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TECHNICAL NOTE
Radiat Med (2008) 26:92–97
DOI 10.1007/s11604-007-0198-3
Carbon dioxide microbubbles-enhanced sonographically guided
radiofrequency ablation: treatment of patients with local progression of
hepatocellular carcinoma
Noriyuki Miyamoto · Kazuhide Hiramatsu
Kazuhiko Tsuchiya · Yukihiko Sato
Abstract
Purpose. The aim of our study was to evaluate the useful-
ness of percutaneous radiofrequency ablation (RFA)
using CO2 microbubbles-enhanced sonography for
patients with local tumor progression of hepatocellular
carcinoma (HCC).
Materials and methods. The tumors of 14 patients with
local progression of HCC were treated with CO2
microbubbles-enhanced RFA ablation via a catheter
that had been placed in the hepatic artery. We assessed
tumor detectability and technical effectiveness. The
mean follow-up period was 14.1 months.
Results. Only 6 of the tumors could be found on con-
ventional sonography, whereas 14 tumors were detected
on CO2 microbubbles-enhanced sonography. These 14
lesions were successfully treated with RFA guided by
CO2 microbubbles-guided sonography. Technical effec-
tiveness was complete in all patients. No serious compli-
cations were observed, and there was no local tumor
progression during the follow-up period.
Conclusion. RFA guided by CO2 microbubbles-guided
sonography is a feasible technique for treating local
progression of HCC lesions that cannot be adequately
depicted by conventional sonography.
Key words Hepatocellular carcinoma · Radiofrequency
ablation · Carbon dioxide gas · Local tumor
progression
Introduction
Hepatocellular carcinoma (HCC) is a common malig-
nancy worldwide, and its incidence is increasing because
of the dissemination of hepatitis B and C virus infec-
tions.1 Although surgical resection is usually considered
to be the fi rst choice of treatment,2 it is not infrequently
contraindicated by underlying chronic liver disease based
on hepatitis B or C virus infection.3 Current options for
treatment in patients with unresectable HCC consists
of transcatheter arterial embolization, percutaneous
ethanol injection, and percutaneous radiofrequency
(RF) ablation therapy. Among these treatments, percu-
taneous RF ablation has been accepted as an established
local therapeutic modality of choice for the management
of unresectable HCC.4
However, viable portions of tumors can persist, and
recurrent tumors sometimes appear, regardless of the
treatment used; there is controversy over how to treat
such tumors.5 Local tumor progression after percutane-
ous therapy is also diffi cult to treat because the margin
between a viable lesion and a necrotic lesion is not clear
in many cases.6 Therefore, some reports have indicated
that computed tomography (CT)-guided procedures are
an effective treatment method for HCC tumors that are
not depicted by sonography.7 Some researchers have
reported using CO2-enhanced sonographically guided
percutaneous ethanol injection to treat HCCs that
cannot be identifi ed on unenhanced sonography.8,9 There
have also been some case reports about using CO2-
enhanced sonographically guided RF ablation to insert
the needle electrode accurately into the tumor.10,11 The
purpose of our study was to evaluate the effi cacy of CO2-
enhanced sonographically guided RF ablation when
treating patients with local progression of HCC.
Received: August 6, 2007 / Accepted: October 9, 2007
© Japan Radiological Society 2008
N. Miyamoto (*) · K. Hiramatsu · K. Tsuchiya · Y. Sato
Department of Radiology, JA Hokkaido Koseiren Obihiro
Kosei General Hospital, W6 S8, Obihiro 080-0013, Japan
Tel. +81-155-24-4161; Fax +81-155-25-7851
e-mail: nm-00@fg7.so-net.ne.jp
Radiat Med (2008) 26:92–97 93
Materials and methods
Patients
From April 2003 to March 2007, 14 patients (11 men, 3
women; age range 49–85 years, mean 67 years) with local
progression of their HCC were enrolled in this study.
Written informed consent was obtained from all patients
after the nature of the procedure had been fully explained.
Thirteen patients had Child-Pugh class A liver disease,
and one had Child-Pugh class B. The underlying liver
disease resulted from hepatitis C in eight patients, hepa-
titis B in three, and non-B non-C hepatitis in three. All
of the tumors in these 14 patients were viable tumors
that had been treated previously. The sizes of the hepa-
tocellular carcinomas at initial diagnosis ranged from
0.9 to 7.0 cm (mean 2.6 cm).
The 14 patients had a history of treatment with RF
ablation (n = 13) and transcatheter arterial chemoembo-
lization (TACE) (n = 1). The mean interval between the
latest previous treatment and the time of the current
procedure was 10.5 months (range 2.2–4.3 months).
Three patients were excluded from this study because of
the unfavorable location of their recurrent tumor: one
in proximity to the gastrointestinal tract and two adja-
cent to the gallbladder. These three patients were treated
with segmental TACE. Six patients who had multiple
viable recurrent lesions that were found in areas that had
been treated in the past were also excluded from this
study.
Dynamic CT fi ndings identifi ed 14 viable recurrent
tumors in 14 patients. The patterns of local tumor pro-
gression on dynamic CT were categorized as either
enhanced tissue within the edge of the treated nodule on
arterial phase images or enhanced tissue around the
treated nodule but continuous with its border on the
arterial phase.12 The fi rst pattern (designated ingrowth)
was identifi ed in one tumor managed with TACE. The
second pattern was identifi ed in 13 tumors managed with
RF ablation. In this study, the local tumor progression
consisted of 1 tumor with the ingrowth pattern and 13
with the outgrowth pattern.
We treated 14 patients with CO2-enhanced sono-
graphically guided RF ablation because it was diffi cult
to detect local tumor progression on conventional sonog-
raphy. The tumor size at the time of the procedure was
assessed by CO2-enhanced sonography or CT. The mean
maximum diameter ranged from 0.6 to 3.1 cm (mean
1.7 cm). The histological diagnosis of the lesions detected
on CO2-enhanced sonography was made by 21-gauge
fi ne-needle aspiration biopsy (Majima needle; Top,
Tokyo, Japan) in eight patients; the other cases were
diagnosed by imaging criteria instead of biopsy.
Treatment methods
CO2-enhanced sonography was performed during angi-
ography with a disinfected ultrasound probe. The ultra-
sound machine used was either SSD 2000 or prosound
α 10 (Aloka, Tokyo, Japan) with an electric convex
whose frequency was 3.5 MHz. All procedures were per-
formed with the patients under local anesthesia. The
CO2-enhanced sonographically guided RF ablation
was performed after the patient underwent diagnostic
angiography.
CO2 microbubbles were prepared by vigorously
mixing (by hand) 10 ml of CO2, 10 ml of heparinized
normal saline, and 5 ml of the patient’s own blood. First,
5–10 ml of CO2 microbubbles were injected within
approximately 5 s by hand via an angiographic catheter
placed in the common hepatic artery (n = 6), proper
hepatic artery (n = 1), left hepatic artery (n = 1), right
hepatic artery (n = 1), subsegmental branch of the hepatic
artery (n = 2), or subsubsegmental branch of the hepatic
artery (n = 2). Using a real-time convex scanner with
3.5-MHz probes, we assessed the fl ow of the CO2 gas and
enhancement of the targeted area.
Again, a bolus of 5–10 ml of CO2 microbubbles was
injected into the liver, after which the RF electrode was
placed in the target tumor. We used an RF ablation
device with a 200-W generator (model 1500X; Rita
Medical Systems, Mountain View, CA, USA) and an
active multi-tined, expandable electrode with seven
retractable prongs (model 70SB; Rita Medical Systems).
The algorithm of energy deposition was based on the
manufacturer’s guidelines. All patients were sedated
consciously via an injection of 0.1 mg of fentanyl and
50 mg of fl urbiprofen in a therapeutic angiography room.
The patients were given oxygen at a speed of 2 l/min
through a nasal cannula. During RF treatment, a hyper-
echoic area was observed on sonography around the
electrode tips. Although the tumors in eight patients
were small, we adopted a multiple-overlapping ablation
technique in those cases in which there was a possibility
that there was viable tumor residue based on the tumor
confi guration and direction of the electrode approach.
In three patients whose recurrent nodules were >2.0 cm
in diameter and feeding arteries were patent, we began
to inject gelatin sponge particles immediately before RF
ablation (Spongel; Astellas, Tokyo, Japan) via a 3F
microcatheter (Renegade Hi-Flow; Boston Scientifi c,
Watertown, MA, USA) to cause complete necrosis of
the tumor.
Although a new microbubble contrast agent (Son-
azoid; Daiichi-Sankyo, Tokyo, Japan) has been released,13
we performed CO2 microbubbles-enhanced sonography
instead of Sonazoid-enhanced sonography for two
94 Radiat Med (2008) 26:92–97
reasons. First, Sonazoid-enhanced sonography is often
limited to hepatic masses that are deep in the liver.
Second, the duration of pure arterial-phase imaging is
relatively short, and Sonazoid-guided RF ablation is not
always suitable for treating local tumor progression.
Posttreatment assessment and follow-up
The technical effectiveness of RF ablation guided by
CO2-enhanced sonography was assessed by spiral CT
within 7 days after treatment. Hypoattenuating, non-
enhancing areas observed during both the arterial and
portal venous phases were considered to present com-
plete tumor ablation. Conversely, any portion of the
treated tumor showing persistent nodular enhancement
was considered to represent residual viable tissue.
The follow-up period ranged from 3.0 to 42.0
months (mean 14.1 months). The follow-up protocol
included measurement of α-fetoprotein (AFP) and
PIVKA-II (protein induced by vitamin K absence or
antagonism) levels, US performed at 3-month intervals,
and spiral CT performed at 3-month intervals. The
results from each imaging procedure were interpreted.
The patients were observed for local tumor progression
and for the emergence of new HCC tumors. The clinical
features of the patients and tumors are summarized in
Table 1.
Results
All CO2-enhanced sonographically guided percutaneous
RF ablations were successful. Only 6 (42.9%) of the 14
nodules could be identifi ed on conventional B-mode
sonography. In contrast, 13 (92%) of the 14 nodules with
local tumor progression were detected as well-enhanced
tumors on CO2-enhanced sonography (Fig. 1). In one
nodule (8%), local tumor progression was seen as mildly
enhanced on CO2-enhanced sonography. One patient
who had a recurrent tumor located in the subphrenic
dome that could not be detected by pulmonary air was
treated by artifi cial pleural effusion (after an intratho-
racic infusion of 500 ml of 5% glucose).We were able to
advance a 15-gauge RF electrode into the tumors by
CO2-enhanced sonography in all patients.
A single session of RF ablation was performed in six
patients, whereas in eight patients multiple (as many as
fi ve) overlapping ablations were performed through one
to three insertions by using the pullback technique. The
diameter of the deployed electrode was 3 cm in 12 patients
and 2.5 cm in 2 patients.
Complete tumor necrosis was achieved in all patients
after the procedure (Fig. 1). No local tumor progression
was observed during the follow-up period (mean 14.1
months). The emergence of new HCC was seen in 9
(64.2%) patients. No serious complication, such as
Table 1. Clinical and therapeutic features of the patients and tumors
Parameter Data
Patients (no.) 14
Sex (male/female) 11/3
Age (years) 49–85 (mean 66.9)
Child’s grade (A/B) 13/1
Hepatitis C/B virus 8/3
Past history of treatment (no. of patients)
RFA 12
TACE 1
RFA under laparotom 1
Tumor diameter (cm) 0.6–3.1 cm (mean 1.7 cm)
Treatment procedure
RFA 11
RFA with TAE 3
Ablation sessions
Single session 6
Multisession 8
Deployed diameter of electrode (3.0/2.5 cm) 12/2
Histological diagnosis
Well differentiated HCC 2
Moderately differentiated HCC 4
Poorly differentiated HCC 1
Follow-up (months) 3–42 (mean 14.1)
RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization; TAE,
transcatheter arterial embolization
Radiat Med (2008) 26:92–97 95
hemorrhage, was observed in any of the patients. The
results are summarized in Table 2.
Discussion
Radiofrequency ablation, TACE, and percutaneous
ethanol injection are typically used to treat inoperable
HCC. Among these treatments, RF ablation with a
percutaneously inserted electrode ablates tumors more
completely than other locoregional treatments, reducing
the rate of local recurrence.14 However, treating local
tumor progression is diffi cult.15,16 Previous studies have
shown that tumors exceeding 2 cm in diameter, subcap-
sular tumors, tumors situated at the liver surface, and
incompletely ablated margins are associated with local
tumor progression after RF ablation.17,18 Both viable
lesions and necrotic lesions exhibit a heterogeneous
sonography pattern in cases of local HCC progression
after ablation therapy.6 Thus, effi ciently treating local
progression of HCC after percutaneous ablation is often
diffi cult. TACE is a widely performed procedure for
patients with recurrent HCC.19,20 Although TACE has
been revealed to be benefi cial in some patients, frequent
recurrence has limited its usefulness.19
Various methods have been applied in an attempt to
target hepatic tumors that cannot be clearly defi ned by
standard sonography, including sonography after the
creation of artifi cial pleural effusion,21 CT guidance,22
and contrast harmonic sonography guidance.23,24 With
a
c
d
b
Fig. 1. Percutaneous
radiofrequency ablation
guided by CO2
microbubbles-enhanced
sonography in a 73-year-old
man with recurrent
hepatocellular carcinoma
who had undergone
radiofrequency ablation.
a Computed tomography
(CT) scan 11 months after
initial radiofrequency
ablation reveals local tumor
progression (arrow).
b Conventional sonography
shows the ablated area
(arrow). It is diffi cult to
identify which portion of
the tumor is viable. c CO2
microbubbles-enhanced
sonography shows well-
enhanced recurrent tumor
(arrow). d Contrast-
enhanced CT scan
performed after two sessions
of radiofrequency ablation
shows a necrotic area that is
larger than the viable area
depicted on the CT scan
before treatment
Table 2. Results of CO2-enhanced sonography-guided RFA
Parameter Result
Conventional sonography Lesions detected 6 (42.9%)
CO2-enhanced sonography Lesions detected 14 (100%)
Hyperenhancement 13 (92%)
Mild enhancement 1 (8%)
Technical effectiveness Complete necrosis 14 (100%)
Local tumor progression No recurrence 14 (100%)
Intrahepatic distant recurrence Recurrence 9 (64.2%)
Major complication No complication
Death during follow-up 3/14 (30%)
96 Radiat Med (2008) 26:92–97
CT guidance, several attempts may be needed because
of the diffi culty of accurately targeting the center of the
tumor, which may increase the risk of hemorrhage or
tumor cell seeding at the site of electrode insertion. In
addition, CT-guided procedures expose the patient to
radiation caused by repeated CT penetration. Contrast-
enhanced sonographically guided percutaneous ethanol
injection25 and RF ablation24 have been reported.
However, we think that in the case of contrast-enhanced
sonographically guided ablation the duration of enhance-
ment is too short to allow insertion of the RF electrode
during real-time imaging.
CO2-enhanced sonography is a sensitive means of
detecting small HCC lesions.26,27 Kudo et al.27 reported
that the detection rate of tumor hypervascularity on
CO2-enhanced sonography (86%) showed that this
method is more sensitive than digital subtraction arteri-
ography or CT with iodized oil. Kudo et al. reported
that CO2-enhanced sonography was performed using
CO2 microbubbles, which were made from a mixture
of CO2, heparinized normal saline, the patients’ own
blood,10,11,28,29 and albumin.30 Other studies performed
enhanced sonography using pure CO2.5,31,32 Enhanced
sonography with pure CO2 provides a longer duration
of nodular enhancement than the microbubble injection
method.31,32 In this study, we used the microbubble injec-
tion method because it permits precise observation of the
vascular pattern of small nodules, and it is easy to control
the injection volume of the microbubbles. In this study,
using the microbubbles method allowed a suffi cient
amount of time for CO2 to accumulate in the nodules
and for the needle electrode to be inserted accurately
into the targeted tumor because its location could be
confi rmed. All patients completed the treatment. Thus,
CO2-microbubble sonography may improve the effi cacy
of RF ablation for HCC nodules that are not clearly
depicted by B-mode sonography.
The limitations of CO2-enhanced sonographically
guided RF ablation must be acknowledged. CO2-
enhanced sonography requires angiography, which is a
more invasive technique for diagnosing local progres-
sion of HCC than other techniques, such as CT and
magnetic resonance imaging. Newer intravenous con-
trast agents such as Sonazoid, suitable for a low mechan-
ical index, are useful in the detection and treatment of
HCC.33,34 However, there is an advantage to angiogra-
phy. When performing CO2-enhanced sonography, it is
possible to perform TACE according to the tumor size
and tumor staining. In four patients, complete tumor
necrosis was successfully achieved by RF ablation and
TACE. A few sessions of ablation might be possible by
the combined application of RF ablation and TACE. In
our study, however, no additional viable portion was
detected, and we believe that for patients with more than
two viable sites or with recurrent tumors CO2-enhanced
sonography guided RF ablation may be diffi cult because
multiple needle insertions are required. Other limitations
of the study are that the follow-up time is relatively
short, and further follow-up and studies may be
needed.
Conclusion
Our results suggest that CO2-enhanced sonographically
guided RF ablation may be an effective treatment tech-
nique for patients with a viable tumor or recurrent
tumors that are not clearly depicted on B-mode
sonography.
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