Endoscopic Ultrasound (EUS)-Guided Fine Needle Aspiration (FNA) With Rapid On-site Evaluation (ROSE) of Cytopathology vs. EUS-guided Fine Needle Biopsy (FNB) Alone in the Diagnosis of Pancreatic Solid Lesions: a Randomized Controlled Trial
Phase: NA
Conditions: Solid Pancreatic Tumor
Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre

 
Cover letter 
 
 
 
Study title:  
EUS-guided FNA with rapid on-site evaluation (ROSE) 
of cytopathology vs. EUS-guided FNB alone in the 
diagnosis of pancreatic solid lesions: a randomized 
controlled trial 
 
 
Date of the document: 3rd of Feb 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

EUS-guided FNA with rapid on-site evaluation (ROSE) of cytopathology vs. EUS-
guided FNB alone in the diagnosis of pancreatic solid lesions: a randomized 
controlled trial 
 
 
Principal Investigator: 
 
Yen-I Chen, MD 
Assistant Professor of Medicine, Division of Gastroenterology and Hepatology 
McGill University Health Center, McGill University, Montreal, QC, Canada 
Email: yen-i.chen@mail.mcgill.ca 
Tel: 514-291-3154 
 
Co-investigators: 
 
Alan Barkun, MD1 
George Zogopoulos, MD2 
Jeffrey Mosko, MD3 
Kevin Waschke, MD1 
Josee Parent, MD1 
Jonathan Wyse, MD4 
Manon Auger, MD5 
Yonca Kanber, MD5 
Christopher Teshima, MD3  
 
1) Division of Gastroenterology and Hepatology, McGill University Health Center, 
McGill University, Montreal, QC, Canada 
2) Department of surgery, McGill University Health Center, McGill University, 
Montreal, QC, Canada 
3) Division of Gastroenterology and Hepatology, St-Michael’s Hospital, University of 
Toronto, Toronto, ON,CA 
4) Division of Gastrotenterology and Hepatology, Jewish General Hospital, McGill 
University, Montreal, QC, Canada 
5) Department of pathology, McGill University Health Center, McGill University, 
Montreal, QC, Canada 
 
Coordinating Center: 
Division of Gastroenterology and Hepatology, McGill University Health Center 
1001 Decarie Blvd 
Montreal, QC, Canada 
yen-i.chen@mail.mcgill.ca 
 
 
 
 
 

 
Background: 
 
EUS-guided tissue acquisition of pancreatic masses is the main modality for the diagnosis 
of pancreatic solid tumors including adenocarcinoma and neuroendocrine tumor. 
Traditionally, this is done through sampling with fine needle aspiration (FNA); however, 
this approach has led to variable diagnostic yield with approximately 20% of the samples 
being non-diagnostic1-3 needing repeat procedures. Several tertiary centers worldwide 
have adopted rapid on-site evaluation (ROSE) of cytopathology, where a cytopathologist 
is at the bedside of the procedure and looking at each samples in real-time to give 
feedback to the endoscopists in terms of adequacy and preliminary diagnosis of their 
EUS-guided FNA. ROSE has been shown to increase the diagnostic yield by 10 to 15%1 
4. Although currently unavailable at most Canadian sites, hospitals have been 
contemplating the implementation of ROSE in hopes of improving care for patients with 
pancreatic cancer and to prevent the need for repeat procedures and its associated costs 
and potential adverse events. Recently, however, novel core biopsy needles have been 
developed for fine needle biopsy (FNB) and histological assessment5. These needles 
allow for the acquisition of core samples with intact tissue architecture enabling 
immunohistochemical staining thereby enhancing the diagnostic yield. Although some 
studies suggest that FNB alone may be just as effective as FNA with ROSE, there are no 
comparative outcomes trials.  As such, the goal of our study is to compare EUS-FNB 
with core needle sampling alone vs. EUS-FNA with ROSE in pancreatic solid lesions. If 
shown to be equivalent, FNB could potentially obviate the need for ROSE and be 
implemented in a more readily and affordable fashion across Canada. 
 
Objectives: 
 
Aim: To compare the diagnostic accuracy of EUS-FNB alone vs. EUS-FNA with ROSE 
in patients with solid pancreatic masses suspected to be of malignant origin. 
 
Hypothesis: EUS-FNB is non-inferior to EUS-FNA with ROSE in the diagnostic 
accuracy for solid pancreatic masses while being associated with fewer needle passes and 
shorter procedure time.    
 
Primary outcomes 
 
• Diagnostic accuracy defined as (true positive + true negative)/all samples 
• Final diagnosis will be based on the following criteria 
A) Final diagnosis of malignancy (one of the following):  
• histological evidence of malignancy on the corresponding subsequent surgical 
specimen  
• presence of an unresectable lesion during subsequent surgery  
• malignant cytology/pathology on EUS-sampling followed by documented loco-
regional progression/development of metastases on follow-up axial imaging.  
B) Final diagnosis of benign pancreatic mass (one of the following):  
• surgical pathology or exploration showing the absence of malignancy  

• follow-up imaging at > 6 months reporting stability of the pancreatic lesion   
• cytological or histopathological diagnosis of benign disease with an appropriate 
clinical course of disease for minimum of 6 months 
 
Secondary Outcomes 
• Diagnostic characteristics: sensitivity, specificity, positive and negative predictive 
value 
• Specimen adequacy: defined as the proportion of samples in which a final 
histopathological diagnosis could be made 
• Median number of needle passes, procedural time  
• Rate of procedure-related adverse events with severity graded as per the ASGE 
lexicon6  
• Cost-effectiveness  
 
Methods: 
 
EUS procedure : 
Procedures are performed with a linear echoendoscope under conscious sedation. EUS-
FNB is performed with a 22 gauge Core-needle. Tissue sampling technique is 
standardized between the endoscopists.  Two passes are performed using the core needle. 
The biopsied samples are then expressed using a stylet into a jar filled with 10% 
formalin. A third pass is allowed if, on macroscopic inspection of the acquired sample, 
the specimen is deemed insufficient by the endoscopist.  EUS-FNA with ROSE is 
performed with a 22 gauge FNA needle. The sampled specimen is expressed into a glass 
slide with a stylet; then using another glass slide the sample is spread out to make smears 
on two slides. Each pair of slides is then numbered according to their respective needle 
passes. One slide is air dried and stained with modified Giemsa stain for ROSE, while the 
other slide is fixed in 95% ethanol and later coated with with Pananicolaou stain.  
 
This is a multi-center, randomized, single blinded, non-inferiority, trial comparing EUS-
FNB alone to EUS-FNA with ROSE in the diagnosis of solid pancreatic masses.  
Following consent, patients are randomized, at the time of the procedure, to undergo 
either EUS-FNB alone or EUS-FNA with ROSE. The randomization sequence will be 
generated by a computerized randomization scheme using a block size of 10 stratified 
according to the endoscopist.  
   
Inclusion Criteria:  
1. Age > 18 years   
2. Patients referred for EUS evaluation of a definite solid pancreatic mass noted on 
CT/MRI/EUS, in which malignancy is suspected with no previous histological 
diagnosis  
 
Exclusion Criteria: 1.  
1. Age < 18 years, pregnant patients   
2. Uncorrectable coagulopathy PT>50% of control, PTT>50 sec, or INR>1.5 and/or 
uncorrectable thrombocytopenia platelet count<50, 000109/L. 

 
Feasibility:  The primary analysis is a noninferiority comparison of EUS-FNB vs. EUS-
FNA with ROSE in terms of diagnostic accuracy, which, according to the most recent 
literature, is approximately 90% for both modalities. The margin of noninferiority is set 
at 10% in accordance with the USFDA recommendations.  To achieve a statistical power 
of 80% with a two-sided type I error of 5%, a total of 224 patients (112 per group) is 
needed.  Assuming a 5% dropout rate, a final sample size of 236 (118 per group) is 
estimated. The study is anticipated to take 2 years to complete. 
 
Analysis:  An intention-to-treat analysis will be carried out. The noninferiority hypothesis 
for the primary outcome will be assessed using the Z-test with a 95% two-sided 
confidence interval of the difference in the diagnostic accuracy and the margin of 
noninferiority. Interim analysis is planned after 50% of the cohort is recruited.  If a > 
20% difference in sensitivity is found between both methods then the study will be 
terminated early.  Exploratory imaging and patient predictors of a diagnostic sampling is 
carried out using standard multivariable logistic regression analysis. 
 
Cost-effectiveness: 
A decision tree will be created for the two possible sampling approaches. Probability 
assumptions will be extracted from the RCT. Costs will be determined from the RAMQ.  
Third-party costs related to the procedure and downstream management costs will be 
determined based on the RCT resource utilization data. Deterministic and probabilistic 
sensitivity analyses will be undertaken. 
 
Patient follow-up: 
Patients will be contacted by telephone interview at 48-72 hours post procedure to ensure 
that no adverse events have occurred. All other follow-up will be standard of care and at 
the discretion of the treating physician. 
 
Anticipated results: 
We anticipate that the results will show that EUS-FNB alone will be non-inferior to EUS-
FNA with ROSE in the diagnostic accuracy of solid pancreatic masses. We also expect 
that both modalities will have similar diagnostic characteristics such as sensitivity, 
specificity, and positive and negative predictive value. Finally, the use of EUS-FNB will 
likely be associated with fewer needle passes, shorter procedure time, and be more cost-
effective.  
 
If our data is consistent with the anticipated results then it would have a large impact on 
improving diagnostic yield of EUS tissue acquisition in pancreatic mass and potentially 
obviate the need for on-site cytopathology at a time where centers across Canada are 
contemplating the addition of this effective but expensive and resource intensive 
modality. 
 
MULTICENTER GUIDELINES 
 
Protocol Chair 
 
The Protocol Chair is responsible for performing the following tasks: 

• Coordinating, developing, submitting, and obtaining approval for the protocol 
as well as its subsequent amendments 
• Assuring that all participating institutions are using the correct version of the 
protocol. 
• Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study. 
• Reviewing and ensuring reporting of Serious Adverse Events (SAE) 
• Reviewing data from all sites 
 
Coordinating Center 
 
The Coordinating Center is responsible for performing the following tasks: 
• Ensuring that REB approval has been obtained at each participating site prior 
to the first patient registration at that site, and maintaining copies of REB 
approvals from each site. 
• Managing central patient registration. 
• Collecting and compiling data from each site. 
• Establishing procedures for documentation, reporting, and submitting of AE’s 
and SAE’s to the Protocol Chair, and all applicable parties. 
• Facilitating audits by securing selected source documents and research records 
from participating sites for audit, or by auditing at participating sites. 
 
Participating Sites 
 
Participating sites are responsible for performing the following tasks: 
• Following the protocol as written 
• Submitting data to the Coordinating Center. 
• Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the 
protocol. 
• Maintaining regulatory binders on site and providing copies of all required 
documents to the Coordinating Center. 
• Collecting and submitting data according to the schedule specified by the 
protocol. 
 
ANTICIPATED RISKS 
 
We do not anticipate major risk or discomfort beyond that associated with the 
conventional procedure. Both EUS-FNA with ROSE and FNB alone are part of standard 
or care. The following are conventional risks associated with EUS-FNA or FNB. 
1) Perforation: Only physicians specially trained in EUS will be performing 
these procedures. The exact risk is minimal (<1%). 
2) Infection: It is not standard practice to give antibiotics to all patients 
prophylactically for either percutaneous liver biopsy or EUS-FNA of non-
cystic lesions. Therefore, no subjects will receive antibiotics prophylactically 
for EUS sampling except those patients at risk for infective endocarditis 
according to American Heart Association guidelines. 
3) Bleeding: The exact risk is minimal (1 in 5,000 chance). Doppler 
examination will be performed under EUS guidance prior to biopsy to ensure 
that the needle does not traverse a blood vessel. As a precautionary measure, 

furthermore, all patients will have PTT, PT/INR, hemoglobin, and platelet 
count checked prior to the procedure. Those below acceptable standards will 
not be offered inclusion into the study. Frequent vital signs will be measured 
and recorded. If vital signs are abnormal and prolonged, a repeat CBC and 
possibly CT scan will be performed after procedure to ensure the absence of 
internal or external hemorrhage. These measures should ensure any clinically 
significant hemorrhage is detected and treated in a timely manner.   
4) Pancreatitis (risk: 1%): Will be detected by the presence of pain with or 
without nausea and vomiting after pancreatic biopsy. If present, the patient 
will be hospitalized, kept NPO, and receive IV hydration. 
 
a. Steps taken to minimize the risks. 
Adherence to the standard of practice of EUS-guided tissue sampling at the 
McGill University Health Center as outlined above  
 
b. Financial risks to the participants. 
None. 
 
 
 
ADVERSE EVENT REPORTING 
 
Definition of Adverse Event (AE) 
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to 
a procedure done, whether or not considered causally related to the procedure.  
An undesirable medical condition can be symptoms (e.g., nausea, chest pain), 
signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation 
(e.g., laboratory findings, electrocardiogram).   
Definition of Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during the procedure or any time after 
the procedure, that fulfills one or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing 
hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the patient or may 
require medical intervention to prevent one of the outcomes listed above 
 
Coordinating Center 
The Coordinating Center is the central location for the collection and maintenance 
of documentation of adverse events and is responsible for submitting adverse 
event reports to the REB promptly.  The Coordinating Center will maintain 
documentation of all adverse event reports for each participating site.  Adverse 
event reports submitted to the Coordinating Center must be signed and dated by 

the participating site’s Principal Investigator.  The Coordinating Center will 
provide appropriate forms to be used by all participating sites for reporting 
adverse events.  Information to be provided must include: 
• Subject ID number, and initials 
• Date of the event 
• Description of the event 
• Description of site's response to the event 
• Assessment of the subject's condition 
• Subject's status on the study (on study, off study, etc.) 
Participating Sites 
Participating sites are responsible for reporting adverse events to their REB 
according to its specific requirements and to the Coordinating Center as follows: 
Fatal Events whether anticipated or unanticipated, and whether or not related 
to the study must be reported to the Coordinating Center within 24 hours of 
the participating site Principal Investigator's learning of the event. 
 
Serious and Unanticipated Adverse Events must be reported  
to the Coordinating Center within 24 hours of the participating site Principal 
Investigator's learning of the event.  
 
Other Serious Adverse Events which may result in a change to the protocol, 
informed consent, or risk to subjects as specified in the protocol must be 
reported within three (3) working days of the participating site Principal 
Investigator's learning of the event.  
 
Adverse events which result in no change to protocol, informed consent, or 
risk to subjects must be reported to the Coordinating Center on a monthly 
basis.  
 
All SAEs must be collected whether or not they are considered causally related to 
the investigational procedure.  Investigators and other site personnel are 
responsible for reporting all casually related SAEs to their REB and the 
coordinating center. 
 
 
 
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