Interventional Endosonography

Surakit Pungpapong, Kyung W Noh, Massimo Raimondo
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine.
Jacksonville, Florida, USA
Endoscopic ultrasound (EUS) was initially
developed in the early 1980s as a research
tool to overcome limitations of
transabdominal ultrasound for an examination
of the pancreas caused by intervening gas,
bone, and fat. Since its introduction into
clinical practice, EUS has revolutionized the
diagnosis and treatment of gastrointestinal
disorders, particularly pancreatic cancer. The
ability to position the transducer in direct
proximity to the pancreas via the stomach and
proximal duodenum, combined with the use
of high-frequency ultrasound, provides
detailed high-resolution images of the
pancreas that are superior to those of
computerized tomography and trans-
abdominal ultrasound. The incorporation of
fine-needle aspiration (FNA) technique has
significantly improved the accuracy of cancer
staging and has encouraged a therapeutic
capability that may parallel the evolution of
endoscopic retrograde cholangiopancreato-
graphy (ERCP) from a diagnostic to a
therapeutic procedure. Injection with
therapeutic agents can also be accomplished
under EUS guidance leading to many
therapeutic techniques being developed for
the treatment of pancreatic cancer.
Pancreatic cancer is the fourth leading cause
of cancer-related deaths in the United States.
According to the American Cancer Society,
estimated 33,730 Americans will be
diagnosed with pancreatic cancer in 2006 [1].
The disease is associated with a high
mortality rate and the 5-year survival rate is
estimated to be only 4% with the median
survival of less than 6 months in untreated
patients [1]. Currently, surgical resection is
the only opportunity for a cure. However,
surgical resection is possible in only 15% of
cases - due to the late presentation of the
disease - with a 5-year survival of
approximately 20% [2, 3]. When the tumor is
unresectable, chemotherapy, radiation therapy,
or a combination thereof can be used to
increase overall survival and to improve the
quality of life [4]. Consequently, pancreatic
cancer has become a target for novel therapies
such as immunotherapy and gene therapy.
This review will focus on the available
evidence of EUS as a therapeutic intervention
for pancreatic cancer, including EUS-guided
fine-needle injection therapy, EUS-guided
radiofrequency ablation, EUS-guided photo-
dynamic therapy, and EUS-guided celiac
plexus neurolysis.
EUS-Guided
Fine-Needle
Injection
Therapy
Locally advanced pancreatic cancer remains a
major clinical challenge with limited options
of treatment and a very poor prognosis.
Because of limited efficacy of systemic
chemotherapy with or without radiotherapy
with potential systemic side effects, a major
effort is underway to develop therapeutic
agents that can be locally and directly
delivered to the tumor. The advance of this
area is based on the ability of EUS to place
fine needles precisely within the tumor.
Several therapeutic agents have been

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proposed, including allogenic mixed
lymphocyte culture (cytoimplant) and gene
therapy through viral vectors.
The immunologic approach to treatment of
tumor is based on the activation of host
immune effector cells (cytotoxic T-
lymphocyte) by cytokines. Cytokines may be
instilled directly within the tumor or can be
produced by a mixed lymphocyte reaction
generated by the coincubation of host and
allogenic donor peripheral blood mononuclear
cells [5].
The first phase I clinical trial was reported by
Chang et al. in 2000 [6]. The early study was
conducted in 8 patients with unresectable
pancreatic cancer. The feasibility and safety
of EUS-guided injection with immunologic
therapy was demonstrated. In this study, the
allogenic mixed lymphocyte culture
(cytoimplant) at the dose of 3, 6, or 9 billion
cells was delivered within the tumor by a
single injection through a 22-gauge FNA
needle. No procedure-related complications or
major toxicities were demonstrated. Tumor
regression occurred in 3 of the 8 patients, no
change in 3 patients, and increased growth in
2 patients. There was no correlation of tumor
response with the dose of cytoimplant and
survival. The median survival was 13.2
months. Based on these encouraging results
from the phase I study, a randomized trial
comparing EUS-guided fine-needle injection
of cytoimplant with systemic gemcitabine was
initiated. Unfortunately, the interim analysis
demonstrated that patients who received
cytoimplant did worse than the patients who
received systemic gemcitabine. Thus, the trial
was subsequently suspended [7].
Besides immunologic therapy, gene therapy
has also been studied for pancreatic cancer [8,
9]. Gene therapy involves the transfer of
genetic constructs, which alter the neoplastic
potential of the cancer cells. Once genetic
transfer has developed, expression of the gene
product may modify the biologic behavior of
the tumor. This modification can occur due to
blocking transformation of known oncogenes,
restoration of tumor suppressor function, or
augmentation of the immunologic attack
against cancer cells. In addition, viral
constructs can be altered to create attenuated
viruses that replicate specifically in the tumor
and destroy cancer cells without being
responsible for an infectious process [10]. An
attenuated adenovirus has been proposed as a
possible therapeutic vector for pancreatic
cancer. Using the similar technique of EUS-
guided fine-needle injection, vectors for gene
therapy can be directly delivered to the tumor.
The first clinical trial of gene therapy was
conducted in 21 patients with locally
advanced pancreatic cancer to assess the
feasibility, safety, and efficacy of such
approach [11]. In this study, the patients
underwent 8 sessions of EUS-guided injection
to deliver viral vectors (ONYX-015) directly
within the tumor over 8-week duration and
received intravenous systemic gemcitabine at
the dose of 1,000 mg/mconcomitantly with
the final 4 sessions. Significant toxicity and
procedure-related
complications
were
demonstrated early in the study. Two patients
developed bacterial infections, which were
felt to be secondary to the EUS-guided
injection. Both infections were easily treated
with antibiotics. No further infections were
noted after the modification of study protocol
which included the administration of
prophylactic oral ciprofloxacin. Two patients
developed duodenal perforation prior to the
study protocol was revised to require all
injections to be performed using only
transgastric approach. The investigators
concluded that repetitive EUS-guided
injection therapy is well tolerated if the
administration is performed using transgastric
approach and with prophylactic antibiotics
treatment. However, no convincing evidence
proving the efficacy of ONYX-015 for the
treatment of pancreatic cancer was found. No
objective responses were demonstrated on day
35, following 4 injections of ONYX-015 as a
single agent. After combination treatment
with virus and gemcitabine, objective partial
regressions of more than 50% were seen in 2
of 21 (10%) patients. Eight patients (38%)
had stable diseases, and 11 (52%) had
progressive disease or had to be removed
from the study because of treatment toxicity.
The median time to injected tumor

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progression was approximately 6 weeks, and
14% of patients were free from local
progression at 6 months. The median survival
time was 7.5 months.
Several active studies are underway
investigating EUS-guided gene therapy for
pancreatic cancer. Local gene transfer has the
potential to locally deliver high concentration
of a therapeutic agent while limiting systemic
toxicity. Direct local gene delivery to the
tumor cells via EUS-guided injection
theoretically maximizes the anti-tumor effect
limited to those cells expressing the gene and
their local milieu. Phase I and II studies have
been completed, confirming the safety,
tolerability, and potential efficacy of EUS-
guided fine-needle injection with a
replication-deficient adenovector containing
the human tumor necrotic factor (TNF)-alpha
gene
(TNFeradeTM,
GenVec,
Inc.,
Gaithersburg, Maryland, USA) in patients
with locally advanced and unresectable
pancreatic cancer undergoing chemoradiation
[12]. A phase III multicenter, randomized,
controlled study is currently conducted to
compare TNFeradeTM plus standard of care
and standard of care [13]. Preclinical and
phase I/II studies have demonstrated that
tumors transfected with adenovector have a
favorable response to radiation with induction
of TNF-alpha expression and substantial
increases in antitumor activity [12].
EUS-Guided Radiofrequency Ablation
Percutaneous ablative therapies with thermal
energy including radiofrequency, microwaves,
and laser energy have received much attention
as minimally invasive strategies for the
management of focal neoplasms [14].
Potential advantages of these techniques are
real-time imaging guidance, the ability to
ablate tumor in patients with high risk for
surgical treatment, reduced morbidity
compared to surgical intervention, and the
potential to perform the procedure on an
outpatient basis.
EUS-guided radiofrequency ablation has been
studied in the normal porcine pancreas by
Goldberg et al. [15]. The study demonstrated
the feasibility and safety of using EUS to
guide transgastric placement of an endoscopic
radiofrequency needle-electrode to induce
coagulation necrosis in the pancreas of 13
Yorkshire pigs. The radiofrequency electrode
used in the study was a modified 19-gauge
biopsy needle. Thus the placement of
radiofrequency electrode into the pancreas
under EUS guidance was no more challenging
than performing EUS-guided pancreatic
biopsy with a 19-gauge needle.
Radiofrequency current (285±120 mA) was
delivered for 6 minutes. The results confirmed
the excellent correlation between EUS or
computed tomography (CT) and gross
pathologic findings for all lesions larger than
5 mm. Three transmural burns extending from
the gastric mucosa through the serosa were
seen in the first 2 pigs, probably due to
incomplete penetration of the gastric serosa,
which is significantly thicker in pigs than in
humans and frank perforation was not
observed. No further burns were seen in the
subsequent applications in which the entire
distal needle was inserted within the pancreas
before and during ablation. No clinical
evidence of distress, fever, or pancreatitis was
demonstrated following the procedures. The
author concluded that EUS-guided
radiofrequency ablation of pancreas is
feasible and can be used safely to produce
discrete zones of coagulation necrosis in the
porcine pancreas. Resultant coagulation
necrosis is well visualized with EUS or CT
with
excellent
radiologic-pathologic
correlation. The technique appears to be well
tolerated. Most complications developed in
the study were related to initial technical
problems or differences between porcine and
human anatomy. Potential clinical uses of this
technique include management of small
neuroendocrine tumors or other focal lesions
within the pancreas, liver, spleen, or kidney.
In addition, it may be used for palliation of
unresectable pancreatic cancers. However,
further studies are required to standardize
several parameters including duration of
radiofrequency application, electrode tip
temperature, impedance, and wattage to
optimize the diameter of coagulation necrosis
in human pancreatic tissue.

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EUS-Guided Photodynamic Therapy
Photodynamic therapy (PDT) has emerged as
one of the useful methods for the ablation of
malignant or benign tumors of epithelial-lined
or solid organs [16, 17, 18, 19, 20]. Role of
PDT has been previously established for
malignancies of the esophagus, stomach,
urinary bladder, brain, bronchial tree, and
hepatobiliary system [16, 17, 18, 19, 20].
Following the intravenous infusion of a
photosensitizing drug, the target tissue is
exposed to light of appropriate wavelength.
The activated drug interacts with oxygen to
generate singlet oxygen, which produces
localized tissue necrosis.
Studies of PDT in the pancreas demonstrate
that photosensitizing drugs are avidly taken
up by pancreatic tissue [21]. In addition, a 7-
fold greater concentration of photosensitizing
drug has been observed in malignant
pancreatic tissue compared to normal tissue
[22]. Light exposure with resulting tissue
necrosis has not resulted in significant
structural damage to the gastroduodenal
musculature [23]. Phase I study by Bown et al.
using PDT for inoperable cancer in the human
pancreas demonstrated that light catheters
placed percutaneously could produce necrosis
in pancreatic cancers with an acceptable
morbidity [21]. A study by Chan et al.
demonstrated the role of EUS to guide the
placement of a quartz optical fiber with light
diffuser in the pancreas, liver, spleen, and
kidney to assess the feasibility and safety of
EUS-guided, low-dose laser light delivery to
intra-abdominal solid organs [24]. The study
was performed in 3 pig models injected with
intravenous porfimer sodium (Photofrin®,
Axcan Pharma Inc., Mont-Saint-Hilaire,
Quebec, Canada) at 1 mg/kg 24 hours before
the procedure. Experienced endosonographers
encountered no technical difficulty in
performing the procedure, including passage
of the light delivery fiber into solid tissue and
administration of the light dose. There was no
immediate or delayed complication in any of
the 3 animals. Total of 26 treatment locations
were performed in liver (5), pancreas (9),
kidneys (9), and spleen (3). The area of PDT-
induced necrosis was similar in the pancreas,
liver, and kidney, but smaller in the spleen
compared to the other organs. The authors
concluded that EUS-guided low-dose PDT
ablation of the pancreas is feasible and safe.
This technique may be applicable to small
lesions in the pancreas or liver. PDT can
cause a focal necrotic area of 3.6 mmduring
each application of light (50 J/cm for 120
seconds), thus a lesion with a diameter of 10
mm and a wall thickness of 1 mm could be
ablated with 3 light exposures. However,
further studies are required to confirm similar
results in human pancreas.
EUS-Guided Celiac Plexus Neurolysis
Pain is a significant source of morbidity in the
patients with unresectable pancreatic cancer
and chronic pancreatitis. Mechanisms of pain
production in both conditions have much in
common but may also differ [25]. Pancreatic
cancer has a predilection for perineural
invasion leading to the generation of pain [26].
In addition, increased intrapancreatic or
intraductal pressures, ulceration, stretching of
the capsule, ductal obstruction, and spread to
celiac or other retroperitoneal lymph nodes
may also contribute [25, 26]. The majority of
pancreatic pain is mediated by sympathetic
visceral afferent fibers relaying via the celiac
plexus, through the crurae of the diaphragm to
the splanchnic nerves, entering the spinal cord
at the fifth to ninth thoracic segments. The
celiac plexus consists of a variable number of
ganglia which lies in front of the
diaphragmatic crurae, slightly anterior and
cephalad to the celiac trunk.
Celiac plexus neurolysis (CPN) is a chemical
splanchnicectomy and has been performed for
almost 100 years as a palliative treatment to
alleviate pancreatic pain. A variety of
techniques, routes, and chemical agents have
been used to maximize the efficacy and
minimize the complications [27, 28, 29]. CPN
has been most commonly performed under
fluoroscopic or computerized tomography
(CT) guidance using either bilateral posterior
or an anterior approach. Recently, a few
studies using EUS guidance have confirmed

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the similar or probably superior results [30].
EUS-guided approach offers several
theoretical advantages over the other routes.
The celiac plexus can be clearly visualized
from the lesser curvature of the gastric body
by tracing the aorta to the origin of the main
celiac trunk using curvilinear echoendoscope.
The procedure can be performed under real-
time guidance with Doppler study to avoid
inadvertent injection into blood vessels. EUS-
guided FNA to confirm the diagnosis and
staging can also be performed at the same
time. In addition, the anterior approach avoids
the retrocrural space and should minimize the
risk of neurological complications from
thrombosis or spasm of the anterior spinal
artery or artery of Adamkiewicz [30].
There are few prospective studies of EUS-
guided CPN in the patients with pancreatic
cancer. Gunaratnam et al. reported the results
of a prospective observational study in 58
patients with pancreatic cancer [31]. EUS-
guided CPN provided pain relief in 78% of
patients, which was sustained to 24 weeks and
independent of changes in analgesic doses or
use of adjuvant therapy.
A randomized controlled trial comparing
EUS-guided CPN versus sham injection is
currently underway to confirm the efficacy at
our Institution.
Conclusions
EUS has matured over the past several years
as an essential investigation for pancreatic
cancer. The capability of EUS to precisely
access the tumor has led to the development
of therapeutic indications. A better
understanding of the molecular biology and
events that lead to the development and
progression of pancreatic cancer are
underway with the anticipation that many
potential targets for therapy will be identified.
These developments will revolutionize the
role of EUS from a purely diagnostic
procedure to a powerful therapeutic tool. EUS
with fine needle injection in pancreatic cancer
therapy represents an approach worth
pursuing, given the poor prognosis of this
disease and the feeling that survival benefits
associated with conventional therapy have
nearly maximized.
Keywords Carcinoma, Pancreatic Ductal;
Endosonography; Pancreatic Neoplasms
Abbreviations CPN: celiac plexus neurolysis;
CT: computed tomography; ERCP:
endoscopic retrograde cholangiopancreato-
graphy; EUS: endosonography; FNA: fine
needle aspiration; PDT: photodynamic
therapy; TNF: tumor necrotic factor
Correspondence
Massimo Raimondo
Mayo Clinic College of Medicine
4500 San Pablo Road
Jacksonville, FL 32224
USA
 
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