Endoscopic Retrograde Cholangiopancreatography (ERCP) Based Sampling of Indeterminate Bile Duct Strictures

Optimizing the Role of ERCP in Evaluating Indeterminate Bile Duct Strictures

Differentiating malignant from benign bile duct strictures is a conundrum, since no diagnostic test is highly sensitive for diagnosing cancer. While ERCP is effective in palliating obstructive jaundice, standard diagnostic tools in ERCP have a low diagnostic sensitivity and confirm the stricture's etiology in <50% of cases. During the first ERCP, standard practice is to obtain routine cytology (RC) using a single brush sample. If this is not diagnostic, patients often undergo repeat ERCP, endoscopic ultrasound or other, increasing health care costs. The incremental yield of performing alternate ERCP-based diagnostic tools during the first ERCP including fluorescence in situ hybridization (FISH), cholangioscopy w/biopsy and multiple brushes for routine cytology is currently unknown. There are no studies quantifying the amount of testing utilized to firmly diagnose the etiology of the stricture, or the most efficient combination of diagnostic tools during the first ERCP. These are important knowledge deficiencies since a definitive tissue diagnosis during the first ERCP could reduce the need for downstream tests and expedite treatment, thereby improving patient-centered and economic outcomes. The added costs of using multiple tools during the first ERCP may be offset by these benefits.

Among patients with indeterminate bile duct strictures, the investigators hypothesize that a multimodality approach will be more sensitive without a significant reduction in specificity compared to multiple brush samples for routine cytology. The investigators will test this hypothesis using an experimental trial design by randomizing patients during their first ERCP to multiple brushing samples for cytology vs. a single brush sample for cytology + FISH + cholangioscopy w/biopsy. To obtain preliminary data for a definitive multi-center trial, the investigators propose a pilot and feasibility study to compare the performance characteristics of each approach by evaluating the prospective clinical course, including treatment delay, quality of life, and life expectancy for each enrolled patient. If our hypothesis is validated in a subsequent definitive study, the standard approach to tissue sampling during the first ERCP may be altered.

Study Overview

• Status: Completed
• Conditions: Indeterminate Bile Duct Stricture
• Intervention / Treatment: Procedure: Multimodality tissue sampling; Procedure: Multiple brushings

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health University Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Extrahepatic BDS with no discrete mass on CT/MRI (either or both)
• A BDS is defined as a segmental narrowing of the bile duct > 50% of the proximal or distal unaffected duct.
• Biochemical evidence of cholestasis (increase in alkaline phosphatase ≥ 2x upper limit of normal ± total bilirubin ≥2.0mg/dL)

Exclusion Criteria:

• No clinical suspicion for malignancy
• Associated mass seen on CT or MRI
• Age ≤18, pregnancy, incarceration, inability to give informed consent
• Inability to undergo standard ERCP (e.g., postsurgical anatomy)
• Previous ERCP with sampling of BDS, other than a single brushing specimen sent for routine cytopathology

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Multimodality Approach; Patients in the multimodality arm will undergo a single brushing for routine cytology, a second brush sample for Fluorescence In Situ Hybridization and a cholangioscopy with site-directed biopsies for histology.	Procedure: Multimodality tissue sampling; Single brush for cytology + single brush for FISH + cholangioscopy with site-directed biopsies
Active Comparator: Multiple brush samples; In patients randomized to multiple brushing samples, subsequent brushings #2-7 will be labeled separately and consecutively and sent to cytology. The cytopathologist will review each specimen for cellularity using a previously validated scoring system and presence of malignancy (positive, highly suspicious, atypical, normal).	Procedure: Multiple brushings; Seven consecutive brush samples for cytology.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Performance characteristics	A definite diagnosis of malignancy (i.e., "true positive") will be defined as either 1) a cytological or histological interpretation "positive for malignancy" based on brushing for RC or biopsy; 2) subsequent cytological or histological confirmation of malignancy within one year of the index procedure, via repeat ERCP, surgery, other diagnostic test. If a diagnosis of cancer is not confirmed after one year of follow-up, then the stricture will be classified as non-malignant and the negative cytology, FISH and histology from the index ERCP considered "true negatives."	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incremental yield of multiple brushings	The additive role of each additional brushing will be analyzed for 1) adequacy of cellularity for cytological interpretation and 2) assessment of malignancy. The cytopathologist will be asked to interpret each of these outcomes using the first pass only (control group), first two passes only, first three passes only, and so on until all seven brushings are analyzed. The performance characteristics (see primary outcome) will be compared for each incremental brushing, assuming that a single intraductal brushing for RC is the reference standard.	12 months
Incremental cost effectiveness ratio	Complete data on medical utilization (e.g. hospitalizations, procedures, ambulatory visits) will be collected prospectively using Indiana Network for Patient Care (INPC) health information exchange databases (clinical electronic health record (EHR) and claims). Direct costs associated with the diagnostic evaluation of the indeterminate bile duct stricture (BDS) will be measured in both groups, including those costs associated with the index ERCP and all treatment costs associated with each study arm.	12 months

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Boston Scientific Corporation

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: April 17, 2012
• First Submitted That Met QC Criteria: April 18, 2012
• First Posted (Estimate): April 19, 2012

Study Record Updates

• Last Update Posted (Estimate): September 20, 2016
• Last Update Submitted That Met QC Criteria: September 19, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: pancreatic adenocarcinoma; cholangiocarcinoma; ERCP; bile duct; stricture
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathological Conditions, Anatomical; Biliary Tract Diseases; Bile Duct Diseases; Constriction, Pathologic; Cholestasis
• Other Study ID Numbers: 10895519; K23DK095148 (U.S. NIH Grant/Contract)