Can I Predict the Clinical Outcome of my IBD Patient?

Report
Progress in Understanding How to
Manage Dysplasia in IBD
David T. Rubin, MD, FACG, AGAF, FACP
@IBDMD
Joseph B. Kirsner Professor of Medicine
Chief, Section of Gastroenterology, Hepatology and Nutrition
Co-director Digestive Diseases Center
Disclosure Statement
• I have no relevant disclosures.
The IBD-Cancer Prevention Formula
Accurate Risk
Identification
• Which
patients?
• How to
quantify risks?
Accurate
Detection of
Precancer
• Understanding of
predictive value of
lesions
• Colonoscopy
• Accurate biopsies
• Reliable pathology
Effective
Prevention
Strategies
• Pts and MDs implement
strategies
• Colectomy
• Polypectomy
• Chemoprevention
Outcome of
interest
•  Cancer
• Mortality
•  Colectomy
• HRQoL
Updated Risk Factors for Dysplasia and
Colorectal Cancer in Ulcerative Colitis
MODIFIABLE (Potentially)
• Increased inflammatory
activity
• Backwash ileitis
• Pseudopolyps
• Prior dysplasia
• Mass/stricture
IMMUTABLE
• Male gender
• Longer duration of disease
• Greater extent of colonic
involvement
• Family history of CRC
• Primary sclerosing
cholangitis
• Younger age of diagnosis
Askling J et al. Gastroenterol. 2001; 120(6): 1356–1362.
Lindberg BU et al. Dis Colon Rectum. 2001; 44(1):77-85.
Lutgens M et al. Inflamm Bowel Dis. 2013;19(4):789-99.
Rutter M et al. Gastroenterol. 2004 ;126(2):451-9.
Rubin DT et al. Clin Gastroenterol Hepatol. 2013;11(12):1601-8.
Evolution of Cancer Prevention in IBD
Modality
Physical
examination
Primary Lesion
Detected
PROGRESS
Digital scopes
(CCD
technology)
HD scopes
Chromoscopy
Intervention
Metastatic disease
Death
Prophylactic
colectomy
Masses, tubular colons
Insensitive to early
stage lesions; Cancer
detected later
Colectomy
Masses, “DALMs”
Dysplasia thought
to be “invisible”
Colectomy
Polypoid/raised lesions
Era of random
biopsies
Colectomy
Raised lesions, mucosal
defects/abnormal pit
patterns
Random/Targeted
biopsies
Lesion resection,
follow-up with
more “intensive”
surveillance
Raised lesions, flat
lesions/mucosal
defects/abnormal pit
patterns
Targeted biopsies
(fewer?)
Lesion resection,
follow-up with
more “intensive”
surveillance
Barium enemas
Fiberoptics
Outcome
Evolution of Cancer Prevention in IBD
Modality
Physical
examination
PROGRESS
Barium enemas
Fiberoptics
Primary Lesion
Detected
Metastatic disease
Masses, tubular colons
Masses, “DALMs”
Digital scopes
(CCD
technology)
Polypoid/raised lesions
HD scopes
Raised lesions, mucosal
defects/abnormal pit
patterns
Chromoscopy
Raised lesions, flat
lesions/mucosal
defects/abnormal pit
patterns
Outcome
Intervention
Death
Prophylactic
colectomy
Insensitive to early
stage lesions; Cancer
detected later
Colectomy
Dysplasia thought
to be “invisible”
Colectomy
Era of random
biopsies
Colectomy
Random/Targeted
biopsies
Lesion resection,
follow-up with
more “intensive”
surveillance
Targeted biopsies
(fewer?)
Lesion resection,
follow-up with
more “intensive”
surveillance
Evolution of Cancer Prevention in IBD
Modality
Physical
examination
Outcome
Metastatic disease
Death
Masses, tubular colons
Insensitive to early
stage lesions; Cancer
detected later
Masses, “DALMs”
Dysplasia thought
to be “invisible”
Digital scopes
(CCD
technology)
Polypoid/raised lesions
Era of random
biopsies
HD scopes
Raised lesions, mucosal
defects/abnormal pit
patterns
Barium enemas
PROGRESS
Primary Lesion
Detected
Fiberoptics
Chromoscopy
Raised lesions, flat
lesions/mucosal
defects/abnormal pit
patterns
Intervention
Prophylactic
colectomy
Colectomy
Colectomy
Colectomy
Random/Targeted
biopsies
Lesion resection,
follow-up with
more “intensive”
surveillance
Targeted biopsies
(fewer?)
Lesion resection,
follow-up with
more “intensive”
surveillance
Evolution of Cancer Prevention in IBD
Modality
Physical
examination
Outcome
Intervention
Metastatic disease
Death
Prophylactic
colectomy
Masses, tubular colons
Insensitive to early
stage lesions; Cancer
detected later
Colectomy
Masses, “DALMs”
Dysplasia thought
to be “invisible”
Colectomy
Digital scopes
(CCD
technology)
Polypoid/raised lesions
Era of random
biopsies
Colectomy
HD scopes
Raised lesions, mucosal
defects/abnormal pit
patterns
Random/Targeted
biopsies
Lesion resection,
follow-up with
more “intensive”
surveillance
Targeted biopsies
(fewer?)
Lesion resection,
follow-up with
more “intensive”
surveillance
Barium enemas
PROGRESS
Primary Lesion
Detected
Fiberoptics
Chromoscopy
Raised lesions, flat
lesions/mucosal
defects/abnormal pit
patterns
Movement away
from random
biopsies
Movement away
from surgery
There is Low Yield of Random Biopsies in Colitis
Surveillance
• N=167 patients, 466 surveillance colonoscopies
– 24 of 11,772 random biopsies detected neoplasia (0.2% perbiopsy yield)
• ~1 in 500 random biopsies1
• Most dysplasia is visible with white light examinations2,3
1van
den Broek FJ, et al. Am J Gastroenterol. 2014;109(5):715-22.
2Rutter et al. Gastrointest Endoscopy. 2004.
3Rubin DT, et al. Gastrointest Endoscopy, 2006.
Resected “Raised” Dysplasia has Less Risk of
Progression than “Flat” Dysplasia
Flat dysplasia
Raised dysplasia
n=41
Pekow JR, et al. Inflamm Bowel Dis. 2010;16(8):1352-6.
Quality of Pathology and Pathologists Important!
There is Poor Correlation for Some Grades of Dysplasia
• Adequate biopsy specimens
• Labeled properly
• Communication with your pathologist
is key!
?
Rubin DT, Turner JR. CGH. 2006 Nov;4(11):1309-13.
No dys
IND
LGD
HGD
Cancer
K=0.51
Good
K=0.18
Poor
K=0.36
Fair
K=0.54
Good
?
Expert review of digitized slides
Odze RO, et al., Mod Pathol 2002;15:379-86.
This is Not Your Mentor’s Dysplasia!
• OLD: dysplasia “invisible”
• NEW: technology makes most
“visible”
• HYPOTHESIS: Dysplasia found by
newer technologies may not have the
same meaning as that found in the
past
• PROPOSED: This should allow a
different approach to detection and
follow-up
Changing Terminology: Need for Consistency!
Previously called ALM
Previously called DALM
The terms “DALM” and “ALM” are being replaced by:
“polypoid”
“non-polypoid”
“flat”
“invisible” dysplasia
Pictures from Neumann H et al. World J Gastroenterol 2011;17(27):3184-91.
Approach to Visible Dysplasia in IBD
Dysplasia
Endoscopic appearance
Visible by WLE/raised
Flat*
Grade?
High
Complete endoscopic
resection
Low
Multifocal?
Yes
No
Colectomy vs.
Colectomy
aggressive
follow-up
Colonoscopy
6 months and
follow-up
Flat = diagnosed by random biopsy or only visibile by chromoendoscopy.
Modified from Rubin DT, Turner JH. Clin Gastroenterol Hepatol. 2006;4(11):1309-13.
What is the utility of enhanced visualization?
Chromoendoscopy is Highly Sensitive and
Specific for Dysplasia in UC
• Meta-analysis of 6 randomized controlled trials comparing dyespray to white light/conventional colonoscopy
• Methylene blue or indigo carmine
Wu L et al. Colorectal Dis. 2012;14(4):416-20.
What Happens to Dysplasia Found on
Chromoendoscopy?
•
•
•
•
Are we missing occult cancers?
Dysplasia in the current age has a different predictive value
than dysplasia found with earlier technology
Current therapies prevent progression of dysplasia
Chromoendoscopy studies:
•
•
Follow-up in only one study
Marion (NYC)
– Follow-up with colectomy specimens
– 5 of original 102 had colectomy due to unresectable LGD
– No CRC
Marion J, et al. Am J Gastroenterol, 2008;103:2342..
Which Dye Should You Use?
1.
2.
3.
4.
Methylene Blue
Indigo Carmine
• Interactions with Serotonergic
medications (eg. SSRIs)? 1,2
• Carcinogenic? (DNA damage to
colonocytes) 3
• Absorptive, rich dye coloring
• Doesn’t require moving
patient around
• Cost comparable to IC
• Shortage (on back order) 5
• No known drug interactions
• Not thought to be
carcinogenic3
• Surface dye, less rich staining
• Requires moving patient
around to get even
distribution of dye
• Cost comparable to MB
• Shortage (on back order)
(expected release Dec 2014) 6
Shah-Khan, et al. Am J Surg. 2012; 204(5):798-9.
http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm
Davies J, et al. Gut, 2007;56(1):155-156..
Lee and Sharifi Urology 47(5):783-4.
4.
5.
http://www.ashp.org/menu/DrugShortages/CurrentShortages/Bulletin
.aspx?id=27
http://www.ashp.org/menu/DrugShortages/CurrentShortages/Bulletin
.aspx?id=861
Newer Approaches to Dysplasia Management
Technique
Level of Evidence
• Some dysplasia does not
require proctocolectomy
• Polypectomy sufficient
• Endoscopic mucosal
resection
• Endoscopic Submucosal
Dissection
• Subtotal colectomy
• Cohort studies of
outcomes1,2
• Case series3
• Case reports
• Anecdotal
1. Pekow JR et al. Inflamm Bowel Dis. 2010;16(8):1352-6.
2. Ullman T et al. Gastroenterology. 2003;125(5):1311-9.
3. Lang GD et al. Am J Gastroenterol. 2013;108:S597.
Challenges to Chromoendoscopy in IBD
• Perception of time consuming and expensive (time
plus supplies)
• Unclear if it changes outcomes (cancer or mortality)
• Many patients don’t “qualify” for it due to poor prep
or too much inflammation
• No consensus on its use in our field
• No defined training pathway or competency
requirement
• Comparison to newer high definition scopes not
completed
Billing for Chromoendoscopy
• There is no CPT code for this procedure,1 nor is there one in the
revised Procedural Codes.
• Can try to use -22 modifier (I do)
– “unusual time, intensity, technical difficult or severity”
– May pay +10-20% of allowable charge for procedure. Reports
as well that it may result in decreased reimbursement2
• 43499 and -59 modifier, indicate “chromoendoscopy”2
– “most time the insurance will deny…”
1ASGE
Technology Committee report, 2007.
2http://www.aapc.com/memberarea/forums/ accessed
December 14, 2012
Consider Chromoendoscopy for:
• Patients with previous confirmed dysplasia
(flat or raised) and high risk and not going to
colectomy
• Lesions found and require clarification
(selective chromo)
• Patient has minimal inflammation and very
good to excellent prep
Farraye FA et al. Gastroenterology. 2010;138(2):738
More Sensitivity to Detect Dysplasia is Not
Necessarily Better?
Time
Training
Direct Costs
1
Specificity for “Clinically
Significant” Lesions
0.9
Raised lesion identified
by chromoendoscopy
0.8
0.7
0.6
0.5
0.4
0.3
Flat lesion identified by
chromoendoscopy
DALM seen by
White Light (or
Barium Enema)
Polypoid dysplasia
seen by White
Light
0.2
0.1
0
Increased Sensitivity for Dysplasia
Movement Towards Quality Endoscopy for
Surveillance in IBD: SCENIC
(Funded by the Maxine and Jack Zarrow Family Foundation)
• SCENIC: Surveillance for Colorectal
Endoscopic Neoplasia detection and
management in Inflammatory bowel disease
patients: International Consensus (March 78, 2014).
• Rated statements related to surveillance
practices based on multiple factors.
• Systematic reviews performed on each topic
based on Cochrane methodology.
• Panel recommendations “strength” based on
voting: “should” vs. “suggest”.
SCENIC: Summary of Preliminary
Consensus Statements
• High definition scopes > standard definition
scopes
• Narrow band imaging not better than white
light, especially with HD scopes
• Chromoscopy (dye spray) > white light
endoscopy (but is not necessarily for all
patients)
• Newer technologies enable ongoing
surveillance instead of colectomy when certain
types of dysplasia are found
• Distinction is made between follow-up of
visible and resectable dysplasia and
flat/“invisible” dysplasia
What Do the Guidelines Tell Us?
Because the sensitivity for detecting dysplasia by chromoendoscopy is higher
than that of white light endoscopy, chromoendoscopy with targeted biopsies is
recommended as an alternative to random biopsies for endoscopists who have
expertise with this technique.
-AGA Technical Review 2010
East J. Clin Endosc 2012;45:274-277.
British Society Guidelines 2010
Screening colonoscopy at 10 years
(preferably in remission, pancolonic dye-spray)
Lower Risk
Intermediate Risk
Higher Risk
Extensive colitis with NO ACTIVE
endoscopic/histological inflammation
Extensive colitis with MILD ACTIVE
endoscopic/histological inflammation
Extensive colitis with MODERATE/SEVERE
ACTIVE endoscopic/histological inflammation
OR left-sided colitis
OR Crohn’s colitis of <50% colon
OR post-inflammatory polyps
OR family history CRC in FDR aged 50+
OR stricture in past 5 years
OR dysplasia in past 5 years declining surgery
OR PSC / transplant for PSC
OR family history CRC in FDR aged <50
FDR, first-degree relative; PSC, primary sclerosing cholangitis
Cairns SR et al. Gut 2010;56:666.
British Society Guidelines 2010
Screening colonoscopy at 10 years
(preferably in remission, pancolonic dye-spray)
Lower Risk
Intermediate Risk
Higher Risk
Extensive colitis with NO ACTIVE
endoscopic/histological inflammation
Extensive colitis with MILD ACTIVE
endoscopic/histological inflammation
Extensive colitis with MODERATE/SEVERE
ACTIVE endoscopic/histological inflammation
OR left-sided colitis
OR Crohn’s colitis of <50% colon
5 Years
OR post-inflammatory polyps
OR family history CRC in FDR aged 50+
3 Years
OR stricture in past 5 years
OR dysplasia in past 5 years declining surgery
OR PSC / transplant for PSC
OR family history CRC in FDR aged <50
1 Year
FDR, first-degree relative; PSC, primary sclerosing cholangitis
Cairns SR et al. Gut 2010;56:666.
British Society Guidelines 2010
Screening colonoscopy at 10 years
(preferably in remission, pancolonic dye-spray)
Lower Risk
Intermediate Risk
Higher Risk
Extensive colitis with NO ACTIVE
endoscopic/histological inflammation
Extensive colitis with MILD ACTIVE
endoscopic/histological inflammation
Extensive colitis with MODERATE/SEVERE
ACTIVE endoscopic/histological inflammation
OR left-sided colitis
OR Crohn’s colitis of <50% colon
OR post-inflammatory polyps
OR family history CRC in FDR aged 50+
5 Years
3 Years
Pancolonic dye spraying with targeted biopsy of
abnormal areas is recommended, otherwise 2–4
random biopsies from every 10 cm of the
colorectum should be taken
OR stricture in past 5 years
OR dysplasia in past 5 years declining surgery
OR PSC / transplant for PSC
OR family history CRC in FDR aged <50
1 Year
Other Considerations
Patient preference, multiple postinflammatory polyps, age and comorbidity,
accuracy and completeness of examination
FDR, first-degree relative; PSC, primary sclerosing cholangitis
Cairns SR et al. Gut 2010;56:666.
What We Still Need!
• Updated guidelines
• Clarification of quality measures
– Prep
– Detection rates
• Uniformity of endoscopy reports
• Improved techniques
Rubin DT et al. Gastrointest Endosc. 2014;80(5):849-851.
Future Techniques
• Fecal DNA
– Stool assays of methylated genes (such
as vimentin, EYA4, BMP3, NDRG4) may
detect colorectal neoplasms1
• Other Markers (mucosal antigens,
genetics)
• Confocal Laser Endomicroscopy2
1Kisiel
2Teubner
JB et al. Alliment Pharmacol Ther. 2013 Mar;37(5):546-54.
D et al. Gastrointestinal Endscopy Clin N Am. 2014;24(3):427-34.
Why It’s Time to Enter a NEW Era of
Surveillance and Cancer Prevention in IBD
• Evidence for guidelines is weak or
moderate at best
• Clinicians don’t follow existing
guidelines
• We can stratify based on individual
risk factors for neoplasia
– Includes inflammation
• We can learn and apply new
techniques
Risk Stratification of Dysplasia in Colitis
Guide Follow-up and Colectomy Recommendations
Pt/Disease-Related Factors:
Dysplasia-related factors:
•
•
•
•
• GRADE:
PSC
Family history of CRC
Duration
Degree of inflammation over
time and on last exam
• Male v Female
• Willingness and ability to
follow your recommendations
– IND vs. LGD vs. HGD
• MORPHOLOGY:
– Flat* vs. Polypoid
– “Invisible” vs. raised
• FIELD EFFECT/SYNCHRONICITY:
– Unifocal vs. multifocal
• LONGITUDINAL FOLLOW-UP?
– Dysplasia on a single exam vs.
metachronous lesions on serial exams
Flat = diagnosed by random biopsy or only visibile by chromoendoscopy.
Summary:
Updated Approach to Dysplasia in IBD
• Evolving optical technology has made identification of
dysplasia easier.
• Random biopsies for surveillance are of limited utility.
• Not all dysplasia requires immediate colectomy.
• Stratify your UC (and Crohn’s colitis) patients by individual risk
factors.
• Consider chromoendoscopy (with methylene blue or indigo
carmine)
–
–
–
–
when you have been trained
in higher risk patients
previous confirmed dysplasia (flat or raised)
lesions found and require clarification
• Don’t hesitate to get a second opinion (from IBD endoscopist
or surgeon).

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