Trial Information

Endoscopic Ultrasound Guided Fine Needle Biopsy With a New Core Histology Needle Versus Conventional Fine Needle Aspiration.

Background:

Endoscopic ultrasound (EUS) is a well-established tool for the diagnosis and staging of many
gastrointestinal conditions, including but not limited to, malignant and pre-malignant
neoplasms of the pancreas, esophagus, rectum, and submucosal tumors developing along the
gastrointestinal tract. EUS provides endoscopic video imaging within the lumen of the
gastrointestinal tract combined with ultrasound images via a transducer positioned at the
tip of the endoscope. This diagnostic ability is enhanced by a biopsy method called fine
needle aspiration (FNA). FNA via EUS (EUS-FNA) enables a small needle to be passed into a
lesion of interest under ultrasound guidance, obtaining cellular material for cytology
analysis. EUS-FNA is currently recommended for the confirmation of locally advanced pancreas
adenocarcinoma, for the diagnosis of pancreatic cystic neoplasms and neuroendocrine tumors
as well as autoimmune pancreatitis, for the characterization of submucosal tumors of the GI
tract, and for the determination of malignant lymph node status in the staging of various
cancers.

While EUS-FNA has an impressive technical success rate between 90-95%, the diagnostic
accuracy is less robust for mass lesions, and in particular for pancreatic masses, for which
the sensitivity and specificity is 75% and 100% respectively, translating into a negative
predictive value of only 72%. And in the setting of chronic pancreatitis, a condition that
is itself a major risk factor for the development of cancer and in which focal,
non-malignant nodules often develop that may mimic tumors, the sensitivity of EUS-FNA may
only be 54-74%. The diagnostic accuracy of EUS-FNA is of particular importance for pancreas
adenocarcinoma and pancreatic neuroendocrine tumors because the 5-year survival rates are
only 5% and 32% respectively. Thus, it is crucial that patients found to have a focal mass
lesion have a reliable test that effectively excludes malignancy. Currently, EUS-FNA does
not have the necessary negative predictive value in order to do so because the sensitivity
of the test is too low. This means that a positive result on FNA confirms malignancy but
that a negative result is unable to exclude it with confidence. This conundrum tends to
leave the patient in the unfortunate position of having to often return for multiple
investigations to perform repeat EUS-FNA when the clinical suspicion for a mass lesion
remains high but the cytology result is thought to be falsely negative.

In order to overcome the current limitations of EUS-FNA cytology, the new EchoTip® ProCore™
fine needle biopsy (FNB) needle was developed in order obtain core tissue samples for both
histology and cytology. This is important because histology is expected to increase the
diagnostic yield of EUS-guided biopsy compared to cytology. In addition, in certain clinical
circumstances it is more desirable and sometimes necessary to obtain a core tissue biopsy
for histology rather than cellular material for cytology obtained with EUS-FNA.

In addition to the assessment of mass lesions in the pancreas, there are several other
clinical areas in which the acquisition of core tissue samples for histology may prove
superior to cytology from conventional EUS-FNA. For instance, EUS is part of the
standard-of-care for the staging of esophageal cancer and histology may improve the
sensitivity of EUS-biopsies for the determination of lymph node metastases. Also, although
EUS is the preferred method for the work-up of submucosal lesions in the gastrointestinal
tract, the value of EUS-FNA for differentiating the various subtypes of lesions is often
limited, typically because FNA provides insufficient cellular material to reliably do so.
Finally, it is clear that cytology from EUS-FNA is inadequate for the diagnosis of
autoimmune pancreatitis and that a core biopsy sample for histology is needed. We expect the
new EchoTip® ProCore™ FNB needle to potentially prove superior to FNA in all of these areas.

Study Objectives The purpose of this study is to determine if the new EchoTip® ProCore™
needle (FNB for histology) is superior to the current standard EchoTip® Ultra™ needle (FNA
for cytology) for the diagnosis of focal, solid lesions for which biopsy sampling during EUS
is clinically indicated. In particular, the objective is to compare the sampling adequacy of
FNB with that of FNA for solid mass lesions within the pancreas, for submucosal lesions in
the gastrointestinal tract and for the malignant status of lymph nodes as part of esophageal
cancer staging. The sampling adequacy will be determined according to the ability of the
pathologist to provide a definitive diagnostic interpretation based on the sample provided.

Study Design This is a prospective, comparative trial examining the use of the new EchoTip®
ProCore™ FNB needle with the existing EchoTip® Ultra™ FNA needle stratified by lesion type
(solid pancreas lesion, intra-abdominal mass, submucosal tumor, suspected metastatic lymph
node). Both the FNB and FNA needle will be used in each lesion with randomization to needle
type for first pass, alternating subsequent passes; thus each lesion will serve as its own
internal control.

Methods Consecutive patients referred for EUS assessment of a solid lesion requiring FNA
will be approached regarding study enrollment. Only those patients for whom EUS-FNA is
clinically necessary will be selected. Consenting patients will undergo the standard EUS
examination as indicated based on their lesion subtype, which will not differ from the EUS
exam they would receive if they choose to not participate. Participating patients who have a
lesion visualized during EUS that is technically amenable to FNA will then have their lesion
biopsied by both FNB and FNA needles. The choice of needle size (19g or 22g) will be left to
the clinical discretion of the endoscopist. However, the same needle size must be used for
both the FNB and FNA needles.

Patients will be randomized to the type of needle used for the first pass into the lesion,
with subsequent passes alternating between needle types. For the EchoTip® ProCore™ FNB
needle, if a good sample is obtained (as assessed by the endoscopist performing the EUS
examination) with the first pass, no further passes will be made. If the sample obtained
with the first pass is considered likely insufficient or if no tissue was acquired, a second
pass will then be performed. Regardless of what is obtained after the second needle pass, no
additional passes will be made using the FNB. The core tissue obtained by the FNB needle
will be placed in formalin and sent for histology analysis.

For the conventional EchoTip® Ultra™ FNA needle, a minimum of 2 passes will be performed. In
cases in which a cytotechnologist is present, no feedback will be given to the endoscopist
until after the 2nd pass. In cases where no cytotechnologist is present, up to 4 separate
passes will be made, or fewer if the endoscopist is satisfied with the sample obtained. The
sample obtained with the FNA needle will be placed on slides and also in cytology media
(according to our standard clinical protocols).

The histology and cytology specimens will be sent to the pathology department at each site
where the interpretation of samples will be done in the usual fashion as per standard
clinical care. The pathologist will first describe the biopsy specimen in terms of the
"adequacy of the sample for pathologist interpretation" - i.e. the ability of the
pathologist to provide a definitive diagnostic interpretation based on the sample provided.
Next, the pathologist will provide the diagnostic interpretation itself.