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