EUS-FNB With ROSE Vs. EUS-FNB Without ROSE

Since its initial report in 1992, endoscopic ultrasound-guided fine needle aspiration
(EUS-FNA) has become an increasingly important tool for the evaluation of lesions of the
gastro-intestinal tract and of adjacent organs. The diagnostic accuracy of EUS-FNA ranges
from 60% to 90% according to the site of investigation and it is especially low for neoplasms
such as stromal tumors, lymphomas, and well-differentiated adenocarcinomas that are difficult
to be diagnosed by cytology alone. Moreover, the accuracy of EUS-FNA strongly relies on rapid
on-site evaluation (ROSE) of the adequacy of the collected specimens by a cytopathologist or
a cytotechnician, who can also help in establishing the need for additional samples to
perform ancillary studies that are required in some cases to reach an effective diagnosis.

However, cytology requires a high degree of expertise rarely found outside high volume
tertiary care centers and ROSE is not available in many countries Both these needs have
created a barrier to the dissemination of EUS in the community and in many countries, because
the lack of cytological expertise has resulted in a low diagnostic accuracy and, therefore,
in a limited perceived utility of EUS.

Therefore, it would be of vital importance to have needles able to provide at the same time
material for ROSE and histological core biopsy specimens to allow for further analyses, i.e.
immunohistochemistry and molecular analysis. The availability of such needles would determine
the centers with an established ROSE service to continue to use it and would also increase
the chances that the patient will leave the service with a diagnosis and will have available
additional material, so much needed in difficult cases or, in the near future, necessary to
perform molecular studies in order to drive treatments. On the other hand in centers with no
ROSE availability, needles with an accuracy not inferior to the one obtainable with ROSE will
help overcome the limitations of cytology and ROSE and will facilitate the widespread
utilization of EUS in the community and throughout the world.

To answer this important question, the investigators propose to perform an international
multicenter randomized study with the aim of comparing EUS-FNB with ROSE versus EUS-FNB
without ROSE using three novel needles (the 20-gauge ProCoreTM, the 22-gauge SharkCoreTM and
the 22-gauge AcquireTM needle) in patients with solid pancreatic masses. These needles have
become recently available and preliminary results for both pancreatic and non-pancreatic
lesions are extremely encouraging Indeed, all these needles demonstrated a very high accuracy
rate (>92%). Each center involved in the present study must have at least 2 of the 3 needles
available. The non-inferiority design of the study will test the investigators hypothesis
that EUS-FNB, by providing adequate samples for histologic examination, will perform at least
as good as EUS-FNB with ROSE. The choice of the 20G ProCore ™, the 22G SharkCore™ or 22G
Acquire™, instead of the 25G or the 19G, balances the need to use a needle that acquires
enough tissue to perform all the studies needed to reach the definitive diagnosis, with its
usability, i.e. a needle that can be used by most, if not all the endosonographers and not
only by the experts. In this regards, the 25-gauge seems too small to gather enough tissue in
a consistent number of patients while the 19-gauge is less maneuverable and more difficult to
use thus preventing its utilization by all endosonographers.

This is an international randomized multicenter trial with two parallel arms in a (1:1)
ratio. Consecutive patients with solid pancreatic masses and an indication to perform
EUS-guided tissue acquisition will be evaluated and, if eligible, will be enrolled into the
study.Patients will be randomized in a 1:1 ratio, using random 10 patients block sizes for
allocation concealment between groups. An online randomization module will be made available
to the participating centers. Randomization will take place after the lesion will have been
visualized with EUS and the patient will be found suitable for inclusion. The choice of the
needle to be used will be at the discretion of each endosonographer and will be done before
randomization so that the choice of the needle does not create bias in the results. Nor the
endoscopist, neither the pathologist will be blinded to which needle will be used.

The sample size has been calculated in order to demonstrate the non-inferiority of EUS-FNB
without ROSE compared to EUS-FNB with ROSE in terms of diagnostic accuracy, having
established a clinically acceptable margin of non-inferiority of 5%. The reported diagnostic
accuracy of EUS-FNA with ROSE is 92%. With a type I error α of 5% and a power 1 - β of 80%,
the total required sample size amounts to 730 patients (one-sided hypothesis testing of
categorical data, comparing two binomial proportions of independent samples. Calculations
executed with PASS, version 14.0.3). Considering, than, a 9.5% of patients to add in order to
counteract the estimated rate of drop-out and lost to follow-up, 800 patients will be needed
on the whole that is 400 per group.

Inclusion Criteria:

- Solid pancreatic mass referred for EUS-guided tissue acquisition

- Lesion can be visualized with EUS and needle puncturing can be technically feasible

- Written informed consent.

Exclusion Criteria:

- Known bleeding disorder that cannot be sufficiently corrected with co-fact or fresh
frozen plasma (FFP)

- Use of anticoagulants that cannot be discontinued

- International Normalized Ratio (INR) >1.5 or platelet count <50.000

- Cystic lesions even with solid component

- Previous inclusion in other or present study

- Pregnancy