Transcript No Slide Title

Colorectal Cancer Screening
Contributors:
Molly Gabel, M.D.
Michael Nissenblatt, M.D.
Tamir Ben-Menachem, M.D.
David August, M.D.
Rebecca A. Moss, M.D.
The American Cancer Society
Project made possible by
The Robert Wood Johnson Foundation
Colon Cancer Overview
I. Pathogenesis
II. Definition of Risk
III. Screening Tests: Methods and
Comparison
IV. Overcoming Barriers to Screening
V. 2009 Screening Recommendations
Colorectal Cancer Screening:
Technologic and Social Factors
Advocacy
Education
Government:
Screen for Life Act!
Social
Patients
Physicians
Administrators
Improved Screening
||
More Lives Saved
Molecular Testing
Improved Genetic Testing
Fecal DNA
Polyp Detection
CT Colonography
Improved Preparation
Improved Sedation Better
Colonoscopes
United States 2008 Ten Leading
Cancer Types
Estimated New Cancer Cases and Deaths by Sex
Copyright ©2008 American Cancer Society
Burden of Disease
• Too Many People Dying from CRC
– 57,000 deaths per year in the U.S.
– Second leading cause of cancer deaths
– Rate not declining appreciably
• Far Too Few Being Screened for CRC
– 30-40% of eligible patients have ever been screened
– Many of those screened infrequently
– Disease- and test-specific reasons for lack of screening
• Disease Curable if Caught Early
Pathogenesis
Adenoma to Carcinoma Pathway
5 q LOH*
(APC/β-catenin)
Normal
epithelium
Cancer
Adenoma
Normal
?K-ras
Dysplastic
ACF
?K-ras
Early
adenoma
18 q LOH
DCC/SMAD4/SMAD2
17 q LOH
Late
adenoma
MMR activation
ACF = aberrant crypt foci; MMR = mismatch repair.
Modified from Lynch HP, Hoops TC. Hematol Oncol Clin North Am. 2002;16:775.
Carcinoma
Metastatic
carcinoma
Definition of Risk
• Average
• Above Average
• High
Simplified Risk Classification
Average Risk
Increased Risk
> Age 50
No other risk factors
Hereditary syndromes
FAP
HNPCC
Personal history of polyps or CRC
Family history of polyps or CRC
Inflammatory bowel disease
Modifiable Risk Factors
•
•
•
•
Low fiber diet
Obesity
Smoking
Heavy alcohol consumption
– All place patient at increased risk, but no data
to support more aggressive surveillance
Incidence of CRC Increases With Age
300
Rate/100,000
250
200
150
100
50
0
20–30
30–40
40–50
Age (y)
Jemal A et al. CA Cancer J Clin. 2005;55:10-30.
50–60
60–70
>75
Risk by Medical/Genetic
Risk Factor
Lifetime Risk by
Familial Risk Classification
Familial Risk for Colorectal Cancer
10 0
70%
80
Approximate
lifetime
CRC risk
(%)
60
40
20
2%
6%
8%
10%
17%
0
None
One 1° One 1° and One 1°
two 2°
age <45
Aarnio M et al. Int J Cancer 64:430, 1995
Houlston RS et al. Br Med J 301:366, 1990
St John DJ et al. Ann Intern Med 118:785, 1993
Two 1°
HNPCC
mutation
Affected family members
ASCO
Incidence of CRC
According to Risk
CRC Risk Groups
IBD 1%
FAP 1%
HNPCC 5%
FH 15%–20%
Sporadic
average risk
~75%
Sporadic = men and women ?50 years with average risk; IBD = inflammatory bowel disease;
FAP = familial adenomatous polyposis; HNPCC = hereditary nonpolyposis CRC; FH = positive family
history.
Adapted from Winawer SJ et al. J Natl Cancer Inst. 1991;83:243-253.
Familial Adenomatous
Polyposis(FAP)
• Mutation in APC (Autosomal Dominance)
• >100 adenomas in colon
• 100% Cancer Risk if untreated (endoscopic surveillance +/- colectomy)
– 90% will develop colorectal cancer
– After colectomy, 10% still develop extracolonic tumors:
•
•
•
•
•
•
•
duodenal adenomas/Ca
Ampullary tumors
Desmoid tumors
Thyroid cancer
Hepatoblastoma (pediatric patients)
Glioblastoma
Adrenal tumors
– Other manifestation: congenital hypertrophy of retinal pigmented
epithelium
Lynch Syndrome (HNPCC):
Hereditary Non-Polyposis Colon Cancer
• Also associated with
thyroid, pancreatic,
hepatobiliary and
prostate Ca
• Muir-Torre: sebaceous
gland tumors,
keratoxanthomas
Cancer
Risk
CRC
40-70%
Most.in proximal colon
Endometrial
40-60%
Ovarian
(mucinous)
9%
Urinary tract
RR 0-76
Small bowel
RR 103-292
Gastric
RR 4.4-19.3
Lynch Syndrome (HNPCC):
• Carriers not at increased risk
• Endoscopic surveillance is of proven benefit
to increase survival
• No evidence that increased surveillance of
other cancers increases survival
What are the Amsterdam &
Bethesda Criteria?
1. Amsterdam Criteria:
Used to r/o HNPCC in patients with clinical family history
•
•
•
•
•
•
3 relatives with an HNPCC-associated cancer
1 is a 1st degree relative of the other 2
 2 successive generations affected
 1 diagnosed before age 50
FAP excluded in the colorectal cancer case(s)
Tumors verified by pathological examination
2. Modified Bethesda Criteria:
Used to determine if benefit from genetic testing for HNPCC
• Meet Amsterdam criteria
• 2 HNPCC-related cancers
• Has CRC and a 1st degree relative with CRC and/or
HNPCC-related extracolonic cancer and/or a
colorectal adenoma before age 40.
• Right-sided CRC having an undifferentiated pattern
before age 45.
• Signet-ring cell type before age 45.
• Adenomas before age 40.
The Audience
Month Day, Year
Other Genetic Syndromes
• Familial CRC Type X
– Meet Amsterdam criteria, but negative genetic testing
– No risk for other cancers, except possibly endometrial
• Juvenile Polyposis
• Peutz-Jeghers Syndrome
• Common Familial Colon Cancer
The Audience
Month Day, Year
The Genetic Testing Process:
Key Points
• Consider multiple motivations for testing
• Counsel patients on the benefits, risks, and
limitations of testing
• Facilitate informed decision making
• Begin testing with an affected person, if
possible
• Use multidisciplinary approach
• Keep current with continuing research
Informed Consent:
Potential Benefits of Genetic Testing
• Improved cancer risk management
• Relief from uncertainty and anxiety about
cancer risk
• Information for individual and family
members
• Lifestyle decision making
Informed Consent:
Limitations of Genetic Testing
• Not all mutations are detectable
• Uncertain significance of some mutations
• Negative results is fully informative only if
mutation has been identified in family
• Results indicate probability, not certainty, of
developing cancer
• Unproven efficacy of most interventions
Cancer Genetics Professionals
Can Assist With:
• Pedigree interpretation and cancer risk
assessment
• Complex psychosocial issues
• In-depth counseling and education
• Ordering and interpreting genetic test
• Facilitating entry into clinical studies
Importance of Longitudinal
Follow-Up
• Review management plan periodically
• Assess and promote adherence to plan
• Coordinate primary care and specialty
services
• Provide psychological support
• Keep current on new information and tools
for managing inherited cancer susceptibility
• Update family history
Points to Remember
Genetic Susceptibility Testing
Is not a
screening test
for the general
population
Can be one
component of a
comprehensive
cancer riskassessment plan
General Screening Guidelines
• Increased Risk:
– Surveillance is all colonoscopy-based
– Refer for risk-specific management
• Average Risk:
– Follow consensus guidelines
5-Year Relative Survival Rates by
CRC Stage at Diagnosis
100
90
90
Survival (%)
80
70
67
64
60
50
35
40
30
20
10
10
0
All Stages
Localized
Regional
Distant
Unstaged
Surveillance, Epidemiology and End Results (SEER) Program. CRC Facts & Figures. Special Edition 2005. Atlanta, Ga:
American Cancer Society, 2005.
Screening Purpose
• Improved survival
– Early detection markedly improves chances of long
term survival
• Cancer Prevention
– Removal of pre-cancerous polyps prevent cancer
(unique for colon cancer screening)
Test Categories
• Invasive Tests: Diagnostic and Therapeutic
– Colonoscopy
• Endoscopic
– Flexible Sigmoidoscopy
• Non-Invasive Tests: Diagnostic
– Fecal Occult Blood Testing (FOBT)
– Barium Enema
– CT Colography
• Virtual Colonoscopy
– Stool DNA Analysis
How Did We Screen for CRC circa
2003?
Look for Blood in Stool
Look for Polyps
Occult
blood test
Barium
enema
Colonoscopy
New Tests Since 2003 Guidelines
• Stool DNA
• CT Colography
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*
American Cancer Society, 2008
*All positive tests should be followed with colonoscopy
sDNA: Evidence
Study with One-Time Testing
Ahlquist, et al
Gastro, 2000
Imperiale, et al
NEJM, 2004
Sensitivity for
Cancer
91%
51.6%
Syngal, et. al
Cancer, 2006
63%
Whitney, et al
J Mol Diagn, 2004
70%
Chen, et al
JNCI, 2005
46%
Itzkowitz, et al
DDW-AB, 2006
88%
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
Stool DNA: Limitations
• Sensitivity for adenomas with current commercial version of
test is low
misses some cancers
• 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
CT Colography
“Virtual Colonoscopy”
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
CT Colography:
Process
• Colon is prepped
• Gas is insufflated into the colon (air
or CO2).
• CT scan with patient in two
positions.
• Computer processing.
• Radiologist reading and problemsolving.
Virtual Colonoscopy 2D Image
Standard
Virtual Colonoscopy
“Fly Through”
CT Colography Sensitivity:
Polyp Size
Patient
Polyps
s
≥10
mm
5-10
mm
≤5mm
Author
Year
Rockey
2005
614
76
(>10mm)
53%
Pickardt
2004
1233
298 (>6
92.2%
~90%
Cotton
2002
>500
44%
42%
Langhi
2002
165
52
92%
82%
50%
Yee
2001
300
524
90.2%
80.1%
59%
Fletcher
2000
180
263
75.2%
47.2%
__
Fenlon
1999
100
114
91%
82%
59%
Dachman
1998
44
22
83%
33%
15%
mm)
CT Colography vs.
Optical (Endoscopic) Colonoscopy:
Sensitivities for All Polyps
Polyp Size
>10mm
>8mm
>6mm
CTC
92.2%
92.6%
85.7%
Colonoscopy
88.2%
89.5%
90.0%
Pickhardt et al, NEJM 2003
CT Colography:
Potential Applications
• Screening?
– Public appeal?
• High-risk Colonoscopy
– Warfarin
– Sedation risk
– Previous complication
• Incomplete Colonoscopy:
– superior to barium enema
CT Colonography: Limitations
• Requires full bowel prep (which most patients find to be the most unpleasant
aspect of colonoscopy)
• Non-therapeutic: colonoscopy is required if abnormalities detected, requiring 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
Current Controversies over CTC
• No defined method of communicating findings to
gastroenterologist
• Unclear threshold of detection: what size polyp should be
“followed”?
– Implications for repeat exam recommendations and cost
• Ethical concerns over implementation to a vulnerable public
• Particularly when test is not covered by insurance
CT Colography:
Summary and Recommendations
Although there is a desperate need for better screening
tests and improved compliance, new tests should be
rigorously studied prior to widespread adoption.
– CT colography is making strides in its potential application
in CRC screening, but remains experimental in most
situations.
– Patients at increased risk and especially those suspected or
known to have cancer syndromes should not use this test as
their primary tool.
Colorectal Cancer Screening:
Choosing the Method
Sensitivity Cost
Risk
Community Evidence
Access
FOBT
Low
Low
Low
Unlimited
++
FOBT & Flexible
Sigmoidoscopy
High
High
High
Limited
++
Fecal DNA
High
Mod
Low
Unlimited
+
B.E.
Mod (later
stage)
Mod
Mod
Limited
(evaluation)
+/-
Virtual Colonoscopy
High (> 1cm)
High
Mod
Limited
(evaluation)
+
Colonoscopy
High
High
High
Limited
++
Ideal Screen
High
Low
Low
Unlimited
++
Corporate Physicians Encouraging
Systematic Screening
•
•
•
•
Managing health; not health care costs
Getting people screened whom otherwise would
not get screened
Detecting cancers / pre-cancerous lesions that
might have been fatal if not detected early
Save company and medical system cost associated
with treating late stage disease
Barriers to Colorectal Cancer
Screening
• Patient Barriers:
– cost, discomfort, fear, misunderstand diet or prep,
embarrassing
• System Barriers:
– lack of insurance, access to health care
• Physician Barriers:
– knowledge, time, inadequate training
– biases: gender, asymptomatic patients
General Cancer Screening Compliance
Subjects
Reporting
FOBT
(Age>50)
Flex Sig or
colonoscopy
(Age>50)
Mammogram
(Age>40)
Ever
Completed
40%
44%
82%
Up to date
21%
34%
71%
(in last year)
(in last 5 years)
(in last 2 years)
Cancer Screening Compliance in
New Jersey
Screening
U.S.
N.J.
U.S.
N.J.
U.S.
N.J.
Average
Screening
Rate
Average
Screening
Rate
No Usual
Source of
Medical
Care
Screening
Rate
No Usual
Source of
Medical
Care
Screening
Rate
No Health
Insurance
Screening
Rate
No Health
Insurance
Screening
Rate
Colorectal
60%
59%
33%
34%
32%
32%
Breast
67%
63%
32%
43%
35%
44%
Cervix
80%
84%
73%
73%
73%
73%
Behavioral Risk Factor Surveillance System , 2006
Trends in Recent* Fecal Occult Blood Test Prevalence (%), by
Educational Attainment and Health Insurance Status, Adults 50 Years
and
Older,
US,
1997-2004
30
1997
Prevalence (%)
2001
2002
2004
24
25
20
1999
20
22
21
19
18
16
16
16
14
15
12
10
8
9
9
9
5
0
Total
Less than a high school
education
No health insurance
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.
Trends in Recent* Endoscopy Prevalence (%), by
Educational Attainment
and Health Insurance Status, Adults 50 Years and
Older, US, 1997-2004
50
45
45
39
Prevalence (%)
40
35
1997
1999
2001
2002
2004
41
36
34
32
31
28
30
33
29
25
20
16
16
17
18
19
15
10
5
0
Total
Less than a high school
education
No health insurance
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.
Colorectal Screening Rate
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!”
Factors At Play
During Counseling About CRC
Screening
Patient Factors
Physician Factors
Clinician recommendation
Understanding alternatives
Personal beliefs
Family effects
Access to services
Fear / embarrassment
Insurance coverage
Personal beliefs
Familiarity with data
Access to services
Insurance coverage
Evaluating the Evidence: Cost
Evidence
Mortality
Reduction
Annual Flex Sig FOBT + DCBE ColonosFOBT q 5 yrs Flex Sig q 5 yrs copy
q 10 yrs
RCT
CaseCaseNone
Cohort*
control Control
33% @ 60% for 48% @ Not
75-90%
13 yrs
distal
18 yrs
known
lesions
Cost$10,000-$30,000 per life-year gained.
Effectiveness Most favorable C/E: colonoscopy or FOBT+Flex
Counseling Patients
• Above Average Risk: refer to
– Colorectal surgeon
– Gastroenterologist
• Average Risk
– Follow Consensus Guidelines
History: 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)
CRC Screening Guidelines:
Need for New Consensus Statement
• Two new tests developed with evidence:
• stool DNA (sDNA) and
• computerized tomographic colonography
• 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 the updated consensus statement was to
provide a practical guideline for physicians and the public
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
2008 CRC Screening Guidelines
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
A Joint Guideline from the American Cancer Society, the
US Multi-Society Task Force on Colorectal Cancer, and
the American College of Radiology
CA Cancer J Clin 2008; 58:130-160
The Audience
Month Day, Year
Joint Guidelines, continued
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
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
Colorectal Cancer Screening:
Choosing the Method
Sensitivity Cost
Risk
Community Evidence
Access
FOBT
Low
Low
Low
Unlimited
++
FOBT & Flexible
Sigmoidoscopy
High
High
High
Limited
++
Fecal DNA
High
Mod
Low
Unlimited
+
B.E.
Mod (later
stage)
Mod
Mod
Limited
(evaluation)
+/-
Virtual Colonoscopy
High (> 1cm)
High
Mod
Limited
(evaluation)
+
Colonoscopy
High
High
High
Limited
++
Ideal Screen
High
Low
Low
Unlimited
++
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!”