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Early Assessment of Therapeutic Response in
Hepatocellular Carcinoma Treated with
Percutaneous Radio-frequency Ablation A
Comparison of Multiphase Helical CT and Power
Doppler US with a Microbubble Contrast
Agent   Dongil Choi, M.D., Hyo Keun Lim, M.D.,
Seung Hoon Kim, M.D., Won Jae Lee, M.D., Soon Jin
Lee, M.D., Jae Hoon Lim, M.D. Department of
Radiology, Samsung Medical Center, Sungkyunkwan
University School of Medicine
The other experienced radiologist without
knowledge of immediate posttreatment CT findings,
performed PDUS at next morning (14 24 hours
after RF ablation mean, 18 hours) after RF
ablation to avoid artificial signals resulting
from intratumoral gas in all patients. PDUS
examinations were performed before and after
injection of a microbubble contrast agent using
2-5-MHz convex array transducer (HDI 5000,
Advanced Technology Laboratories, Bothell, WA,
U.S.A.). PDUS parameters were optimized, which
were the same as pretreatment studies. We used a
microbubble US contrast agent (Levovist?
Schering AG, Berlin, Germany), which is a
suspension of galactose in sterile distilled
water. We started to scan with PDUS 20 seconds
after initiation of infusion of contrast agent
and scanned intermittently to avoid early bubble
destruction. With this technique, the enhancement
effect lasted for more than 10 minutes. Tumor
vascularity on PDUS was analyzed by three other
radiologists who did not know the results of
immediate follow-up CT findings. Final decisions
on the existence of residual tumor were reached
by a consensus. The second follow-up four-phase
CT scans were obtained at one month after RF
ablation. If the tumors were completely treated,
repeated postcontrast three-phase CT was
performed every three months. One experienced
radiologist compared findings of immediate
follow-up CT with those of postablation PDUS, and
evaluated their therapeutic efficacy on the basis
of findings of all subsequent follow-up CT
examinations.
INTRODUCTION
Although surgical resection is the best
curative option of treatment modality for
hepatocellular carcinoma (HCC), advanced hepatic
cirrhosis or multicentricity make surgery
impossible in a majority of cases at the time of
diagnosis 1. Several effective minimally
invasive techniques for the local control of
unresectable malignant hepatic tumors have been
introduced in the last decade 2. One of these,
radio-frequency (RF) interstitial thermal
ablation resulting in coagulation necrosis of the
tumor has been shown to be an effective method
with the development of new techniques 3, 4.
Recently, RF ablation has been more widely used
for the treatment of malignant hepatic tumors due
to higher rate of complete necrosis and required
fewer treatment sessions than percutaneous
ethanol injection 4-6. Even though
contrast-enhanced computed tomography (CT) or
magnetic resonance (MR) imaging has some
limitations to their use as a gold standard to
detect small viable tumors after RF ablation,
they have been generally used to determine the
extent of RF-induced coagulation necrosis 3, 7.
The ablated area devoid of focal enhancement,
which covers the entire tumor and the cuff of
surrounding normal hepatic tissue, represents
successful treatment. Focal enhancement
suggesting viable tumor portion in the ablated
area requires additional ablation to achieve
complete treatment. Three preliminary reports
suggested that ultrasonography (US) with a
microbubble US contrast agent was useful in
assessing early (postprocedural) effect of RF
ablation for the malignant hepatic tumors 7-9.
It could depict the residual tumor portions in
the ablated area and help to guide the residual
tumor during the additional ablation. However, to
our best knowledge, no study has focused on
comparison of multiphase helical CT and
contrast-enhanced US for the early evaluation of
residual foci in the HCC after RF ablation
therapy. The purpose of this study was to compare
the results of multiphase helical CT and power
Doppler US (PDUS) with a microbubble contrast
agent in the early assessment of therapeutic
response to RF ablation in HCC.
RESULTS
Immediate follow-up CT after RF ablation showed
no enhancing portion on hepatic arterial and
portal venous phases in 65 (89) among 73 HCCs
(Fig. 1). In the remaining eight HCCs (11),
focal enhancing portions representing viable
tumors were observed in the ablated area. In 55
(75) of 73 HCCs, immediate follow-up CT showed
peripheral rim enhancement around the ablated
tumor, which were considered to be reactive
hyperemia.
MATERIALS METHODS
Patients One hundred twenty-nine patients with
nodular HCCs were referred for US-guided
percutaneous RF ablation between April 1999 and
February 2000. Of these, 43 patients with
previous history of treatment with percutaneous
ethanol injection or transcatheter arterial
chemoembolization were excluded from this study.
We also excluded 12 patients in whom
contrast-enhanced US examinations or immediate
follow-up CT after RF ablation were not
performed, and eight patients who were lost to
follow-up less than one year after RF ablation.
The remaining 66 patients who had 73 nodular HCCs
finally formed the study population. Seven
patients had two HCCs. There were 54 men and 12
women ranging from 29 to 82 years in age (mean,
56 years). Tumors ranged 1.0-4.0 cm in diameter
(mean, 2.6 cm). The range of the last follow-up
CT examinations of the patients was from 13
months to 19 months (mean, 17 months). The
diagnosis of HCC was confirmed by US guided
percutaneous needle biopsy in 36 masses of 36
patients. The remaining 37 masses in 30 patients
were considered to be HCCs by means of
characteristic imaging findings (three-phase
helical CT and angiography) and elevated serum
tumor marker (?-fetoprotein level above 100
ng/mL).   RF Ablation Technique The RF
ablation was performed using a 480-kHz, monopolar
RF generator (Radiofrequency Interstitial Thermal
Ablation Medical System, Mountain View, CA,
U.S.A.) and an active expandable RF needle
electrode 11. The RF ablation was performed on
inpatients after 12 hours of fasting. Laboratory
tests including CBC and blood coagulation tests
were obtained before each session. We performed
RF ablation with only local anesthesia
(Lidocaine? Kwang Myung Pharmaceutical Co.,
Seoul, Korea) in patients who had small tumors
located in the central part of the liver. For the
large tumors exceeding 3 cm in diameter or the
tumors located in the difficult areas
(subcapsular, subphrenic, and perivascular), we
used intramuscular injection of pethidine HCl 50
mg (Pethidine? Sam Sung Pharmaceutical Co.,
Seoul, Korea) 10 20 minutes before the
procedure. All procedures were performed with a
2-5-MHz convex array transducer (HDI 5000,
Advanced Technology Laboratories, Bothell, WA,
U.S.A.), using free-hand technique.   CT and US
Examinations Postprocedural CT examinations
were obtained with a helical scanner (HiSpeed GE
Scanner GE medical systems, Milwaukee, WI,
U.S.A.) within two hours after RF ablation. A
total of 120 mL of 300 mg I/mL non-ionic contrast
material (Ultravist 300? Schering AG, Berlin,
Germany) was administrated at a rate of 3 mL/sec.
Images were obtained before, and 30, 60, 180
seconds after initiation of the injection of
contrast material, representing precontrast,
hepatic arterial, portal venous, and equilibrium
phases, respectively. Images were obtained in a
craniocaudal direction with 7 mm collimation and
7 mm/sec table speed. CT images were
retrospectively reviewed by three experienced
radiologists. The tumors were considered to be
completely necrotic when there was no enhancing
portion within the ablated lesion both on hepatic
arterial and portal venous phases. When the
ablation area showed nodular enhancement either
on hepatic arterial or portal venous phase, we
considered that the tumor has viable portion 6,
7.
Fig. 1. __ 62-year-old man with HCC before and
after RF ablation. A, Axial helical CT scan on
hepatic arterial phase before RF ablation shows
3.0-cm HCC (arrows) with contrast enhancement in
segment 8. B, Axial helical CT scan obtained 15
minutes after RF ablation shows round-shaped
ablated area (arrows) of low attenuation on
hepatic arterial phase, which represents complete
necrosis of tumor tissue. Note that the ablated
area covers the entire tumor and the cuff of
surrounding normal hepatic tissue on A. C,
Unenhanced PDUS performed 17 hours after RF
ablation shows ablated area (arrows) of low
echogenicity without intratumoral flow signal. D,
Contrast-enhanced PDUS again shows no flow signal
within the ablated area (arrows). E, Axial
helical CT scan obtained 13 months after RF
ablation shows round-shaped ablated area (arrows)
of low attenuation on hepatic arterial phase,
which is significantly resolved. Focal
enhancement representing marginal recurrence is
not evident.
2
Unenhanced PDUS after RF ablation showed no
flow signals within the tumor in all 73 HCCs.
However, in eight HCCs (11), focal intratumoral
flow signals newly appeared on contrast-enhanced
PDUS (Fig. 2). These eight tumors with
intratumoral flow signals had enhancing portions
on immediate follow-up CT (Fig. 2). The areas of
the tumors where power Doppler signals were found
were well correlated with the enhancing portions
at CT in all eight tumors. Therefore, diagnostic
agreement between contrast-enhanced US and
immediate follow-up CT was achieved in 100.
Contrast-enhanced PDUS after RF ablation showed
increased flow signals representing reactive
hyperemia around the ablated areas in 34 (25 of
73 HCCs).
Fig. 3. __ 43-year-old man with HCC before and
after RF ablation. A, Axial helical CT scan on
hepatic arterial phase before RF ablation shows
4.0-cm HCC (arrows) with contrast enhancement in
segment 5. B, Axial helical CT scan obtained 25
minutes after RF ablation shows round-shaped
ablated area (arrows) of low attenuation on
hepatic arterial phase, which represents complete
necrosis of tumor tissue. Note that the ablated
area is slightly larger than initial tumor on A.
Also seen is semicircular peripheral reactive
hyperemia (arrowheads). C, Unenhanced PDUS
performed 16 hours after RF ablation shows
ablated area (arrows) of mixed echogenicity
without intratumoral flow signal. D,
Contrast-enhanced PDUS again shows no flow signal
within the ablated area (arrows). Increased flow
signals indicating reactive hyperemia are seen
around the ablated area. E, Axial helical CT scan
on hepatic arterial phase obtained 4 months after
RF ablation shows that most ablated area (arrows)
is of low attenuation, but a subtle focal
enhancing portion (arrowhead) is noted in the
posterior side of the ablated area. The nodular
enhancement represents viable tumor portion. F,
T1-weighted fast multiplanar spoiled gradient
echo (TR200/TE4.2/flip angle 90) image shows the
ablated area (arrows) with high signal intensity,
probably representing coagulation necrosis. G,
T1-weighted fast multiplanar spoiled gradient
echo image obtained 1-minute after administration
of gadolinium shows a new nodular lesion
(arrowhead) with high signal intensity. This
nodular enhancement represents viable tumor,
which is well correlated with that at CT on E.
Fig. 2. __ 46-year-old man with HCC before and
after RF ablation. A, Axial helical CT scan on
hepatic arterial phase before RF ablation shows
3.8- cm HCC (arrows) with contrast enhancement in
segment 5. B, Axial helical CT scan on hepatic
arterial phase obtained 20 minutes after RF
ablation shows that most ablated area is of low
attenuation, but a focal enhancing portion
(yellow arrowhead) is noted in the right anterior
side of the ablated area (arrows) with
semicircular peripheral reactive hyperemia (black
arrowheads). The nodular enhancement represents
viable tumor portion. C, Unenhanced PDUS
performed 19 hours after RF ablation shows
ablated area (arrows) of low echogenicity without
flow signal. D, Contrast-enhanced PDUS shows
focal peripheral flow signals (yellow arrowhead)
within the ablated area (arrows), which represent
residual tumor vessels. Also seen is reactive
hyperemia (white arrowheads). The residual tumor
was treated with additional RF ablation on the
same day. E, Axial helical CT scan obtained 1
month after additional ablation shows oval-shaped
ablated area (arrows) of low attenuation on
hepatic arterial phase, which represents complete
necrosis of tumor tissue.
DISCUSSION
We believe that contrast-enhanced US enables a
practical early assessment of HCCs treated with
RF ablation. It satisfies to determine the
clinical decision for additional ablation and
helps to guide the residual foci of tumors. We
can adopt the strategy of performing
contrast-enhanced US scans in the next morning
after RF ablation. If vessels are found in the
ablated tumor on contrast-enhanced US, an
additional RF ablation therapy is performed with
targeting intratumoral vessels. In our opinion,
immediate follow-up CT scans are not necessary.
Considering possibility of CT and subsequent US
for additional RF ablation, immediate follow-up
CT scans can be expensive and too much. Although
postprocedural PDUS with a microbubble contrast
agent may depict many residual tumors in HCCs
treated with percutaneous RF ablation, it can not
completely prevent marginal recurrence. However,
newer development of US contrast agent and US
technology such as harmonic imaging can improve
the ability to detect smaller viable tumor in the
ablated area 10. In conclusion, compared with
the findings of immediate follow-up CT, the
results of contrast-enhanced PDUS correlated well
for the early detection of residual tumor in HCCs
treated with RF ablation. Both techniques,
however, had a limitation in predicting the local
re-growth in the treated lesion.
Among the 65 ablated HCCs without residual
tumor at both immediate contrast-enhanced CT and
PDUS after the initial RF ablation, ten (15) had
CT findings of marginal recurrence at 4-month
(n5) (Fig. 3), at 7-month (n 4), and at
10-month follow-up CT (n 1), respectively.
These findings of marginal recurrence could not
be retrospectively observed at immediate
follow-up CT. Among eight patients with
residual nodular enhancement at CT and
intratumoral flow signals on contrast-enhanced
PDUS, seven were treated with additional RF
ablation. The remaining one patient was treated
with transcatheter arterial chemoembolization
because the residual tumor was located in
difficult area -just below the cardiac base.
After RF ablation, we observed no major
complication and five minor complications (four
cases of minor perihepatic hemorrhage and one
small pneumothorax), which disappeared
spontaneously with no specific treatment.
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