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Update in Colorectal Cancer Screening
Douglas K. Rex, M.D.Indiana University
Medical CenterIndianapolis, IN
Colorectal Cancer – Molecular Basis
Pathway Frequency Genes MSI Precursor Speed
CIN 65-70% APCK-rasp53
No Adenoma Slow
Lynch 3% MLH1MLH2MLH6PMS2
Yes Adenoma Fast
CIMP 30-35% BRAF Sometimes Serrated Can be fast
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)
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)
Features of major categories of serrated lesions
WHO classification
Prevalence Shape Distribution Malignant potential
Hyperplastic polyp
Very common
Sessile/flat Mostly distal Very low
Sessile serrated adenoma/polyp
Common Sessile/flat 80% proximal Significant
Traditional serrated adenoma
Rare Sessile/ pedunculated
Mostly distal Significant
Pathologic differentiation of SSA/P from HP
§ HP § SSA/P
SSA/P without and with cytological dysplasia
§ SSA/P without dysplasia
§ SSA/P with dysplasia
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
The serrated pathway
Hyperplastic polyp ? ↓ ? Sessile serrated adenoma/polyp ↓ probably slow SSA/P with cytologic dysplasia ↓ sometimes fast CIMP colon cancer
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
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
Can screening tests detect serrated lesion ?
Sensitivity for serrated lesions
Colonoscopy highly variable
FIT ?Fecal DNA ?CT colonography ?Flex sig ?Capsule colonoscopy ?Serum assays ?
Colorectal Cancer Screening Tests
§ Non-invasive tests§ gFOBT √§ FIT √
§ Fecal DNA§ Serum tests
§ Imaging tests§ Colonoscopy √
§ Flex sig (seldom used)
§ CT colonography (seldom used)
§ Capsule colonoscopy (not FDA approved)
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
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
Variable Performance of FITs
Hundt Ann Intern Med 2009;150:162-9
Performance of the Fecal DNA Versions 1.0, 1.1, 2.0
1.0 1.1 2.0
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
Fecal DNA testing vs Septin 9Ahlquist CGH 2012;10:272
Fecal DNA test Septin 9
Sensitivity for cancer Stage I-III
91% 50%
Sensitivity for cancerStage IV
75% 88%
Sensitivity for large adenomas
82% 14%
specificity 93% 73%
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
First RCT of Colonoscopy vs CTCNetherlands (abstract 353;DDW 2011)
§ Colonoscopy: 5,924 invited§ Adherence: 21%
§ Advanced adenomas per 100 participants:
– 8.4§ Advanced adenomas per
100 invitees:
– 1.7
§ CTC: 2,920 invited§ Adherence: 32%§ Advanced adenomas per
100 participants:
– 5.2§ Advanced adenomas per
100 invitees:
– 1.7
Expected vs actual burden- prep
§ Colonoscopy § CTC
Expected vs Actual burden - procedure
§ Colonoscopy § CT colonography
Capsule colonoscopy
§ Not FDA approved§ PillCam 2
– Angle of view 172° from each end– Variable frame speed (4-35 fps)
§ Sensitivity > 80% for polyps ≥ 6mm§ Specificity < 80%§ Requires an extensive bowel preparation
Colonoscopy
Operator dependence of screening tests
§ Low (good)§ Fecal DNA§ FIT
– Commercial variability
§ ? gFOBT– Interpretation– Digital exams
§ High (bad)§ Colonoscopy§ Flex sig
§ CT colonography§ Capsule
colonoscopy
Flat Lesions – Paris Classification
Pre-cancerous lesions in the colo-rectum: the basics
Lesion Paris shape Distribution Prevalence Pathology
Traditional adenomatous polyps
1p
1s
Left
Throughout
Low
Common
Mostly LGD
Mostly LGD
Flat adenomas(lesions)
2a Greater to right
Common Mostly LGD
Sessile serrated adenoma (polyp)
1s or 2a Right colon Common Distinction from HP may not be reliable
TSA 1s or 1p Left colon rare Uncertain
Depressed (adenomas)
2c2a + 2c2c+ 2a
Greater to right
rare ↑↑HGD and invasive CA
Residual risk after colonoscopy:right vs left colon
Associations with interval cancers
§ Serrated associations§ Features of interval cancers
– Proximal location– MSI positive – CIMP positive
§ Other associations§ Colonoscopy by
non-GI doctors§ Doctors with low
ADRs§ Low cecal
intubation rates§ Low polypectomy
rates§ Indication of FOBT
vs screening§ Incomplete
polypectomy
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
Operator dependence – cancer prevention
Kaminski et al NEJM2010;362:1795-803
Adenoma detection rate (ADR)
Hazard ratio
< 11% 10.94
11.0 14.9% 10.75
15.0-19.9% 12.50
Polypectomy rates (relative to rates ≤ 10%) – Residual right colon cancer
Residual right colon protectionSingh, H et al GASTRO 2010;139:1128-37
Right colon cancers after colonoscopyBaxter et al GASTRO 2011;140:65-72
Variable detection of adenomas among GI docs
Number of doctors
Lowest ADR Highest ADR Range
BarclayIllinois2006
12 9.4% 32.7% 3.5
ChenIndiana2007
9 15.5% 41.1% 2.7
ImperialeIndiana2009
25 7% 44% 6.3
ShaukatMinnesota2009
51 10% 39% 3.9
Variable detection of proximal colon serrated lesions among GI docs
Number of doctors
Lowest proximal colon serrated lesion
detection rate
Highest proximal colon serrated lesion detection rate
Range
HetzelBoston 13 1.1% 7.6% 6.9
KahiIndiana 15 1% 18% 18
What underlies variable detection?
§ Training– Lesion recognition– Withdrawal technique– Withdrawal time
§ Personality– Poor documentation of procedures
§ Visual gaze patterns§ Withdrawal time
Flat adenoma
§ White light § Narrow-band imaging
Sessile serrated polyp
§ White light § Narrow-band imaging
Serrated lesions
Serrated lesion
Depressed lesion
Depressed lesions
Pseudodepression (2a dip)
Bowel Preparation and Polyp Detection Rates
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*
Froehlich et al. Gastrointest Endoscop. 2005;61:378-384.
*P<0.05 for all measures.
Europe (N=5,832)
Split-Dosing Provides More Satisfactory Results
Than Traditional Dosing (cont)
47
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.
Reprinted from Aoun et al. Gastrointest Endosc. 2005;62(2):213-218.
Perc
ent
56.2
43.8
76.5
23.5
0
10
20
30
40
50
60
70
80
90
Satisfactory Unsatisfactory
Group AGroup B
Perc
ent
4.1
39.7
50.7
5.54.4
19.1
44.1
32.4
0
10
20
30
40
50
60
Poor Fair Good Excellent
Group AGroup B
Efficacy of Suprep in 2 studies
§ Study 1 OSS PEG-EASuccess 82.4% 80.3%Excellent 44.6% 37.3%Good 37.8% 43.0% Fair 11.4% 16.1%Poor 4.7% 3.1%
Mean 3.24 3.15 p 0.28Adequate 94% 95%
§ Study 2 OSS PEG-EASuccess 97.2% 95.6%Excellent 63.3% 52.5%Good 33.9% 43.2%Fair 1.7% 3.3%Poor 1.1% 1.1% p 0.043Mean 3.59 3.47 p 0.05Adequate 99% 99%
The impact of split dosing
SplitNot split
Arguments AgainstSplit-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 sedation50
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– Split dosing– Low volume– Better taste
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
§ Give clear written instructions
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?
Withdrawal technique
Right colon retroflexion
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
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
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§ Follow the recommended screening and
surveillance intervals
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
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