Gan

Where do we stand today around the

world?

Ductal indications

S. Ian Gan MD FRCPCVirginia Mason Medical Center

Digestive Disease InstituteSeattle, USA

Ductal indications

1. What are the current guidelines for the characterization of indeterminate pancreatico-biliary strictures?

2. Are they effective? 3. How should pCLE be integrated into the approach to

indeterminant PB strx?4. What further is required for pCLE to become standard

of care? How do we make evidence robust enough to WARRANT guidelines?

5. Can we define an ideal consensus guidelines for pCLE use in pancreaticobiliary strictures?

Ideal pCLE guidelines

• Defined patient populations• Defined indications:

• Indeterminant strictures• Potential change in management – how?

• Methods• Guidelines for learning and competency

Disruptive innovation

Disruptive technology

“Disruptive Technology” - first coined in 1997 by Clayton Christensen

A new technological innovation, product or service that eventually overturns the existing dominant technology or product in the market

Radical disruptive innovations

1. Build on existing patterns of consumer behaviour

2. Attract early adopters and create loyal followers

3. Outperform dominant market or create new market

4. Reduce complexity; simpler in design and easier to use

5. Overcomes initial barriers to acceptance

• New market• Effective• Relatively low

costs• Easy to use, learn• Wide indications

Dr. Gavriel D. Meron

Radical disruptive innovations

1. Build on existing patterns of consumer behaviour

2. Attract early adopters and create loyal followers

3. Outperform dominant market or create new market

4. Reduce complexity; simpler in design and easier to use

5. Overcomes initial barriers to acceptance

Defining the problem

Indeterminant stricturesBenign vs. malignant

3000 CCA/ year USA

ddx biliary stenosis

Malignant• Cholangiocarcinoma• Pancreatic CA, GB cancer, metastasisBenign• Ischemia• Mirizzi’s• Radiation• Primary sclerosing cholangitis• Autoimmune pancreatitis/cholangiopathy• AIDS cholangiopathy• Parasites

Current guidelines for dx of CCA

AGA, ACG, ESGE – no guidelinesGIE (ASGE) 2003

The role of endoscopy in the evaluation and treatment of patients with pancreaticobiliary malignancy

Gut 2002 – Khan et.al.Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document

Tumor markers: Ca 19-9, CEA, Ca 125CTMRIMRCP, ERCP, PTCHistology

Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus documentKhan Gut 2002

• Serum tumor markers – Evidence level 2b• CA 19-9 > 100U/L – 75% Sn 80% Sp

• Imaging• CT and US – Evidence level 4 – useful to confirm biliary

obstruction, may identify mass• MRI – Evidence 2b and 3a – OPTIMAL investigation for

suspected CCA giving extent of tumor, mets, vascular involvement

• ERCP• Brushings 30% yield• Brushing PLUS bx – yield 40-70%

Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus documentKhan Gut 2002

Biliary drainage (recommendation grade A).• Routine biliary drainage before assessing resectability,

or preoperatively, should be avoided except for certain clinical situations such as acute cholangitis

Confirmatory histology (evidence level 5)• Although positive histology and cytology are often

difficult to obtain at ERCP, they are recommended for confirmation of a diagnosis of cholangiocarcinoma. Histology is also important for planning clinical trials....

Treatment options

• Surgery – Whipple, Trisegmentectomy• Radiation • Chemotherapy• Photodynamic therapy• RFA

Complications of missed diagnosisDelayed treatmentNo treatmentRepeated diagnostic procedures

Before pCLE…..

Ca19-9

Brush

ing

BiopsyERCP

Cholangio

scopy

FISH

PET EUS

0

20

40

60

80

100

120

SensitivitySpecificityAccuracy

Radical disruptive innovations

1. Build on existing patterns of consumer behaviour

2. Attract early adopters and create loyal followers

3. Outperform dominant market or create new market

4. Reduce complexity; simpler in design and easier to use

5. Overcomes initial barriers to acceptance

Where does pCLE stand now?

• ~200 hospitals worldwide• 30 in USA;

Current guidelines for PB pCLE

N. America• ASGE

• The role of endoscopy in the evaluation and treatment of patients with pancreaticobiliary malignancy, 2003

❯ No mention

• Confocal laser microscopy - Technology guidelines, 2009❯ Cholangioflex probe mentioned❯ Use in pancreaticobiliary strictures not acknowledged

• AGA - • ACG - • CAG -

EUROPE• ESGE -

Current agreed indications for pancreaticobiliary pCLE

• Indeterminant strictures• De novo• Eluding diagnosis despite standard tissue

sampling

Miami classification

Miami validation Meining Endoscopy 2012

Part I• Consensus meeting x 2 with 5 investigators• 47 consecutive patients, 112 pCLE videos• Blinded and randomized

Part II• 42 videos previously unreviewed• Evaluated for Miami criteria

Miami classification

73%

36%

27%

27%

Inter-observer agreement

kThin dark bands (BENIGN) 0.49

Thick dark bands with flow (MALIGNANT) 0.47

Thin white bands (MALIGNANT) 0.43

Visualization of epithelium (MALIGNANT) 0.56

Dark clumps NS

Radical disruptive innovations

1. Build on existing patterns of consumer behaviour

2. Attract early adopters and create loyal followers

3. Outperform dominant market or create new market

4. Reduce complexity; simpler in design and easier to use

5. Overcomes initial barriers to acceptance

Standard of care…. The Holy Grail

• Safety and feasible• Effective• Proven clinical impact• Cost-effective• Accessible

Brush cyto Biopsy pCLE0

10

20

30

40

50

60

70

80

90

SensitivitySpecificityAccuracy

Giovannini Surg Endos 2011

Meining GIE 2011

SN SP PPV NPV ACC0

20

40

60

80

100

120

Std pathpCLE

Radical disruptive innovations

1. Build on existing patterns of consumer behaviour

2. Attract early adopters and create loyal followers

3. Outperform dominant market or create new market

4. Reduce complexity; simpler in design and easier to use

5. Overcomes initial barriers to acceptance

Barriers to expanded use

• Cost• Reimbursement• Learning curve• Evidence for change in

management• Limited patient

population• Expansion of indications• Increase awareness

Cost

pCLE

Capital costs CellvizioProbe CPT code reimbursement?

Improved accuracy• Add vs. supplant• avoid repeat studies?• better outcomes?• Reduced delay in diagnosis

Cytology brushing

$30/brushProfessional fee $186$152 cytopath interpretation

Learning curve (Meining GIE 2011)

Cohort 1 Cohort 20

0.10.20.30.40.50.60.70.80.9

1

SensitivitySpecificityAccuracy

Learning curve (Meining GIE 2011)

Cohort 1 Cohort 202468

101214161820

Time required

Time required

Competency

• The minimum level of skill, knowledge, and/or expertise derived through training and experience, required to safely and proficiently perform a task or procedure.

• Eg. EUS: For comprehensive competence in all

aspects of EUS, a minimum of 150 supervised cases, of which 75 should be pancreaticobiliary and 50 EUS-guided FNA, is recommended.

Clinical impact

Broadening indications

Inflammatory criteria

Questions > Answers

• Can the criteria be made more definitive to improve interobserver agreement?

• Stratification of criteria? • Fitting pCLE into the algorithm…

• Add to vs supplant tissue acquisition?

• Where will molecular imaging fit?• How do we ensure learning and competency? • Can pCLE perform well outside of high-volume

centers?

Possible consensus

• Indications• Any de novo indeterminant pancreaticobiliary stricture

without evidence of associated mass• Pre-or post stenting• Dominant strictures in PSC

• Consensus criteria• “Miami PLUS” (inclusive of new inflammatory criteria)

• Competency: • X number of formal review of benign, inflammatory and

malignant video series• Testing score - > 80% accuracy

Summary

• Current indications for pCLE in pancreaticobiliary system reserved for indeterminant strictures

• Further required areas of research and development• Special patient populations – PSC, AIP, pancreatic stx• Effect of stenting• Clinical impact• Cost analysis• Formal MD education, learning curves, assessment