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Digital single-operator peroral cholangioscopy-guided biopsy sampling versus ERCP-guided brushing for indeterminate biliary strictures: a prospective, randomized, multicenter trial (with video)
Journal Pre-proof Digital single-operator peroral cholangioscopy-guided biopsy versus ERCP-guided brushing for indeterminate biliary strictures: a prospective, randomized multicenter trial (with video) Christian Gerges, MD, Torsten Beyna, MD, Raymond S.Y. Tang, MD, Farzan Bahin, FRACP PhD, James Y.W. Lau, MD PhD, Erwin van Geenen, MD PhD, Horst Neuhaus, MD, Duvvur Nageshwar Reddy, MD, Mohan Ramchandani, MD PII:
S0016-5107(19)32475-7
DOI:
https://doi.org/10.1016/j.gie.2019.11.025
Reference:
YMGE 11843
To appear in:
Gastrointestinal Endoscopy
Received Date: 4 September 2019 Accepted Date: 10 November 2019
Please cite this article as: Gerges C, Beyna T, Tang RSY, Bahin F, Lau JYW, van Geenen E, Neuhaus H, Reddy DN, Ramchandani M, Digital single-operator peroral cholangioscopy-guided biopsy versus ERCP-guided brushing for indeterminate biliary strictures: a prospective, randomized multicenter trial (with video), Gastrointestinal Endoscopy (2019), doi: https://doi.org/10.1016/j.gie.2019.11.025. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2019 by the American Society for Gastrointestinal Endoscopy
Digital singleingle-operator peroral cholangioscopycholangioscopy-guided biopsy versus versus ERCPERCPguided brushing for indeterminate biliary strictures: strictures: a prospective, randomized multicenter trial Christian Gerges1MD*, Torsten Beyna1MD*, Raymond S.Y. Tang2MD, Farzan Bahin1FRACP PhD, James Y.W. Lau2MD PhD, Erwin van Geenen3 MD PhD, Horst Neuhaus1MD, Duvvur Nageshwar Reddy4 MD, Mohan Ramchandani4 MD
*Christian Gerges and Torsten Beyna are shared first authors
1
Evangelisches Krankenhaus Düsseldorf, Department of General Internal Medicine and
Gastroenterology, Düsseldorf, Germany
2
Institute of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong
3
Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin,
Hong Kong.
4
Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen,
The Netherlands.
5
Asian Institute of Gastroenterology Hospitals, Hyderabad, India.
Short Title: DSOC vs. ERCP in indeterminate Biliary strictures Keywords: Single-Operator Cholangioscopy, Indeterminate Biliary Stricture, SpyGlass, per-oral cholangioscopy, Grant support: none Word Counts: 2896 Corresponding author: Mohan Ramchandani Asian Institute of Gastroenterology Hospitals Gachibowli, 1
Hyderabad 500032, India Email: [email protected] Financial Support and potential competing interests
Christian Gerges: Consultant for MTE, no competing interests Torsten Beyna: Investigator in Boston Scientific and Olympus sponsored trials, no competing interests Raymond Tang: no disclosure, no competing interests Farzan Bahin: no disclosures, no competing interests James Y.W.Lau: Investigator in Boston Scientific sponsored trials, no competing interests Erwin van Geenen: no disclosures, no competing interests Horst Neuhaus: no disclosure, no competing interests Nageshwar Reddy: no disclosures, no competing interests Mohan Ramchandani: Investigator in Boston Scientific sponsored trials, no competing interests
2
Study Support
Guarantor of the article: Mohan Ramchandani
Specific Author Contributions:
Study concept and design: Christian Gerges, Torsten Beyna, Mohan Ramchandani, Raymond Tang, James Y.W.Lau, Horst Neuhaus, Nageshwar Reddy Acquisition of data: Christian Gerges, Torsten Beyna, Raymond S.Y.Tang, James Y.W.Lau, Horst Neuhaus, Nageshwar Reddy, Mohan Ramchandani Study coordination: Christian Gerges, Mohan Ramchandani Statistical analysis: Christian Gerges, Farzan Bahin Interpretation of data: Christian Gerges, Torsten Beyna, Farzan Bahin, Erwin van Geenen, Mohan Ramchandani Drafting of the manuscript: Christian Gerges, Torsten Beyna, Farzan Bahin, Mohan Ramchandani Critical revision of the manuscript for important intellectual content: All Authors
Support: Statistical and database support by Boston Scientific Corporation, Marlboro, MA, USA
3
Abstract
Background and Aims: ims: Accurate diagnosis of indeterminate biliary strictures is challenging but important for patient prognostication and further management. Biopsy under direct cholangioscopic vision might be superior to standard ERCP techniques such as brushing or biopsy. Our aim was to investigate whether digital single-operator cholangioscopy (DSOC) compared with standard ERCP work-up improves the diagnostic yield in patients with indeterminate biliary strictures.
Methods: Patients with an indeterminate biliary stricture on the basis of MRCP were randomized to standard ERCP visualization with tissue brushing (Control Arm [CA]) or DSOC visualization and DSOC-guided biopsy (Study Arm [SA]). This was a prospective international multicenter trial with a procedure-blinded pathologist.
Results: First sample sensitivity of DSOC-guided biopsies was significantly higher than ERCPguided brushing (SA 68.2% vs CA 21.4%, P<0.01). The sensitivity of visualization (SA 95.5% vs CA 66.7%; P=0.02) and overall accuracy (SA 87.1% vs CA 65.5%, P=0.05) were significantly higher in the SA compared with the CA whereas specificity, positive predictive value, and negative predictive value showed no significant difference. Adverse events were equally low in both arms.
Conclusions Conclusions: DSOC-guided biopsies were shown to be safe and effective with a higher sensitivity compared with standard ERCP techniques in the visual and histopathological diagnosis of indeterminate biliary strictures.
4
Background and Aims: Aims:
Biliary strictures arise from a range of entities ranging from benign (eg, postsurgical or stone disease) to inflammatory (eg, sclerosing or IgG4-related cholangitis) to malignant conditions (eg, cholangiocarcinoma, hepatocellular carcinoma, or local extension of other tumors)1,2. In the absence of apparent extrinsic compression, accurate characterization of strictures caused by biliary ductal disease can be challenging3,4. Because of the major differences in treatment comprising endoscopic intervention, medical treatment, extensive surgery, and palliation, a correct diagnosis, preferably at first ERCP, is crucial for patient prognosis and management. For example, although a benign postsurgical biliary stricture can be often treated successfully with an endoscopic approach, a cholangiocarcinoma needs aggressive surgical and oncological management associated with appreciable morbidity and not insignificant mortality4,5. Because conventional ERCP-based cholangiography has poor sensitivity in distinguishing the cause of the stricture tissue acquisition is neccessary4,6. The standard evaluation of indeterminate biliary strictures therefore always involves cross-sectional imaging followed by ERCP plus biopsy and/or brushing7. Transpapillary biopsy and/or brushing (TPB) is easy to perform and fairly inexpensive, but is limited by well-documented poor diagnostic accuracy8. EUS-guided sampling is considered an additional diagnostic approach if TPB fails, but is limited to distal or unresectable intrinsic biliary lesions, and seeding remains a potential concern9-11. Digital single-operator cholangioscopy (DSOC) is an established tool that provides highresolution direct visualization of the bile duct, allows for histopathological acquisition and also enables interventional therapy. DSOC appears to be a logical next step to increase diagnostic accuracy in indeterminate biliary strictures. Indeed, several cohort studies and a meta-analysis reported significant superior diagnostic yield and potential cost effectiveness of DSOC compared with TPB6,12-18. The meta-analysis reported a sensitivity for TPB of 45% with a 95% confidence interval (CI) of 40% to 50%8, whereas the medical literature for DSOC shows sensitivity ranging from 49% to 100%6,17,18. To date, no 5
prospective, randomized studies have compared standard ERCP work-up (comprising TPB) with DSOC. Our aim was to investigate whether DSOC compared with standard ERCP work-up improves the diagnostic yield in patients with indeterminate biliary strictures.
Material and Methods: The objective of this study was to assess the diagnostic accuracy of DSOC using single-use cholangioscope technology (SpyGlassDS, Boston Scientific Corporation, Marlboro, Mass, USA) compared with ERCP-based assessment using traditional sampling technology in patients with indeterminate biliary strictures. Indeterminate biliary stricture was defined as a suspected intrinsic biliary stricture of unknown entity (benign or malignant) based on prior MRCP imaging. The study design was a prospective, international, multicenter, randomized controlled trial. This was an investigator-initiated study. The study was approved by the Institutional Review Board (IRB) at each site and was registered (clinicaltrials.gov NCT03140007). All investigators agreed on the study protocol and could only access data from their own study center. All proceduralists were highly experienced operators performing over 200 ERCPs and over 30 SpyGlassDS per year. All authors reviewed the final manuscript.
Participants
Inclusion Criteria 1. Age 18 or older. 2. Willing and able to comply with the study procedures and provide written informed consent to participate in the study. 3. Biliary obstructive symptoms. 4. Indeterminate biliary stricture suspected to be intrinsic and proximal to the distal common bile duct (CBD) based on prior MRCP.
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Exclusion Criteria 1. Contraindications to endoscopic intervention (coagulopathy, ASA 4 or greater, pregnancy). 2. Prior ERCP with TPB for assessment of indeterminate biliary stricture. 3. Extrabiliary compression identified on prior noninvasive imaging and thought to be the cause of the biliary obstructive symptoms. 4. Age less than 18.
A local multidisciplinary team made up of experienced radiologists, surgeons, and endoscopists assessed the indication for endoscopic evaluation of the indeterminate biliary stricture. All imaging studies were reviewed by a dedicated hepatobiliary-certified radiologist. Treatment strategies were standardized across sites. Suspected intrinsic biliary strictures except distal CBD strictures were included. This was in order to exclude patients with extrinsic biliary obstruction from a pancreatic mass. According to the MRCP, strictures were classified based on the Bismuth-Corlette Classification (Figure 1)19,20. Patients were invited to participate in the study if they were eligible based on inclusion and exclusion criteria. Consecutive patients referred for assessment and management of their indeterminate biliary stricture were screened for inclusion. Informed consent was obtained from all patients and documented before enrollment and randomization. Before the procedure, relevant demographic information and patient medical history was recorded. Data were collected and stored securely by a local study nurse at each participating center in written form. It was subsequently sent to a central and secure, anonymous online database as a case report file (CRF).
Procedure •
Patients in the control arm (CA) underwent an ERCP with cholangiography. Cholangiography-based impression of malignancy (yes/no/indeterminate) was recorded. ERCP-guided brushing was performed with a minimum of 9 passes. The samples were fixed on a slide and sent off for cytological analysis. The brushes used for this study were RX Cytology Brush 2.1mmx8FR (Boston 7
Scientific Corporation, Marlboro, Mass, USA) or 3-mm/6F-8F Cytomax II Double Lumen Cytology Brush (CookMedical). •
Patients in the Study Arm (SA) underwent a DSOC (SpyGlassDS, Boston Scientific Corporation, Marlboro, Mass, USA) cholangioscopic evaluation without cholangiography. DSOC-based impression of malignancy (yes/no/indeterminate) were recorded. A minimum of 3 DSOC-guided biopsies were required to be counted as adequate. Biopsy specimens were taken with a purpose-designed biopsy forceps that can be passed through the DSOC miniscope (SpyBite, Boston Scientific Corporation, Marlboro, Mass, USA) and sent off for histopathological analysis in a jar. Representative images can be found in Figure 2.
Histopathological or cytological assessment was performed by a histopathologist with expertise in biliary histopathology at each center. The pathologist was blinded to the randomization status of the study participants. Procedural adverse events were documented, including severity and seriousness of the events, time of onset and resolution, and outcome of the events. All patients underwent a follow-up 30 days after the index procedure with a visit and/or a telephone call. Follow-up ended 6 months after the index procedure or confirmation of malignancy, whichever came first. All equipment was used on label.
Outcomes •
Primary endpoint o Diagnostic accuracy of cholangioscopy or cholangiography was assessed at 6 months after the initial ERCP procedure. Malignancy was determined by cytology or histology on tissue sampling during the index or subsequent ERCP procedure, or surgical specimen histopathology up to 6 months after the index procedure. The assessed stricture was considered benign if malignancy was not confirmed by 6 months after the index procedure. 8
Diagnostic accuracy of only the first procedure was compared between the groups, because subsequent information was not easily comparable. •
Secondary endpoints o Correlation between intraprocedural visual impression of malignancy and cytopathology in the CA and SA. Visual Impression consistently based on previous described criteria (mass, dilated tortuous vessels, papillary or villous projections, intraductal nodules) and documented as suspected malignant or benign lesion17. o Technical success of the procedure, which was defined as the ability to collect tissue deemed adequate for cytological or histological analysis as per the pathologist. o The yield of tissue acquisition, which was defined as benign or malignant cytology or histology results from ERCP-guided brushing and cholangioscopy-guided SpyBite biopsies. o The occurrence and severity of procedure related serious adverse events from index procedure through 30 days after procedure (hospitalization and ICU admissions).
If patients had an initial benign histopathology, but the visual impression of the proceduralist was suspicious for malignancy patients would be rescheduled for a prompt reevaluation with an additional tissue sampling. If the first histopathology was indeterminate, regardless of the visual impression a prompt reevaluation with an additional tissue sampling was scheduled. In these cases, any type of procedure was applicable, as it would be ethically incorrect for patients to stay only in one of the arms and not using all possible procedures to get histopathology. Procedural parameters such as procedure duration (duodenoscope in to duodenoscope out) and number of procedures were recorded in both arms. Change in preprocedural patient management as a result of ERCP cholangiography or DSOC was also recorded (impact of visual impression).
9
Randomization Patients were randomized into 2 groups: • Control/ERCP arm: ERCP impression and ERCP-guided brushing • Study/cholangioscopy arm: DSOC impression and DSOC-guided biopsy Patients were randomized in a 1:1 ratio. Randomization was conducted using study envelopes provided to each center. The randomization scheme was followed by-site block-randomization and was prepared by a statistician. Participants and endoscopist were blinded to randomization until the study nurse opened the envelope revealing the allocated group before commencing the procedure.
Statistics We tested the hypothesis that cholangioscopy-guided biopsy would have a higher sensitivity than ERCP-guided brushing. We assumed that ERCP-guided brushing would have 48% sensitivity and that cholangioscopic-guided biopsy would have 82% sensitivity. We powered the hypothesis at 80%, with a 2-sided alpha of 0.05, using an asymptotic test the number of patients required was 54. We added 10% attrition for possible loss to follow-up and drop outs to get a total sample size of 60. Continuous data was analyzed using median with IQR, differences between the groups were analyzed using a Mann-Whitney U test. However, because the number of procedures is a count variable, it was reported with mean and standard deviation and was tested using a negative binomial model. Binary variables were analyzed using frequencies and differences were tested using asymptotic methods, except for the correlation between visualization and biopsy, which was calculated using the Fisher exact test. P value <0.05 was considered significant, and all analyses and sample size calculations were performed using SAS version 9.4 (SAS Institute, Inc, Cary, NC, USA). Diagnostic accuracy was derived from the following components: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy (OA).
10
Results: Sixty-one patients in 3 tertiary referral centers were consecutively screened and enrolled from May 2017 to December 2018. The study was ended after reaching the primary endpoint and ended at 6 months follow-up of the last enrolled patient. Thirty-two were randomized to SA and 29 to CA. One patient in the SA was excluded from all analyses because they withdrew their consent before the procedure being performed. The flow of participants is demonstrated in Figure 3. Demographic and baseline characteristics were equally distributed in both arms (Table 1). In the SA one patient was excluded due to confirmation of extrinsic biliary compression after undergoing DSOC. This left 30 patients for primary endpoint analysis, of which 22 patients had a malignant final diagnosis and 8 patients had a benign final diagnosis. In the CA, one patient was excluded due to inability to reach the duodenum because of an obstructing esophageal cancer as well as another patient in whom brushings were not performed after removal of an obstructing CBD stone. This left 27 patients for primary endpoint analysis, of which 14 patients had a malignant final diagnosis and 13 patients had a benign final diagnosis. In the CA, 44.8% (13/29) completed the study without malignancy and 48.2% (14/29) with malignancy. In the SA, 25% (8/32) completed the study without malignancy and 68.8% (22/32) with malignancy (Figure 3).
The vast majority of patients received preinterventional antibiotics (CA 86.2% vs SA 96.8%; P=0.14). Most patients underwent a sphincterotomy (CA 69% vs SA 74.2%; P=0.64) and stent placement (CA 81.5% vs SA 77.4%; P=0.7) without significant difference in the 2 arms. The mean number of procedures to get a final diagnosis was 1.16 for CA and 1.18 in the SA (1.17 overall, P=0.95). Median duration of the procedure showed no significant difference in both arms (CA 30 (IQR 20-87) mins vs SA 50 (IQR 2673) mins; P=0.2) (Table 2).
Diagnostic Accuracy of Histopathology
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Tissue samples could be obtained in all cases at first evaluation. In the SA one sample was inadequate for histological analysis (1/31) resulting in a yield for DSOC of 30 out of 31 (96.8%). In this case, biopsies were inadequate because only 2 biopsies were performed as the lesion seemed to be pulsating on DSOC imaging. On average 6 biopsy specimens were taken (2.0-8.0). In the CA, brushings were adequate for cytological analysis in all patients. In one participant in the CA, the proceduralist suspected a stone as a reason for the stricture with no wire passage being possible. In this case DSOC was used and visualized a stone which was not seen on prior imaging and successfully treated with DSOC-guided electrohydraulic lithotripsy. No brushings were performed in this case. Sensitivity of DSOC-guided biopsies were significantly higher than ERCP-guided brushing (SA 68.2% vs CA 21.4%, P<0.01)). All other parameters such as specificity, PPV, NPV and OA showed no significant difference (Table 3). Table 4 demonstrates the diagnostic parameters when benign and indeterminate tissue samples were combined. The main difference is that in this scenario of malignant versus nonmalignant distinction the specificity of both TPB and DSOC increases to 100%.
Impact of visual impression All lesions in the SA could be visualized. In approximately half of the cases in both arms the visual impression had an impact on the patient management (CA 50% vs SA 56.7%; P=0.62). The sensitivity (SA 95.5% vs CA 66.7%; P=0.02) and OA (SA 87.1% vs CA 65.5%, P=0.05) were significantly higher in the SA compared with the CA whereas specificity, PPV, and NPV showed no significant difference (Table 5). In the SA a significant correlation between visualization and biopsy could be shown (p=0.02) (Table 6).
Adverse Events No severe adverse events (AEs) could be documented. Mild adverse events occurred in 3 patients in the CA (1 cholangitis, 1 cholecystitis and 1 bleeding) and in 2 patients in the SA (2 pancreatitis). All AE could be treated conservatively with full recovery of the patients (Table 7). 12
Discussion:
Our study found that compared with standard ERCP-based tissue acquisition DSOCguided evaluation had a higher sensitivity in the histological diagnosis of indeterminate biliary strictures. Furthermore, DSOC-based visual impression of the indeterminate biliary stricture provided a higher diagnostic accuracy, sensitivity and positive predictive value compared with conventional ERCP cholangiography without a difference in adverse events.
Accurate diagnosis of indeterminate biliary strictures is of paramount importance due to a potentially vastly different prognosis based on etiology. Because the diagnostic accuracy of conventional ERCP-based tissue acquisition (brushing and/or biopsy) has been suboptimal, DSOC has emerged as a logical innovation that could have a role in the diagnosis of indeterminate biliary strictures. Our results confirm that DSOC is technically successful and safe for biliary visualization and collection of histopathology.
Compared with the current standard of care in most endoscopy units using brushing cytology, DSOC directed biopsies could improve diagnostic sensitivity significantly. In our study the sensitivity with DSOC was 68% compared with 21% with ERCP-guided brushing. A reason for the very low sensitivity of brushing in the CA can be explained through the intrinsic entity of the lesions. Cholangiocarcinomas have a prominent desmoplastic and hypervascularized stroma. This pathophysiology is likely the reason why nontargeted brushing of strictures is ineffective in those particular cases and highlights the potentially low ERCP-based tissue acquisition sensitivity in a prospective real-life study environment. Although the DSOC-guided sensitivity is higher, it is still somewhat limited and may account for a similar number of procedures needed to confirm malignancy compared with conventional ERCP. The slight imbalance in final diagnosis with a greater proportion of malignancy in the study arm may also have contributed to this. The impact of the size of the DSOC-guided biopsy forceps is currently unknown. It is conceivable that larger forceps could further improve histological diagnostic accuracy due 13
to a more suitable tissue sample with the benefit of direct visualization. Mean number of procedures to get final diagnosis showed no significant difference in both arms. The reason for this lies in the nature of the disease. In some cases, the patients either died from their cholangiocarcinoma or went into palliative care after the first procedure. This may have reduced the number of procedures to reach the final diagnosis in the ERCP arm significantly.
A significant advantage of DSOC is the ability to directly visualize the biliary tree and stricture. This is important as it gives the experienced endoscopist further information about the stricture which has an impact on patient management such as planning further investigation despite negative or indeterminate histopathology results. In fact, one case was only clarified after visualizing the stricture using DSOC and finding an impacted stone as the reason for the obstruction. Despite DSOC being potentially a technically more challenging procedure, biliary visualization was successful in almost all DSOC cases with no statistical difference compared with standard ERCP. As described in other publications we could reproduce a very high sensitivity and overall accuracy for the diagnosis of malignant strictures using DSOC. Direct visual impression may be convincing enough to result in surgical treatment even without definitive histopathology in select cases, such as surgically fit patients with indeterminate biliary strictures from potentially resectable tumors.
Based on the results of our study, it appears combining the direct cholangioscopic visual impression with DSOC-guided biopsies provides the highest chance of confirming malignancy in indeterminate biliary strictures. In both groups, visual impression on its own accord made a difference to patient management in at least half of the cohort. It demonstrates that this is an essential component of the diagnostic process and supplements histological acquisition.
To our knowledge this is the first randomized controlled trial that evaluates DSOC in comparison to conventional ERCP for indeterminate biliary strictures. Strengths include 14
the randomized, prospective nature of the study, 3 international study sites, a defined cohort with a structured follow-up and the detailed analysis of visual and histopathological aspects of the procedure.
Our study had several limitations. Even though comparing 60 patients meeting strict inclusion and exclusion criteria for a diagnosis of indeterminate biliary stricture seems to be an adequate number to test the a priori hypothesis set forth in this study absolute number of patients were small. The number of participants in each cohort was slightly imbalanced, particularly in regard to containing a diagnosis of malignancy. We believe this would be rebalanced in larger cohorts, but in this study may have affected the results. In addition, histopathological/cytological analysis was not centrally assessed or compared between the sites. Findings of the study may not be generalizable as procedures were performed by experienced expert endoscopists in tertiary referral centers. Although ESGE guidelines recommend that indeterminate strictures are assessed and managed in tertiary referral centers, especially when DSOC is indicated, it is unclear whether similar results would be found if less-experienced endoscopists performed these procedures21. We did not perform a cost effectiveness analysis in this particular study because it was out of the scope of the primary objective. Purchasing a DSOC device is an additional cost to standard ERCP. Evaluating the cost effectiveness analysis of DSOC and conventional ERCP for indeterminate biliary strictures would be a relevant separate study, but is maybe challenging due to different healthcare settings and true costs of interventions like surgery.
In conclusion, DSOC was shown to be safe and effective with a higher diagnostic sensitivity compared with standard ERCP and brushing for the diagnosis of indeterminate biliary strictures. The visual impression was shown to have a pertinent impact on patient management and should be an essential part of determining the correct diagnosis. DSOC should be considered as a viable diagnostic alternative to conventional ERCP for indeterminate biliary strictures with the potential to change patient management. Further 15
innovations in cholangioscopic characterisation of strictures, image quality and histological acquisition devices are desirable and are likely to advance our understanding in this field even further.
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Tables and Figures
Table 1 Patient demographics and baseline characteristics on treated analysis set
Age Male Bismuth Classification I II IIIa IIIb IV V Other
TPB group (N=29 (N=29) 29) 65 (57-74) 65.5% (19/29)
DSOC group (N=3 (N=31) 62 (54-79) 54.8% (17/31)
P value 0.93 0.40 0.79
37.9% (11/29) 17.2% (5/29) 13.8% (4/29) 13.8% (4/29) 13.8% (4/29) 0.0% (0/29) 3.4% (1/29)
29.0% (9/31) 19.4% (6/31) 12.9% (4/31) 9.7% (3/31) 12.9% (4/31) 3.2% (1/31) 12.9% (4/31)
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Table 2 General procedure characteristics
Prei Preinterventional antibiotics Number of days Location of dominant target lesion IHBD Right main Left main Hilar CHD CBD Ampullary/sphinteric Diffuse/multiple locations Sphincterotomy performed Stent placed Plastic stent UC SEMS PC SEMS FC SEMS Duration of procedure (mins)
TPB group (N=29 (N=29) 29) 86.2% (25/29) 2 (1-3)
DSOC group (N=3 (N=31) 96.8% (30/31) 1 (1-2)
P value 0.14 0.61 0.57
0.0% (0/29) 10.3% (3/29) 3.4% (1/29) 27.6% (8/29) 0.0% (0/29) 55.2% (16/29) 0.0% (0/29) 3.4% (1/29) 69.0% (20/29) 81.5% (22/27) 95.5% (21/22) 0.0% (0/22) 0.0% (0/22) 4.5% (1/22) 30 (20-87)
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6.5% (2/31) 12.9% (4/31) 6.5% (2/31) 29.0% (9/31) 3.2% (1/31) 41.9% (13/31) 0.0% (0/31) 0.0% (0/31) 74.2% (23/31) 77.4% (24/31) 91.7% (22/24) 4.2% (1/24) 0.0% (0/24) 4.2% (1/24) 50 (26-73)
0.65 0.70
0.20
Table 3 Diagnostic accuracy of ERCP brushing (TPB) versus ersus DSOC biopsy on first sample Lesion Final diagnosis diagnosis based based Malignant Benign on ERCP brush
Lesion diagnosis based on DSOC biopsy
Malignant
3
0
Benign
6
Indeterminate
5
Measure Sensitivity Specificity Positive predictive value Negative predictive value Overall accuracy
Final diagnosis Malignant
Benign
Malignant
15
0
11
Benign
6
5
2
Indeterminate
1
3
TPB group 21.4% (3/14) 84.6% (11/13)
DSOC group 68.2% (15/22) 62.5% (5/8)
P value
100.0% (3/3)
100.0% (15/15)
0.99
64.7% (11/17)
45.5% (5/11)
0.31
51.9% (14/27)
66.7% (20/30)
0.25
<.01 0.25
Table 4 Diagnostic accuracy of ERCP brushing (TPB) versu versus ersus DSOC biopsy on first sample (malignant versus versus nonmalignant classification)
Lesion diagnosis based on ERCP brush
Final diagnosis Malignant
Benign
Malignant
3
0
Benign
11
13
Measure Sensitivity Specificity Positive Predictive Value Negative Predictive Value Overall Accuracy
Lesion diagnosis based on DSOC biopsy
ERCP group (N=29) 21.4% (3/14) 100.0% (13/13) 100.0% (3/3) 54.2% (13/24) 59.3% (16/27)
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Final diagnosis Malignant
Benign
Malignant
15
0
Benign
7
8
DSOC group (N=32) 68.2% (15/22) 100.0% (8/8) 100.0% (15/15) 53.3% (8/15) 76.7% (23/30)
P value <.01 0.99 0.99 0.96 0.16
Table 5 Diagnostic accuracy of ERCP visual impression versus ersus DSOC visual impression Measure Sensitivity Specificity Positive predictive value Negative predictive value Overall accuracy
P
TPB group
DSOC group
66.7% (10/15) 64.3% (9/14)
95.5% (21/22) 66.7% (6/9)
value 0.02 0.91
90.9% (10/11)
100.0% (21/21)
0.16
75.0% (9/12)
85.7% (6/7)
0.58
65.5% (19/29)
87.1% (27/31)
0.05
20
Table 6 Relationship of DSOC visual impression and DSOCDSOC-guided biopsy
DSOC Visualization
DSOCDSOC-directed biopsy Malignant Benign Indeterminate
Malignant
14
6
1
Benign
1
3
2
Indeterminate
0
2
1
Table 7 Adverse events
TPB Group
DSOC Group
10.3% (3/29)
6.5% (2/31)
Cholangitis
3.4% (1/29)
0.0% (0/31)
Cholecystitis
3.4% (1/29)
0.0% (0/31)
Pancreatitis
0.0% (0/29)
6.5% (2/31)
Bleeding
3.4% (1/29)
0.0% (0/31)
Overall
21
P value 0.59 0.30 0.30 0.16 0.30
Figure Legends Figure 1: Bismuth-Corlette Classification Figure 2: Top, MRCP of indeterminate biliary stricture, Middle, DSOC pictures showing a stricture with irregular papillogranular surface, luminal contents (mass), irregular, and tortious vessels. Bottom, histopathology with tumor cells Figure 3: Patient flowchart
22
References:
1. Gerges C, Schumacher B, Terheggen G, Neuhaus H. Expandable metal stents for malignant hilar biliary obstruction. Gastrointest Endosc Clin N Am 2011;21:481-97, ix. 2. Bowlus CL, Olson KA, Gershwin ME. Evaluation of indeterminate biliary strictures. Nat Rev Gastroenterol Hepatol 2016;13:28-37. 3. Friman S. Cholangiocarcinoma--current treatment options. Scand J Surg 2011;100:30-4. 4. Paranandi B, Oppong KW. Biliary strictures: endoscopic assessment and management. Frontline Gastroenterol 2017;8:133-7. 5. Costamagna G, Tringali A, Mutignani M, et al. Endotherapy of postoperative biliary strictures with multiple stents: results after more than 10 years of follow-up. Gastrointest Endosc 2010;72:551-7. 6. Ramchandani M, Reddy DN, Lakhtakia S, et al. Per oral cholangiopancreatoscopy in pancreatico biliary diseases--expert consensus statements. World J Gastroenterol 2015;21:4722-34. 7. Hu B, Sun B, Cai Q, et al. Asia-Pacific consensus guidelines for endoscopic management of benign biliary strictures. Gastrointest Endosc 2017;86:44-58. 8. Navaneethan U, Njei B, Lourdusamy V, Konjeti R, Vargo JJ, Parsi MA. Comparative effectiveness of biliary brush cytology and intraductal biopsy for detection of malignant biliary strictures: a systematic review and meta-analysis. Gastrointest Endosc 2015;81:168-76. 9. El Chafic AH, Dewitt J, Leblanc JK, et al. Impact of preoperative endoscopic ultrasound-guided fine needle aspiration on postoperative recurrence and survival in cholangiocarcinoma patients. Endoscopy 2013;45:883-9. 10. Sadeghi A, Mohamadnejad M, Islami F, et al. Diagnostic yield of EUS-guided FNA for malignant biliary stricture: a systematic review and meta-analysis. Gastrointest Endosc 2016;83:290-8 e1. 11. Heimbach JK, Sanchez W, Rosen CB, Gores GJ. Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination. HPB (Oxford) 2011;13:356-60. 12. Deprez PH, Garces Duran R, Moreels T, et al. The economic impact of using singleoperator cholangioscopy for the treatment of difficult bile duct stones and diagnosis of indeterminate bile duct strictures. Endoscopy 2018;50:109-18. 13. Badshah MB, Vanar V, Kandula M, et al. Peroral cholangioscopy with cholangioscopy-directed biopsies in the diagnosis of biliary malignancies: a systemic review and meta-analysis. Eur J Gastroenterol Hepatol 2019;31:935-40. 14. Sun X, Zhou Z, Tian J, et al. Is single-operator peroral cholangioscopy a useful tool for the diagnosis of indeterminate biliary lesion? A systematic review and meta-analysis. Gastrointest Endosc 2015;82:79-87. 15. Navaneethan U, Hasan MK, Lourdusamy V, Njei B, Varadarajulu S, Hawes RH. Single-operator cholangioscopy and targeted biopsies in the diagnosis of indeterminate biliary strictures: a systematic review. Gastrointest Endosc 2015;82:608-14 e2. 16. Draganov PV, Chauhan S, Wagh MS, et al. Diagnostic accuracy of conventional and cholangioscopy-guided sampling of indeterminate biliary lesions at the time of ERCP: a prospective, long-term follow-up study. Gastrointest Endosc 2012;75:347-53. 17. Ramchandani M, Reddy DN, Gupta R, et al. Role of single-operator peroral cholangioscopy in the diagnosis of indeterminate biliary lesions: a single-center, prospective study. Gastrointest Endosc 2011;74:511-9. 18. Chen YK, Parsi MA, Binmoeller KF, et al. Single-operator cholangioscopy in patients requiring evaluation of bile duct disease or therapy of biliary stones (with videos). Gastrointest Endosc 2011;74:805-14. 23
19. Bismuth H, Corlette MB. Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver. Surg Gynecol Obstet 1975;140:170-8. 20. Bismuth H, Castaing D, Traynor O. Resection or palliation: priority of surgery in the treatment of hilar cancer. World J Surg 1988;12:39-47. 21. Tringali A, Lemmers A, Meves V, et al. Intraductal biliopancreatic imaging: European Society of Gastrointestinal Endoscopy (ESGE) technology review. Endoscopy 2015;47:73953.
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Acronymes and Abbreviations In order of appearance: SOC: single-operator-cholangioscopy ERCP: endoscopic retrograde cholangiopancraticography CA: control arm SA: study arm TPB: Trans papillary biopsy and/or brushing IRB: Institutional Review Board CBD: common bile duct ASA: American society of anesthesiology classification HPB: hepatobiliary MRCP: magnetic -resonance-cholangiopancreaticography CRF: case report file ICU: intensive care unit CI: confidence interval IQR: interquartile range PPV: positive predictive value NPV: negative predictive value OA: overall accuracy AE: adverse events ESGE: European society of gastrointestinal endoscopy
S0016-5107(19)32475-7
DOI:
https://doi.org/10.1016/j.gie.2019.11.025
Reference:
YMGE 11843
To appear in:
Gastrointestinal Endoscopy
Received Date: 4 September 2019 Accepted Date: 10 November 2019
Please cite this article as: Gerges C, Beyna T, Tang RSY, Bahin F, Lau JYW, van Geenen E, Neuhaus H, Reddy DN, Ramchandani M, Digital single-operator peroral cholangioscopy-guided biopsy versus ERCP-guided brushing for indeterminate biliary strictures: a prospective, randomized multicenter trial (with video), Gastrointestinal Endoscopy (2019), doi: https://doi.org/10.1016/j.gie.2019.11.025. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2019 by the American Society for Gastrointestinal Endoscopy
Digital singleingle-operator peroral cholangioscopycholangioscopy-guided biopsy versus versus ERCPERCPguided brushing for indeterminate biliary strictures: strictures: a prospective, randomized multicenter trial Christian Gerges1MD*, Torsten Beyna1MD*, Raymond S.Y. Tang2MD, Farzan Bahin1FRACP PhD, James Y.W. Lau2MD PhD, Erwin van Geenen3 MD PhD, Horst Neuhaus1MD, Duvvur Nageshwar Reddy4 MD, Mohan Ramchandani4 MD
*Christian Gerges and Torsten Beyna are shared first authors
1
Evangelisches Krankenhaus Düsseldorf, Department of General Internal Medicine and
Gastroenterology, Düsseldorf, Germany
2
Institute of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong
3
Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin,
Hong Kong.
4
Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen,
The Netherlands.
5
Asian Institute of Gastroenterology Hospitals, Hyderabad, India.
Short Title: DSOC vs. ERCP in indeterminate Biliary strictures Keywords: Single-Operator Cholangioscopy, Indeterminate Biliary Stricture, SpyGlass, per-oral cholangioscopy, Grant support: none Word Counts: 2896 Corresponding author: Mohan Ramchandani Asian Institute of Gastroenterology Hospitals Gachibowli, 1
Hyderabad 500032, India Email: [email protected] Financial Support and potential competing interests
Christian Gerges: Consultant for MTE, no competing interests Torsten Beyna: Investigator in Boston Scientific and Olympus sponsored trials, no competing interests Raymond Tang: no disclosure, no competing interests Farzan Bahin: no disclosures, no competing interests James Y.W.Lau: Investigator in Boston Scientific sponsored trials, no competing interests Erwin van Geenen: no disclosures, no competing interests Horst Neuhaus: no disclosure, no competing interests Nageshwar Reddy: no disclosures, no competing interests Mohan Ramchandani: Investigator in Boston Scientific sponsored trials, no competing interests
2
Study Support
Guarantor of the article: Mohan Ramchandani
Specific Author Contributions:
Study concept and design: Christian Gerges, Torsten Beyna, Mohan Ramchandani, Raymond Tang, James Y.W.Lau, Horst Neuhaus, Nageshwar Reddy Acquisition of data: Christian Gerges, Torsten Beyna, Raymond S.Y.Tang, James Y.W.Lau, Horst Neuhaus, Nageshwar Reddy, Mohan Ramchandani Study coordination: Christian Gerges, Mohan Ramchandani Statistical analysis: Christian Gerges, Farzan Bahin Interpretation of data: Christian Gerges, Torsten Beyna, Farzan Bahin, Erwin van Geenen, Mohan Ramchandani Drafting of the manuscript: Christian Gerges, Torsten Beyna, Farzan Bahin, Mohan Ramchandani Critical revision of the manuscript for important intellectual content: All Authors
Support: Statistical and database support by Boston Scientific Corporation, Marlboro, MA, USA
3
Abstract
Background and Aims: ims: Accurate diagnosis of indeterminate biliary strictures is challenging but important for patient prognostication and further management. Biopsy under direct cholangioscopic vision might be superior to standard ERCP techniques such as brushing or biopsy. Our aim was to investigate whether digital single-operator cholangioscopy (DSOC) compared with standard ERCP work-up improves the diagnostic yield in patients with indeterminate biliary strictures.
Methods: Patients with an indeterminate biliary stricture on the basis of MRCP were randomized to standard ERCP visualization with tissue brushing (Control Arm [CA]) or DSOC visualization and DSOC-guided biopsy (Study Arm [SA]). This was a prospective international multicenter trial with a procedure-blinded pathologist.
Results: First sample sensitivity of DSOC-guided biopsies was significantly higher than ERCPguided brushing (SA 68.2% vs CA 21.4%, P<0.01). The sensitivity of visualization (SA 95.5% vs CA 66.7%; P=0.02) and overall accuracy (SA 87.1% vs CA 65.5%, P=0.05) were significantly higher in the SA compared with the CA whereas specificity, positive predictive value, and negative predictive value showed no significant difference. Adverse events were equally low in both arms.
Conclusions Conclusions: DSOC-guided biopsies were shown to be safe and effective with a higher sensitivity compared with standard ERCP techniques in the visual and histopathological diagnosis of indeterminate biliary strictures.
4
Background and Aims: Aims:
Biliary strictures arise from a range of entities ranging from benign (eg, postsurgical or stone disease) to inflammatory (eg, sclerosing or IgG4-related cholangitis) to malignant conditions (eg, cholangiocarcinoma, hepatocellular carcinoma, or local extension of other tumors)1,2. In the absence of apparent extrinsic compression, accurate characterization of strictures caused by biliary ductal disease can be challenging3,4. Because of the major differences in treatment comprising endoscopic intervention, medical treatment, extensive surgery, and palliation, a correct diagnosis, preferably at first ERCP, is crucial for patient prognosis and management. For example, although a benign postsurgical biliary stricture can be often treated successfully with an endoscopic approach, a cholangiocarcinoma needs aggressive surgical and oncological management associated with appreciable morbidity and not insignificant mortality4,5. Because conventional ERCP-based cholangiography has poor sensitivity in distinguishing the cause of the stricture tissue acquisition is neccessary4,6. The standard evaluation of indeterminate biliary strictures therefore always involves cross-sectional imaging followed by ERCP plus biopsy and/or brushing7. Transpapillary biopsy and/or brushing (TPB) is easy to perform and fairly inexpensive, but is limited by well-documented poor diagnostic accuracy8. EUS-guided sampling is considered an additional diagnostic approach if TPB fails, but is limited to distal or unresectable intrinsic biliary lesions, and seeding remains a potential concern9-11. Digital single-operator cholangioscopy (DSOC) is an established tool that provides highresolution direct visualization of the bile duct, allows for histopathological acquisition and also enables interventional therapy. DSOC appears to be a logical next step to increase diagnostic accuracy in indeterminate biliary strictures. Indeed, several cohort studies and a meta-analysis reported significant superior diagnostic yield and potential cost effectiveness of DSOC compared with TPB6,12-18. The meta-analysis reported a sensitivity for TPB of 45% with a 95% confidence interval (CI) of 40% to 50%8, whereas the medical literature for DSOC shows sensitivity ranging from 49% to 100%6,17,18. To date, no 5
prospective, randomized studies have compared standard ERCP work-up (comprising TPB) with DSOC. Our aim was to investigate whether DSOC compared with standard ERCP work-up improves the diagnostic yield in patients with indeterminate biliary strictures.
Material and Methods: The objective of this study was to assess the diagnostic accuracy of DSOC using single-use cholangioscope technology (SpyGlassDS, Boston Scientific Corporation, Marlboro, Mass, USA) compared with ERCP-based assessment using traditional sampling technology in patients with indeterminate biliary strictures. Indeterminate biliary stricture was defined as a suspected intrinsic biliary stricture of unknown entity (benign or malignant) based on prior MRCP imaging. The study design was a prospective, international, multicenter, randomized controlled trial. This was an investigator-initiated study. The study was approved by the Institutional Review Board (IRB) at each site and was registered (clinicaltrials.gov NCT03140007). All investigators agreed on the study protocol and could only access data from their own study center. All proceduralists were highly experienced operators performing over 200 ERCPs and over 30 SpyGlassDS per year. All authors reviewed the final manuscript.
Participants
Inclusion Criteria 1. Age 18 or older. 2. Willing and able to comply with the study procedures and provide written informed consent to participate in the study. 3. Biliary obstructive symptoms. 4. Indeterminate biliary stricture suspected to be intrinsic and proximal to the distal common bile duct (CBD) based on prior MRCP.
6
Exclusion Criteria 1. Contraindications to endoscopic intervention (coagulopathy, ASA 4 or greater, pregnancy). 2. Prior ERCP with TPB for assessment of indeterminate biliary stricture. 3. Extrabiliary compression identified on prior noninvasive imaging and thought to be the cause of the biliary obstructive symptoms. 4. Age less than 18.
A local multidisciplinary team made up of experienced radiologists, surgeons, and endoscopists assessed the indication for endoscopic evaluation of the indeterminate biliary stricture. All imaging studies were reviewed by a dedicated hepatobiliary-certified radiologist. Treatment strategies were standardized across sites. Suspected intrinsic biliary strictures except distal CBD strictures were included. This was in order to exclude patients with extrinsic biliary obstruction from a pancreatic mass. According to the MRCP, strictures were classified based on the Bismuth-Corlette Classification (Figure 1)19,20. Patients were invited to participate in the study if they were eligible based on inclusion and exclusion criteria. Consecutive patients referred for assessment and management of their indeterminate biliary stricture were screened for inclusion. Informed consent was obtained from all patients and documented before enrollment and randomization. Before the procedure, relevant demographic information and patient medical history was recorded. Data were collected and stored securely by a local study nurse at each participating center in written form. It was subsequently sent to a central and secure, anonymous online database as a case report file (CRF).
Procedure •
Patients in the control arm (CA) underwent an ERCP with cholangiography. Cholangiography-based impression of malignancy (yes/no/indeterminate) was recorded. ERCP-guided brushing was performed with a minimum of 9 passes. The samples were fixed on a slide and sent off for cytological analysis. The brushes used for this study were RX Cytology Brush 2.1mmx8FR (Boston 7
Scientific Corporation, Marlboro, Mass, USA) or 3-mm/6F-8F Cytomax II Double Lumen Cytology Brush (CookMedical). •
Patients in the Study Arm (SA) underwent a DSOC (SpyGlassDS, Boston Scientific Corporation, Marlboro, Mass, USA) cholangioscopic evaluation without cholangiography. DSOC-based impression of malignancy (yes/no/indeterminate) were recorded. A minimum of 3 DSOC-guided biopsies were required to be counted as adequate. Biopsy specimens were taken with a purpose-designed biopsy forceps that can be passed through the DSOC miniscope (SpyBite, Boston Scientific Corporation, Marlboro, Mass, USA) and sent off for histopathological analysis in a jar. Representative images can be found in Figure 2.
Histopathological or cytological assessment was performed by a histopathologist with expertise in biliary histopathology at each center. The pathologist was blinded to the randomization status of the study participants. Procedural adverse events were documented, including severity and seriousness of the events, time of onset and resolution, and outcome of the events. All patients underwent a follow-up 30 days after the index procedure with a visit and/or a telephone call. Follow-up ended 6 months after the index procedure or confirmation of malignancy, whichever came first. All equipment was used on label.
Outcomes •
Primary endpoint o Diagnostic accuracy of cholangioscopy or cholangiography was assessed at 6 months after the initial ERCP procedure. Malignancy was determined by cytology or histology on tissue sampling during the index or subsequent ERCP procedure, or surgical specimen histopathology up to 6 months after the index procedure. The assessed stricture was considered benign if malignancy was not confirmed by 6 months after the index procedure. 8
Diagnostic accuracy of only the first procedure was compared between the groups, because subsequent information was not easily comparable. •
Secondary endpoints o Correlation between intraprocedural visual impression of malignancy and cytopathology in the CA and SA. Visual Impression consistently based on previous described criteria (mass, dilated tortuous vessels, papillary or villous projections, intraductal nodules) and documented as suspected malignant or benign lesion17. o Technical success of the procedure, which was defined as the ability to collect tissue deemed adequate for cytological or histological analysis as per the pathologist. o The yield of tissue acquisition, which was defined as benign or malignant cytology or histology results from ERCP-guided brushing and cholangioscopy-guided SpyBite biopsies. o The occurrence and severity of procedure related serious adverse events from index procedure through 30 days after procedure (hospitalization and ICU admissions).
If patients had an initial benign histopathology, but the visual impression of the proceduralist was suspicious for malignancy patients would be rescheduled for a prompt reevaluation with an additional tissue sampling. If the first histopathology was indeterminate, regardless of the visual impression a prompt reevaluation with an additional tissue sampling was scheduled. In these cases, any type of procedure was applicable, as it would be ethically incorrect for patients to stay only in one of the arms and not using all possible procedures to get histopathology. Procedural parameters such as procedure duration (duodenoscope in to duodenoscope out) and number of procedures were recorded in both arms. Change in preprocedural patient management as a result of ERCP cholangiography or DSOC was also recorded (impact of visual impression).
9
Randomization Patients were randomized into 2 groups: • Control/ERCP arm: ERCP impression and ERCP-guided brushing • Study/cholangioscopy arm: DSOC impression and DSOC-guided biopsy Patients were randomized in a 1:1 ratio. Randomization was conducted using study envelopes provided to each center. The randomization scheme was followed by-site block-randomization and was prepared by a statistician. Participants and endoscopist were blinded to randomization until the study nurse opened the envelope revealing the allocated group before commencing the procedure.
Statistics We tested the hypothesis that cholangioscopy-guided biopsy would have a higher sensitivity than ERCP-guided brushing. We assumed that ERCP-guided brushing would have 48% sensitivity and that cholangioscopic-guided biopsy would have 82% sensitivity. We powered the hypothesis at 80%, with a 2-sided alpha of 0.05, using an asymptotic test the number of patients required was 54. We added 10% attrition for possible loss to follow-up and drop outs to get a total sample size of 60. Continuous data was analyzed using median with IQR, differences between the groups were analyzed using a Mann-Whitney U test. However, because the number of procedures is a count variable, it was reported with mean and standard deviation and was tested using a negative binomial model. Binary variables were analyzed using frequencies and differences were tested using asymptotic methods, except for the correlation between visualization and biopsy, which was calculated using the Fisher exact test. P value <0.05 was considered significant, and all analyses and sample size calculations were performed using SAS version 9.4 (SAS Institute, Inc, Cary, NC, USA). Diagnostic accuracy was derived from the following components: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy (OA).
10
Results: Sixty-one patients in 3 tertiary referral centers were consecutively screened and enrolled from May 2017 to December 2018. The study was ended after reaching the primary endpoint and ended at 6 months follow-up of the last enrolled patient. Thirty-two were randomized to SA and 29 to CA. One patient in the SA was excluded from all analyses because they withdrew their consent before the procedure being performed. The flow of participants is demonstrated in Figure 3. Demographic and baseline characteristics were equally distributed in both arms (Table 1). In the SA one patient was excluded due to confirmation of extrinsic biliary compression after undergoing DSOC. This left 30 patients for primary endpoint analysis, of which 22 patients had a malignant final diagnosis and 8 patients had a benign final diagnosis. In the CA, one patient was excluded due to inability to reach the duodenum because of an obstructing esophageal cancer as well as another patient in whom brushings were not performed after removal of an obstructing CBD stone. This left 27 patients for primary endpoint analysis, of which 14 patients had a malignant final diagnosis and 13 patients had a benign final diagnosis. In the CA, 44.8% (13/29) completed the study without malignancy and 48.2% (14/29) with malignancy. In the SA, 25% (8/32) completed the study without malignancy and 68.8% (22/32) with malignancy (Figure 3).
The vast majority of patients received preinterventional antibiotics (CA 86.2% vs SA 96.8%; P=0.14). Most patients underwent a sphincterotomy (CA 69% vs SA 74.2%; P=0.64) and stent placement (CA 81.5% vs SA 77.4%; P=0.7) without significant difference in the 2 arms. The mean number of procedures to get a final diagnosis was 1.16 for CA and 1.18 in the SA (1.17 overall, P=0.95). Median duration of the procedure showed no significant difference in both arms (CA 30 (IQR 20-87) mins vs SA 50 (IQR 2673) mins; P=0.2) (Table 2).
Diagnostic Accuracy of Histopathology
11
Tissue samples could be obtained in all cases at first evaluation. In the SA one sample was inadequate for histological analysis (1/31) resulting in a yield for DSOC of 30 out of 31 (96.8%). In this case, biopsies were inadequate because only 2 biopsies were performed as the lesion seemed to be pulsating on DSOC imaging. On average 6 biopsy specimens were taken (2.0-8.0). In the CA, brushings were adequate for cytological analysis in all patients. In one participant in the CA, the proceduralist suspected a stone as a reason for the stricture with no wire passage being possible. In this case DSOC was used and visualized a stone which was not seen on prior imaging and successfully treated with DSOC-guided electrohydraulic lithotripsy. No brushings were performed in this case. Sensitivity of DSOC-guided biopsies were significantly higher than ERCP-guided brushing (SA 68.2% vs CA 21.4%, P<0.01)). All other parameters such as specificity, PPV, NPV and OA showed no significant difference (Table 3). Table 4 demonstrates the diagnostic parameters when benign and indeterminate tissue samples were combined. The main difference is that in this scenario of malignant versus nonmalignant distinction the specificity of both TPB and DSOC increases to 100%.
Impact of visual impression All lesions in the SA could be visualized. In approximately half of the cases in both arms the visual impression had an impact on the patient management (CA 50% vs SA 56.7%; P=0.62). The sensitivity (SA 95.5% vs CA 66.7%; P=0.02) and OA (SA 87.1% vs CA 65.5%, P=0.05) were significantly higher in the SA compared with the CA whereas specificity, PPV, and NPV showed no significant difference (Table 5). In the SA a significant correlation between visualization and biopsy could be shown (p=0.02) (Table 6).
Adverse Events No severe adverse events (AEs) could be documented. Mild adverse events occurred in 3 patients in the CA (1 cholangitis, 1 cholecystitis and 1 bleeding) and in 2 patients in the SA (2 pancreatitis). All AE could be treated conservatively with full recovery of the patients (Table 7). 12
Discussion:
Our study found that compared with standard ERCP-based tissue acquisition DSOCguided evaluation had a higher sensitivity in the histological diagnosis of indeterminate biliary strictures. Furthermore, DSOC-based visual impression of the indeterminate biliary stricture provided a higher diagnostic accuracy, sensitivity and positive predictive value compared with conventional ERCP cholangiography without a difference in adverse events.
Accurate diagnosis of indeterminate biliary strictures is of paramount importance due to a potentially vastly different prognosis based on etiology. Because the diagnostic accuracy of conventional ERCP-based tissue acquisition (brushing and/or biopsy) has been suboptimal, DSOC has emerged as a logical innovation that could have a role in the diagnosis of indeterminate biliary strictures. Our results confirm that DSOC is technically successful and safe for biliary visualization and collection of histopathology.
Compared with the current standard of care in most endoscopy units using brushing cytology, DSOC directed biopsies could improve diagnostic sensitivity significantly. In our study the sensitivity with DSOC was 68% compared with 21% with ERCP-guided brushing. A reason for the very low sensitivity of brushing in the CA can be explained through the intrinsic entity of the lesions. Cholangiocarcinomas have a prominent desmoplastic and hypervascularized stroma. This pathophysiology is likely the reason why nontargeted brushing of strictures is ineffective in those particular cases and highlights the potentially low ERCP-based tissue acquisition sensitivity in a prospective real-life study environment. Although the DSOC-guided sensitivity is higher, it is still somewhat limited and may account for a similar number of procedures needed to confirm malignancy compared with conventional ERCP. The slight imbalance in final diagnosis with a greater proportion of malignancy in the study arm may also have contributed to this. The impact of the size of the DSOC-guided biopsy forceps is currently unknown. It is conceivable that larger forceps could further improve histological diagnostic accuracy due 13
to a more suitable tissue sample with the benefit of direct visualization. Mean number of procedures to get final diagnosis showed no significant difference in both arms. The reason for this lies in the nature of the disease. In some cases, the patients either died from their cholangiocarcinoma or went into palliative care after the first procedure. This may have reduced the number of procedures to reach the final diagnosis in the ERCP arm significantly.
A significant advantage of DSOC is the ability to directly visualize the biliary tree and stricture. This is important as it gives the experienced endoscopist further information about the stricture which has an impact on patient management such as planning further investigation despite negative or indeterminate histopathology results. In fact, one case was only clarified after visualizing the stricture using DSOC and finding an impacted stone as the reason for the obstruction. Despite DSOC being potentially a technically more challenging procedure, biliary visualization was successful in almost all DSOC cases with no statistical difference compared with standard ERCP. As described in other publications we could reproduce a very high sensitivity and overall accuracy for the diagnosis of malignant strictures using DSOC. Direct visual impression may be convincing enough to result in surgical treatment even without definitive histopathology in select cases, such as surgically fit patients with indeterminate biliary strictures from potentially resectable tumors.
Based on the results of our study, it appears combining the direct cholangioscopic visual impression with DSOC-guided biopsies provides the highest chance of confirming malignancy in indeterminate biliary strictures. In both groups, visual impression on its own accord made a difference to patient management in at least half of the cohort. It demonstrates that this is an essential component of the diagnostic process and supplements histological acquisition.
To our knowledge this is the first randomized controlled trial that evaluates DSOC in comparison to conventional ERCP for indeterminate biliary strictures. Strengths include 14
the randomized, prospective nature of the study, 3 international study sites, a defined cohort with a structured follow-up and the detailed analysis of visual and histopathological aspects of the procedure.
Our study had several limitations. Even though comparing 60 patients meeting strict inclusion and exclusion criteria for a diagnosis of indeterminate biliary stricture seems to be an adequate number to test the a priori hypothesis set forth in this study absolute number of patients were small. The number of participants in each cohort was slightly imbalanced, particularly in regard to containing a diagnosis of malignancy. We believe this would be rebalanced in larger cohorts, but in this study may have affected the results. In addition, histopathological/cytological analysis was not centrally assessed or compared between the sites. Findings of the study may not be generalizable as procedures were performed by experienced expert endoscopists in tertiary referral centers. Although ESGE guidelines recommend that indeterminate strictures are assessed and managed in tertiary referral centers, especially when DSOC is indicated, it is unclear whether similar results would be found if less-experienced endoscopists performed these procedures21. We did not perform a cost effectiveness analysis in this particular study because it was out of the scope of the primary objective. Purchasing a DSOC device is an additional cost to standard ERCP. Evaluating the cost effectiveness analysis of DSOC and conventional ERCP for indeterminate biliary strictures would be a relevant separate study, but is maybe challenging due to different healthcare settings and true costs of interventions like surgery.
In conclusion, DSOC was shown to be safe and effective with a higher diagnostic sensitivity compared with standard ERCP and brushing for the diagnosis of indeterminate biliary strictures. The visual impression was shown to have a pertinent impact on patient management and should be an essential part of determining the correct diagnosis. DSOC should be considered as a viable diagnostic alternative to conventional ERCP for indeterminate biliary strictures with the potential to change patient management. Further 15
innovations in cholangioscopic characterisation of strictures, image quality and histological acquisition devices are desirable and are likely to advance our understanding in this field even further.
16
Tables and Figures
Table 1 Patient demographics and baseline characteristics on treated analysis set
Age Male Bismuth Classification I II IIIa IIIb IV V Other
TPB group (N=29 (N=29) 29) 65 (57-74) 65.5% (19/29)
DSOC group (N=3 (N=31) 62 (54-79) 54.8% (17/31)
P value 0.93 0.40 0.79
37.9% (11/29) 17.2% (5/29) 13.8% (4/29) 13.8% (4/29) 13.8% (4/29) 0.0% (0/29) 3.4% (1/29)
29.0% (9/31) 19.4% (6/31) 12.9% (4/31) 9.7% (3/31) 12.9% (4/31) 3.2% (1/31) 12.9% (4/31)
17
Table 2 General procedure characteristics
Prei Preinterventional antibiotics Number of days Location of dominant target lesion IHBD Right main Left main Hilar CHD CBD Ampullary/sphinteric Diffuse/multiple locations Sphincterotomy performed Stent placed Plastic stent UC SEMS PC SEMS FC SEMS Duration of procedure (mins)
TPB group (N=29 (N=29) 29) 86.2% (25/29) 2 (1-3)
DSOC group (N=3 (N=31) 96.8% (30/31) 1 (1-2)
P value 0.14 0.61 0.57
0.0% (0/29) 10.3% (3/29) 3.4% (1/29) 27.6% (8/29) 0.0% (0/29) 55.2% (16/29) 0.0% (0/29) 3.4% (1/29) 69.0% (20/29) 81.5% (22/27) 95.5% (21/22) 0.0% (0/22) 0.0% (0/22) 4.5% (1/22) 30 (20-87)
18
6.5% (2/31) 12.9% (4/31) 6.5% (2/31) 29.0% (9/31) 3.2% (1/31) 41.9% (13/31) 0.0% (0/31) 0.0% (0/31) 74.2% (23/31) 77.4% (24/31) 91.7% (22/24) 4.2% (1/24) 0.0% (0/24) 4.2% (1/24) 50 (26-73)
0.65 0.70
0.20
Table 3 Diagnostic accuracy of ERCP brushing (TPB) versus ersus DSOC biopsy on first sample Lesion Final diagnosis diagnosis based based Malignant Benign on ERCP brush
Lesion diagnosis based on DSOC biopsy
Malignant
3
0
Benign
6
Indeterminate
5
Measure Sensitivity Specificity Positive predictive value Negative predictive value Overall accuracy
Final diagnosis Malignant
Benign
Malignant
15
0
11
Benign
6
5
2
Indeterminate
1
3
TPB group 21.4% (3/14) 84.6% (11/13)
DSOC group 68.2% (15/22) 62.5% (5/8)
P value
100.0% (3/3)
100.0% (15/15)
0.99
64.7% (11/17)
45.5% (5/11)
0.31
51.9% (14/27)
66.7% (20/30)
0.25
<.01 0.25
Table 4 Diagnostic accuracy of ERCP brushing (TPB) versu versus ersus DSOC biopsy on first sample (malignant versus versus nonmalignant classification)
Lesion diagnosis based on ERCP brush
Final diagnosis Malignant
Benign
Malignant
3
0
Benign
11
13
Measure Sensitivity Specificity Positive Predictive Value Negative Predictive Value Overall Accuracy
Lesion diagnosis based on DSOC biopsy
ERCP group (N=29) 21.4% (3/14) 100.0% (13/13) 100.0% (3/3) 54.2% (13/24) 59.3% (16/27)
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Final diagnosis Malignant
Benign
Malignant
15
0
Benign
7
8
DSOC group (N=32) 68.2% (15/22) 100.0% (8/8) 100.0% (15/15) 53.3% (8/15) 76.7% (23/30)
P value <.01 0.99 0.99 0.96 0.16
Table 5 Diagnostic accuracy of ERCP visual impression versus ersus DSOC visual impression Measure Sensitivity Specificity Positive predictive value Negative predictive value Overall accuracy
P
TPB group
DSOC group
66.7% (10/15) 64.3% (9/14)
95.5% (21/22) 66.7% (6/9)
value 0.02 0.91
90.9% (10/11)
100.0% (21/21)
0.16
75.0% (9/12)
85.7% (6/7)
0.58
65.5% (19/29)
87.1% (27/31)
0.05
20
Table 6 Relationship of DSOC visual impression and DSOCDSOC-guided biopsy
DSOC Visualization
DSOCDSOC-directed biopsy Malignant Benign Indeterminate
Malignant
14
6
1
Benign
1
3
2
Indeterminate
0
2
1
Table 7 Adverse events
TPB Group
DSOC Group
10.3% (3/29)
6.5% (2/31)
Cholangitis
3.4% (1/29)
0.0% (0/31)
Cholecystitis
3.4% (1/29)
0.0% (0/31)
Pancreatitis
0.0% (0/29)
6.5% (2/31)
Bleeding
3.4% (1/29)
0.0% (0/31)
Overall
21
P value 0.59 0.30 0.30 0.16 0.30
Figure Legends Figure 1: Bismuth-Corlette Classification Figure 2: Top, MRCP of indeterminate biliary stricture, Middle, DSOC pictures showing a stricture with irregular papillogranular surface, luminal contents (mass), irregular, and tortious vessels. Bottom, histopathology with tumor cells Figure 3: Patient flowchart
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Acronymes and Abbreviations In order of appearance: SOC: single-operator-cholangioscopy ERCP: endoscopic retrograde cholangiopancraticography CA: control arm SA: study arm TPB: Trans papillary biopsy and/or brushing IRB: Institutional Review Board CBD: common bile duct ASA: American society of anesthesiology classification HPB: hepatobiliary MRCP: magnetic -resonance-cholangiopancreaticography CRF: case report file ICU: intensive care unit CI: confidence interval IQR: interquartile range PPV: positive predictive value NPV: negative predictive value OA: overall accuracy AE: adverse events ESGE: European society of gastrointestinal endoscopy