1. Update in Colorectal Cancer
Screening
Douglas K. Rex, M.D.
Indiana University
Medical Center
Indianapolis, IN
2. Colorectal Cancer – Molecular Basis
Pathway Frequency Genes MSI Precursor Speed
CIN 65-70% APC No Adenoma Slow
K-ras
p53
Lynch 3% MLH1 Yes Adenoma Fast
MLH2
MLH6
PMS2
CIMP 30-35% BRAF Sometimes Serrated Can be fast
3. Minimal Terminology of Serrated
Lesions (WHO)
§
Hyperplastic polyp (HP)
§
Sessile serrated adenoma/polyp (SSA/P)
–
With cytological dysplasia
–
Without cytological dysplasia
§
Traditional serrated adenoma (TSA)
4. Therefore
§
The WHO recommends that the term
“serrated adenoma” always be preceded
by a qualifier:
–
Sessile serrated adenoma/polyp (SSA/P)
–
Traditional serrated adenoma (TSA)
5. Features of major categories
of serrated lesions
WHO Prevalence Shape Distribution Malignant
classification potential
Hyperplastic Very Sessile/flat Mostly distal Very low
polyp common
Sessile Common Sessile/flat 80% proximal Significant
serrated
adenoma/
polyp
Traditional Rare Sessile/ Mostly distal Significant
serrated pedunculated
adenoma
7. SSA/P without and with
cytological dysplasia
§
SSA/P without §
SSA/P with
dysplasia dysplasia
8. 2416 SSA/Ps
mean age
§
SSA/P 61y
§
SSA/P with LGD 66y
§
SSA/P with HGD 72y
§
SSA/P with cancer 76y
• Lash J Clin Pathol 2010;63:681-6
9. The serrated pathway
Hyperplastic polyp
?↓?
Sessile serrated adenoma/polyp
↓ probably slow
SSA/P with cytologic dysplasia
↓ sometimes fast
CIMP colon cancer
10. So……….
§
SSA/P is the main precursor of CIMP-high CRC
§
No reliable way to distinguish HP from SSA/P
endoscopically
• Kimura et al AJG 2012: “Type O” pit
§
Agreement for pathologists distinguishing HP
from SSA/P is moderate
§
Most large serrated lesions in the proximal colon
are SSA/P
§
SSA/P with cytological dysplasia is a dangerous
lesion
11. Clinical associations of serrated
polyps with CIMP-high CRCs
§
SSA/P histology (vs hyperplastic)
§
Proximal location (vs distal) of serrated
lesions
§
Size (big vs small) of serrated lesions
§
Number (more vs fewer) of serrated
lesions
12. Can screening tests detect
serrated lesion ?
Sensitivity for serrated lesions
Colonoscopy highly variable
FIT ?
Fecal DNA ?
CT colonography ?
Flex sig ?
Capsule colonoscopy ?
Serum assays ?
13. Colorectal Cancer Screening
Tests
§
Non-invasive tests §
Imaging tests
§
gFOBT √ §
Colonoscopy √
§
FIT √
§
Flex sig (seldom
§
Fecal DNA used)
§
Serum tests §
CT colonography
(seldom used)
§
Capsule
14. How do we achieve
excellence in screening?
§
Utilize high quality colonoscopists
–
Should be able to quote ADR
–
Should see split dose preparations
–
Should see consistent photographic
documentation of cecal intubation
–
Should see appropriate use of follow up
exams
§
Switch from gFOBT to FIT
–
Avoid exams on digital rectals
15. RCT of FIT vs g-FOBT
§
20,623 screenees
§
RCT of FIT (OC-
Sensor) vs g-FOBT
(HII)
§
Adherence 59.6%
vs 46.9% (HII)
§
Positivity 5.5% vs
2.4% (HII)
Van Rossum; GASTRO 2008;135:82
18. Septin 9 performance
§
7000 patient sceening trial: manuscript still
not published
§
62% sensitivity for cancer
–
Sensitivity lower for early stage cancer
§
No sensitivity for adenomas
§
88% specificity
19. Fecal DNA testing vs Septin 9
Ahlquist CGH 2012;10:272
Fecal DNA test Septin 9
Sensitivity for cancer 91% 50%
Stage I-III
Sensitivity for cancer 75% 88%
Stage IV
Sensitivity for large 82% 14%
adenomas
specificity 93% 73%
20. CT colonography
§
Not approved by the USPSTF
–
Radiation risk
–
Extracolonic findings
§
Not approved by CMS
–
Insufficient data in the elderly
–
Less cost-effective than colonoscopy
21. First RCT of Colonoscopy vs CTC
Netherlands (abstract 353;DDW 2011)
§
Colonoscopy: 5,924 §
CTC: 2,920 invited
§ invited 21%
Adherence: §
Adherence: 32%
§
Advanced adenomas per §
Advanced adenomas per
100 participants: 100 participants:
–
8.4 –
5.2
§
Advanced adenomas per §
Advanced adenomas per
100 invitees: 100 invitees:
–
1.7 –
1.7
28. Pre-cancerous lesions in the
colo-rectum: the basics
Lesion Paris shape Distribution Prevalence Pathology
Traditional 1p Left Low Mostly LGD
adenomatous
polyps 1s Throughout Common Mostly LGD
Flat 2a Greater to Common Mostly LGD
adenomas right
(lesions)
Sessile 1s or 2a Right colon Common Distinction
serrated from HP may
adenoma not be reliable
(polyp)
TSA 1s or 1p Left colon rare Uncertain
Depressed 2c Greater to rare ↑↑HGD and
(adenomas) 2a + 2c right invasive CA
2c+ 2a
30. Associations with interval
cancers
§
Serrated §
Other associations
§ associationsinterval
Features of §
Colonoscopy by
cancers non-GI doctors
–
Proximal location §
Doctors with low
–
MSI positive ADRs
–
CIMP positive §
Low cecal
intubation rates
§
Low polypectomy
rates
§
Indication of FOBT
31. The Adenoma Detection Rate
§
% of persons age ≥ 50 undergoing
screening colonoscopy with ≥ 1 adenoma
detected and removed
–
Rex et al (USMSTF) 2002
• AJG 2002;97:1296
–
Rex et al (ACG/ASGE Task Force on
Quality) 2006
• GIE 2006;63:S16
32. Operator dependence – cancer
prevention
Kaminski et al NEJM2010;362:1795-803
Adenoma Hazard ratio
detection rate
(ADR)
< 11% 10.94
11.0 14.9% 10.75
15.0-19.9% 12.50
46. Bowel Preparation and Polyp
Detection Rates
Europe (N=5,832)
Adequate
Inadequate
Completion (%) 90.4 71.1*
Time to cecum (min) 11.9 16.1*
Withdrawal time (min) 9.8 11.3*
Any adenoma 29.4 23.9*
Adenoma >1 cm (%) 6.4 4.3*
*P<0.05 for all measures.
Froehlich et al. Gastrointest Endoscop. 2005;61:378-384.
47. Split-Dosing Provides More Satisfactory
Results
Than Traditional Dosing (cont)
60 Group A
Group A 90
Group B
Group B 76.5
50.7 80
50
44.1 70
39.7
40 56.2
60
32.4
Percent
Percent
50
43.8
30
40
19.1
20 30
23.5
20
10
5.5
4.1 4.4 10
0 0
Poor Fair Good Excellent Satisfactory Unsatisfactory
Group A = 4 L of PEG on the night before the procedure; Group B = 2 L of PEG on the
evening before and 2 L on the morning of the procedure.
47
Reprinted from Aoun et al. Gastrointest Endosc. 2005;62(2):213-218.
48. Efficacy of Suprep in 2
studies
§
Study 1 §
Study 2
OSS PEG-EA OSS PEG-EA
Success Success
82.4% 80.3% 97.2% 95.6%
Excellent Excellent
44.6% 37.3% 63.3% 52.5%
Good Good
37.8% 43.0% 33.9% 43.2%
Fair Fair
50. Arguments Against
Split-Dosing Regimens
§
Inconvenient to the patient
–
Unlikely to be a factor once the process is
explained to the patient
–
Patients not more likely to be incontinent en
route to the endoscopy unit
§
Anesthesiologists will not allow split-
dosing
–
Clear liquids allowed up until 2 hours prior
to sedation
50
51. How do we judge preps?
§
Efficacy
–
Split or same day dosing
§
Safety
–
Sodium phosphate use dramatically
decreased
–
Safe preps:
• PEG-ELS (Golytely etc) and SF-ELS (Nulytely)
• Sodium sulfate (SuPrep)
§
Tolerability
–
52. How to achieve effective
preparation
§
Split dose all preps
§
Low volume preps appropriate for routine
patients without severe constipation, on
anti-motility agents
§
Have fall back approach for patients with
clinical factors or proven track record of
being hard to prepare
§
Discuss importance of preparation in your
written instructions
53. What makes up good
detection?
§
Bowel preparation
§
Adequate time
§
Technique:
–
Looking behind folds
–
Cleaning up
–
Adequate distention
§
Central gaze in the monitor
§
Other factors:
–
Personality?
56. Are there technical solutions
to ADR & variable detection?
§
Flat lesions Effective?
–
Chromoendoscopy yes
–
NBI no
–
FICE no
–
iScan limited data
–
Autofluorescence mixed results
–
High definition mixed results
§
Hidden mucosa
–
Cap-fitted mixed results
–
Third-eye maybe
57. Conclusion regarding
technical solutions
§
Any gains in detection from technical
solutions are much smaller than the
variations in detection between examiners
using white light
§
More study in low detectors needed
58. Excellence in colonoscopy
§
Use effective bowel preparation regimens
§
Achieve high cecal intubation rates safely
and document with landmarks and
photography
§
Examine carefully; know the full spectrum
of precancerous lesions in the colon
–
Know your ADR
–
You should see proximal colon serrated
lesions on a regular basis
59. How do we achieve
excellence in screening?
§
Utilize high quality colonoscopists
–
Should be able to quote ADR
–
Should see split dose preparations
–
Should see consistent photographic
documentation of cecal intubation
–
Should see appropriate use of follow up
exams
§
Switch from gFOBT to FIT
–
Avoid exams on digital rectals
