

•90% of colon cancer in age >50

•Benign adenomas are more prevalent after age 50 and especially after age 60

•Chances of finding a polyp is about 25%

•Proximal colon cancers increase with age

Age and Colorectal CancerAge and Colorectal CancerAge and Colorectal CancerAge and Colorectal Cancer

Colon Cancer Adenomas

Winawer SJ. Gastro 1997

Colorectal Cancer ScreeningColorectal Cancer ScreeningDo distal polyps predict proximal Do distal polyps predict proximal

polyps?polyps?

Colorectal Cancer ScreeningColorectal Cancer ScreeningDo distal polyps predict proximal Do distal polyps predict proximal

polyps?polyps?

•Patients who have distal adenomas have a 3-6% chance of having a significant proximal adenoma

•>2/3 of patients with proximal cancer will not have a distal polyp

•Therefore, distal adenomas are insensitive markers for proximal lesions and proximal lesions are unassociated with distal lesionsSchoen RE, Gastro 1998

Rex DK, Gastroentest Endosc 1999

COLORECTAL NEOPLASIACOLORECTAL NEOPLASIAPathologic SubtypesPathologic Subtypes

COLORECTAL NEOPLASIACOLORECTAL NEOPLASIAPathologic SubtypesPathologic Subtypes

Type %Total

<1 cm 1-2 cm >2 cm

Tubular 75 1% 10% 35%

Mixed 15 4% 7% 46%

Villous 10 10% 10% 53%

Overall 100 1.3% 9.5% 46%

Probability of MalignancyProbability of Malignancy

COLORECTAL NEOPLASIACOLORECTAL NEOPLASIAHeritabilityHeritability

COLORECTAL NEOPLASIACOLORECTAL NEOPLASIAHeritabilityHeritability

• 80% sporadic; 20% genetic

• Of genetic Cancers:– 1% FAP– 6% HNPCC– 10-15% familial

• Lifetime risk:– Average American- 6%– One 1st degree

relative >50 - 12%– One 1st degree

relative <50 - 22%

• Two 1st degree relatives - 34%

• One 2nd degree relative - 9%

• One 3rd degree relative - 7%

• Average risk Ashkenazic Jew - 9%

• Ashkenazic Jew with FH and APC gene mutation - 28%

• Women with h/o Breast or Genital cancer - 10%

HNPCCHNPCCHNPCCHNPCC

•Amsterdam Criteria-II– 3 or more relatives with a

histologically verified HNPCC-associated cancer (colorectal, endometrial, small bowel, ureter or renal pelvis), one of whom is a first-degree relative of the other two; AND

– Colorectal cancer involving at least two generations; AND

–One or more colorectal cancer cases diagnosed before the age of 50

COLORECTAL NEOPLASIACOLORECTAL NEOPLASIAAssociationsAssociations

COLORECTAL NEOPLASIACOLORECTAL NEOPLASIAAssociationsAssociations

•Risk Factors:– high serum cholesterol– high saturated fat diet– high “red” meat diet– increased bowel anerobic flora– increased colon pH– low fiber diet– obesity– smoking

COLORECTAL NEOPLASIACOLORECTAL NEOPLASIAChemopreventionChemoprevention

COLORECTAL NEOPLASIACOLORECTAL NEOPLASIAChemopreventionChemoprevention

•?Fiber•Low red meat (animal fat)•Folic acid•Calcium/vitamin D•Selenium•Omega-3 fatty acids•?NSAIDs

Screening Populations for Colorectal Screening Populations for Colorectal CancerCancer

ObstaclesObstacles

Screening Populations for Colorectal Screening Populations for Colorectal CancerCancer

ObstaclesObstacles

• Nonparticipation– estimated 50% of

population to be screened will not participate

• Screening insensitivity– FOBT miss rate ~ 70%

• Incomplete colorectal evaluation– estimated 33% with

positive FOBT will not undergo complete evaluation

• Old Age– ~20% of colorectal cancers

are found in patients older than age 80

– detecting asymptomatic cancers may not benefit them

• Advanced Stage– estimated 25% of

asymptomatic cancers are stage C or D

• Lead-Time Artifact– estimated 50% of

asymptomatic cancers remain stage A or B when symptoms develop

• Screen-Related Mortality– false negatives with

false reassurance, delayed diagnosis

– false positives subject to anxiety, lost work days, procedure morbidity and mortality

FOBT in a Simulated Population at FOBT in a Simulated Population at Moderate Risk for Colorectal CancerModerate Risk for Colorectal Cancer

Adapted from Ahlquist DA, Cancer (Supplement), 1992Adapted from Ahlquist DA, Cancer (Supplement), 1992

FOBT in a Simulated Population at FOBT in a Simulated Population at Moderate Risk for Colorectal CancerModerate Risk for Colorectal Cancer

Adapted from Ahlquist DA, Cancer (Supplement), 1992Adapted from Ahlquist DA, Cancer (Supplement), 1992

Obstacles 100 cancersNonparticipation (50%) 50

FOBT miss rate (70%) 15

Inadequate colorectal evaluation (33%) 10

Old age (>80yr) (20%) 8

Advanced stage (25%) 6

Lead-time artifact (50%) 3

Screen-related mortality (?1-2) 1-2

Assumed target population of 20,000 persons 50 yrs or older. At expectedprevalence of 0.5%, an estimated 100 colorectal cancers would be present at the time of screening

Colorectal Cancer ScreeningColorectal Cancer ScreeningMethods of ScreeningMethods of Screening

Colorectal Cancer ScreeningColorectal Cancer ScreeningMethods of ScreeningMethods of Screening

•Tests of Fecal Occult Blood•Digital rectal exam•Flexible Sigmoidoscopy•Barium Enema (SCBE vs DCBE)

•Colonoscopy•“Virtual Colonoscopy”

Tests of Fecal Occult BloodTests of Fecal Occult BloodTests of Fecal Occult BloodTests of Fecal Occult Blood

•False Positives Occur - Specificity 90-98% (2-10% false positive)–many lesions bleed– dietary factors

•False Negatives Occur - Sensitivity 38-92% (high false negative rate)– not all cancers bleed– reducing substances false neg (Vitamin C)

Tests of Fecal Occult BloodTests of Fecal Occult BloodTests of Fecal Occult BloodTests of Fecal Occult Blood

•Annual FOBT reduces mortality from CRC by 15-33% in randomized, controlled trials

•Tends to detect earlier stage cancers

•FOBT is insensitive for polyps•Poor patient compliance•Diagnostic follow-up is required and compliance with this is poor

Colorectal Cancer ScreeningColorectal Cancer ScreeningFlexible SigmoidoscopyFlexible Sigmoidoscopy


• Widely available• Simple

preparation/no sedation

• Minimal risk• Relatively

inexpensive• Sensitive for

polyp detection in visualized colon

• Biopsy possible

• Poor compliance• Prep often

inadequate• At best, 1/3 of

colon visualized so 1/2 of colon cancers missed

• “Like a mammogram of one breast”

• Full colonoscopy required if polyps found

ProsPros ConsCons



• Few prospective studies

• Flex sig and FOBT fails to detect 24% of advanced neoplasia Leiberman et al NEJM 2001

• Case control studies (predominantly of rigid sigmoidoscopy) show a 60% reduction in mortality from CRC in part of colon examined

• Addition of FOBT to sigmoidoscopy may reduce mortality by an additional 50%

Colorectal Cancer ScreeningColorectal Cancer ScreeningBarium EnemaBarium Enema

Colorectal Cancer ScreeningColorectal Cancer ScreeningBarium EnemaBarium Enema

• No prospective or cohort trial for CRC screening

• Double contrast better than single• DCBE is 50-80% sensitive for polyps <1

cm; 70-90% for polyps >1 cm; 55-85% for stage I and II cancer

• Insensitive in rectosigmoid area (missed 25% of cancers in pts with positive FOBT)

• Anecdotally less comfortable than colonoscopy

• Abnormalities detected require colonoscopy

Kewenter J. Endoscopy 1995

Colorectal Cancer ScreeningColorectal Cancer ScreeningColonoscopyColonoscopy


• No prospective trials for CRC screening and mortality– Sigmoidoscopy and polypectomy

reduce CRC mortality–Nat’l polyp study cleared the colon

of adenomas in high risk pts and there was a 76-90% reduction in CRC and no deaths

– Colonoscopy screening studies show a prevalence of polyps twice that of flexible sigmoidoscopy



• Evaluates entire colon

• Allows diagnosis and treatment of lesions found

• More sensitive than FOBT or sigmoidoscopy

• Theoretically prevents colon cancer

• Operator dependent• Expensive• Difficult preparation• Poor compliance• Uncomfortable,

embarrassing• Potentially risky• Incomplete exam in

5-20%• Polyps can be

missed

• Operator dependent• Expensive• Difficult preparation• Poor compliance• Uncomfortable,

embarrassing• Potentially risky• Incomplete exam in

5-20%• Polyps can be

missed

Pros Cons

Colorectal Cancer ScreeningColorectal Cancer Screening“Virtual Colonoscopy”“Virtual Colonoscopy”

Colorectal Cancer ScreeningColorectal Cancer Screening“Virtual Colonoscopy”“Virtual Colonoscopy”

• Uses spiral CT technology• Bowel preparation required• Sensitivity for polyps >1 cm

– 75% - 93% (<1cm 19-82%)• Specificity

– 90% - 100%• Time will tell if improves patient

compliance for screening• Colonoscopy still needed to remove

polyps• ? Cost-effective at this time

Colorectal Cancer ScreeningColorectal Cancer ScreeningRecommendationsRecommendations

Colorectal Cancer ScreeningColorectal Cancer ScreeningRecommendationsRecommendations

•Annual FOBT and Flexible Sigmoidoscopy every 5 years

•DCBE every 5 to 10 years

•Colonoscopy every 10 years

Average Risk Persons over age 50

Colorectal Cancer ScreeningColorectal Cancer ScreeningThe FutureThe Future

Colorectal Cancer ScreeningColorectal Cancer ScreeningThe FutureThe Future

•A test that detects “significant adenomas”

•Non-invasive test of stool or preferably blood or saliva

•Better tolerated colon preparation

COLORECTAL CANCER SCREENING in December of 2002 Jeffrey W. Frank, MD.

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