DOI:10.2214/AJR.08.1618
AJR 2009; 193:86-95
© American Roentgen Ray Society
Efficacy of Perflubutane Microbubble-Enhanced Ultrasound in the Characterization and Detection of Focal Liver Lesions: Phase 3 Multicenter Clinical Trial
Fuminori Moriyasu1 and
Kouichi Itoh2,3
1 Department of Gastroenterology and Hepatology, Tokyo Medical University, 6-7-1
Nishishinjuku, Shinjuku-ku, Tokyo 160-0023 Japan.
2 Department of Clinical Laboratory Medicine, Jichi Medical School, Tochigi,
Japan.
3 Present address: Hitachiomiya Saiseikai Hospital, Ibaragi, Japan.
Received August 1, 2008;
accepted after revision December 29, 2008.
Funding for this study was provided by Daiichi Pharmaceutical Company.
Perflubutane microbubbles were provided by Amersham Health. Authors who were
not employees of either sponsor controlled the inclusion of any data and
information that might have presented a conflict of interest for employees of
either sponsor.
Address correspondence to F. Moriyasu
(moriyasu{at}tokyo-med.ac.jp).
Abstract
OBJECTIVE. The purpose of this study was to assess the efficacy and
safety of contrast-enhanced ultrasound performed with perflubutane
microbubbles in comparison with unenhanced ultrasound and dynamic CT in the
characterization of focal liver lesions during the vascular phase of imaging
and in the detection of lesions during the Kupffer phase.
SUBJECTS AND METHODS. A total of 196 patients were enrolled at 15
centers in Japan. Vascular phase images were obtained before contrast
injection until 1 minute after injection. Kupffer phase images were obtained
10 minutes after injection. Dual-phase CT was performed as determined by
standard clinical practice at each center. Unenhanced ultrasound,
contrast-enhanced ultrasound, and CT images were read by blinded reviewers,
and the results they reached regarding characterization and detection were
compared with reference standard findings made by onsite investigators. The
safety observation period was 72 hours after contrast administration.
RESULTS. Among the 190 patients included in the characterization
analysis, the accuracy of contrast-enhanced ultrasound (88.9%) was
significantly greater than that of unenhanced ultrasound (68.4%) and dynamic
CT (80.5%) (p < 0.001 and p = 0.008). Among the 191
patients in the detection analysis, the efficacy of contrast-enhanced
ultrasound in detection of lesions was significantly higher than that of
unenhanced ultrasound and dynamic CT (p < 0.001 and p =
0.008), predominantly because more metastatic lesions were detected (both
p < 0.001). In particular, contrast-enhanced ultrasound was
superior to dynamic CT in the detection of metastatic lesions measuring 1 cm
or smaller. The incidence of adverse events was 49.2% and that of adverse drug
reactions was 10.4%. All adverse drug reactions were mild.
CONCLUSION. Compared with unenhanced ultrasound and dynamic CT,
contrast-enhanced ultrasound with perflubutane microbubbles improved
diagnostic efficacy in both characterization and detection of focal liver
lesions with no serious adverse drug reactions.
Keywords: characterization • detection • contrast-enhanced ultrasound • focal liver lesions • perflubutane
Introduction
Contrast agents for sonography are principally gas-encapsulated
microbubbles. Successful efforts have been made to produce microbubbles that
are sufficiently small and stable to pass into the systemic circulation after
IV administration [1,
2]. Initially, the efficacy of
commercially available air-based microbubble agents was limited because the
bubbles were easily destroyed by ultrasound exposure
[3-5].
With modification of the composition of the microbubble shell and use of a
lower-solubility substance such as a perfluorochemical instead of gas,
stability and resistance to pressure were improved
[6,
7]. The critical improvement
has been development of microbubble-specific imaging techniques that work at a
low enough mechanical index to minimize destruction of microbubbles
[8-10].
The development of perfluorochemical gas-encapsulated microbubbles and
high-frame-rate real-time scanning for contrast-enhanced ultrasound (CEUS)
enabled the study of early arterial events, leading to accurate diagnosis of
liver lesions owing to visualization of the tumor vasculature and specific
enhancement patterns
[11-13].
The perflubutane microbubbles used in this study are perfluorochemical
agents consisting of microbubbles of perfluorobutane
(C4F10) stabilized by a monomolecular membrane of
hydrogenated egg phosphatidyl serine
[14]. When the liver is imaged
in the phase-modulation harmonic mode, CEUS with perflubutane microbubbles has
two phases of contrast enhancement: vascular and Kupffer phase. Vascular phase
images are acquired soon after IV contrast injection and can be used to
characterize selected lesions on the basis of the dynamics of contrast
enhancement (e.g., arterial and portal venous), morphologic features of the
tumor vasculature, and tumor perfusion
[15]. Unlike contrast-enhanced
Doppler imaging, CEUS in the phase-modulation harmonic mode is expected to
depict microvessels because the mode does not cause the blooming that often
occurs in Doppler imaging.
Perflubutane microbubbles are taken up by Kupffer cells in the
reticuloendothelial system of the liver, and this phenomenon allows
parenchyma-specific imaging of the liver
[16-18].
Parenchyma-specific imaging, called Kupffer phase imaging, is typically
performed 10 minutes after contrast injection, at which time the normal
hepatic parenchyma is enhanced, and malignant lesions that contain few or no
Kupffer cells are clearly delineated as contrast defects
[15,
19]. Therefore, it is
conceivable that Kupffer phase imaging can be used to detect focal liver
lesions. The diagnostic performance of microbubble agents that can be used for
both the vascular and parenchyma-specific, or Kupffer, phases of hepatic
ultrasound has not, to our knowledge, been evaluated in a controlled clinical
study. The purpose of this prospective open-label multicenter phase 3 study
was to assess the efficacy and safety of CEUS with perflubutane microbubbles
in the characterization and detection of focal liver lesions in the vascular
and Kupffer phases of imaging, respectively, in comparison with unenhanced
ultrasound and dynamic CT (DCT).
Subjects and Methods
Patient Population
Before initiation, this study was approved by the institutional review
boards at each of the 15 participating institutions. All patients provided
written informed consent before entering the study. The subjects were patients
who had at least one untreated focal liver lesion confirmed with a previous
diagnostic study (e.g., DCT, contrast-enhanced MRI, angiography, pathologic
examination). Inclusion criteria were the presence of a hepatic mass or lesion
confirmed at DCT within the past month (past 3 months for benign tumors),
fewer than 10 known lesions, and being a man or woman 20-80 years old.
The exclusion criteria were terminal clinical condition and life expectancy
of 3 months or less; previous administration of perflubutane microbubbles;
ongoing transcatheter chemotherapy or radiation therapy; current or within the
past 180 days participation in another clinical study; pregnancy, possible
pregnancy, or lactation; history of allergy to eggs or egg products; surgical
procedure or liver biopsy within 24 hours before administration of
perflubutane microbubbles; administration or scheduled administration of
another contrast agent within 24 hours before or after administration of
perflubutane microbubbles; difficulty in recognition of a target lesion
previously determined with DCT or difficulty with a scan of the whole liver
with unenhanced ultrasound owing to poor baseline image quality; and mass or
lesion size 10 cm or greater.
Among 196 patients enrolled from April 2002 to March 2003, three patients
were excluded from the study: Two did not receive per flubutane microbubbles
and one had a good clinical practices violation. Of the 193 patients eligible
for safety evaluation, 130 were men and 63 were women. The mean age was 63
years (range, 23-80 years). Among the 193 patients eligible to participate in
the safety evaluation, 190 patients were eligible for evaluation of the
efficacy of vascular phase imaging and 191 for evaluation of the efficacy of
Kupffer phase imaging. One patient was excluded from the efficacy evaluation
for not meeting the study recruitment criteria. In addition, two patients from
vascular and one patient from the Kupffer phase imaging were excluded because
they missed the video recording. The number of patients eligible for vascular
phase imaging included 121 with hepatocellular carcinoma (HCC), 38 with
metastatic lesions, 17 with hemangiomas, nine with other benign lesions, and
five with other malignant lesions. One additional patient with a benign lesion
was included in the evaluation of Kupffer phase imaging.
Contrast Agent
Perflubutane microbubbles (Sonazoid, GE Healthcare) is a lyophilized
preparation reconstituted for injection and contains 16 µL of perflubutane
microbubbles in one vial. The contents of each vial were resuspended in 2 mL
of water for injection. Each patient received a single injection of 0.12
µL/kg of microbubbles (0.015 mL/kg of the reconstituted suspension) into a
forearm vein followed by a 10-mL saline flush.
Ultrasound
All ultrasound scanners (Aplio, Toshiba Medical Systems; Elegra, Siemens
Healthcare; EUB 8500, Hitachi; HDI 5000, Phillips Healthcare; Logiq 7, GE
Healthcare; Sequoia 512, Siemens Healthcare) were equipped with broadband
curved-array transducers adapted for contrast imaging. Ultrasound was
performed before and after enrollment. Unenhanced ultrasound per formed before
enrollment was used as a reference standard and to assess whether the subject
met the inclusion criteria and fulfilled none of the exclusion criteria.
Ultrasound imaging was performed after enroll ment to compare the efficacy of
CEUS with perfluorobutane micro bubbles. In each patient, one lesion of
interest, which had not been treated and was confirmed with DCT, was selected
for vascular phase imaging for lesion characterization. The whole liver was
scanned in the Kupffer phase for lesion detection. Unenhanced ultrasound
images corresponding to both the vascular and the Kupffer phase images also
were acquired for assessment by the blinded reviewers. All ultrasound images
were acquired by onsite investigators according to the following imaging
conditions and were recorded on S-VHS videotape for review by the blinded
readers.
Unenhanced ultrasound (baseline image)— The lesion of
interest was imaged for 15 seconds with each of the following techniques:
fundamental B mode, tissue harmonic B mode, color Doppler, and power Doppler.
Afterward, the whole liver was scanned, first in fundamental B mode and then
in tissue harmonic B-mode.
CEUS—Phase-modulation harmonic mode was used for both
vascular and Kupffer phase imaging (mechanical index, 0.3-0.5; frame rate,
8-10 frames/s; transmitting frequency, 1.5-2 MHz). The focus was set below the
lesion of interest for vascular phase imaging and at 4-8 cm for the left lobe
and 8-10 cm for the right lobe for Kupffer phase imaging. The lesion of
interest was imaged from 15 seconds before injection to 1 minute after
injection (vascular phase imaging). No further scanning was performed until
the Kupffer phase imaging, which was begun 10 minutes after injection. The
whole liver was scanned twice with the same protocol as for unenhanced
ultrasound.
Dynamic CT
Dual-phase dynamic contrast-enhanced studies were performed with helical CT
or MDCT. Twelve centers used MDCT and three centers used helical CT. The
imaging conditions were not standardized for this study because DCT was
performed before enrollment but had been optimized by the respective centers
with a mean slice thickness of 6.9 ± 2.0 (SD) mm (range, 2-10 mm). DCT
was performed within the month before enrollment for malignant tumors and
within 3 months before enrollment for benign tumors. These images were
provided for review by the blinded readers.
Reference Standard
The reference standard procedures, which had been performed by onsite
investigators before study enrollment, included diagnostic imaging with
unenhanced ultrasound and DCT, acquisition of relevant clinical information
such as history or existing disorder, and assessment of clinical and
biochemical biomarkers. If necessary, dynamic MRI, angiography, or pathologic
examination was added.
For characterization, the disease diagnosis was changed when it was
believed it would be changed after CEUS and it was confirmed during treatment,
or it was changed in the process of treatment during this study period. The
disease diagnosis was changed in eight cases, including three cases influenced
by CEUS findings. Seven of the eight cases were confirmed at histologic
examination of specimens obtained at biopsy or surgery, and one case was
confirmed in follow-up. For detection, the number and size of the lesions were
recorded by onsite investigators on the basis of findings at unenhanced
ultrasound, DCT, or other procedure before enrollment and were used as the
reference standards. Patients with newly detected lesions visible only with
CEUS under went follow-up by onsite investigators for 3 months. To confirm
whether a lesion was a true lesion, onsite investigators used techniques such
as DCT, contrast-enhanced MRI, angiography, biopsy, surgery, or a combination
of these procedures, except for unenhanced ultrasound and CEUS.
Image Reading
Two readings were performed: an unblinded reading by onsite investigators
who had access to all clinical and imaging information and an offsite reading
by blinded reviewers. Three blinded reviewers for ultrasound and another three
blinded reviewers for DCT were selected from specialists in the field who were
independent of the onsite investigators and the coordinating investigator.
Unenhanced ultrasound and CEUS videotapes for readings by blinded reviewers
were made after enrollment, whereas DCT images were obtained before
enrollment. Patient and site identification data were removed from the
ultrasound videotapes and CT images. The ultrasound videotapes and CT images
then were randomized into three equal portions. Each reader reviewed one third
of the total number of cases.
Before evaluation, the three reviewers received training to maintain
consistency in the evaluation criteria. For confirmation of reliability after
the training, each reader independently evaluated ultrasound videotapes and CT
images from 20 cases that had been randomized and from which identifying
information was removed. In the characterization assessment, the rates of
complete agreement on unenhanced ultrasound, CEUS, and DCT findings among the
three reviewers were 85%, 90%, and 90%. In detection assessment, the rates
were 95%, 90%, and 90%. These percentages suggest that interobserver
reliability was ensured.
The blinded reviewers assessed the images without clinical information and
without know ledge of the results of the onsite evaluation. For
characterization with ultrasound, the blinded reviewers interpreted unenhanced
ultrasound videotapes depicting only the lesion of interest in each patient
separately from tapes containing the vascular phase of CEUS. For detection
with ultrasound, the reviewers interpreted unenhanced ultrasound videotapes
containing only whole liver scans for each patient separately from those
containing the Kupffer phase of CEUS. For CT, the reviewers read CT images
containing only slices depicting the lesion of interest for characterization.
CT images of all liver slices were used for detection.
In the characterization assessments, the re viewers classified their
diagnoses into five categories: HCC, hepatic metastasis, hemangioma, other
benign lesion, and other malignant lesion. In addition, the reviewers of
ultrasound images reported their degree of confidence in their diagnoses as
definite, probable, or suspect. In detection, the reviewers of both ultrasound
and DCT images recorded the location and size of the lesions.
Efficacy Evaluation
The results of the assessments by the blinded reviewers with each technique
(unenhanced ultrasound, CEUS, and DCT) were compared with reference standard
findings by the onsite investigators. For evaluation of characterization
efficacy, the rates of correct diagnoses for the various lesion types were
assessed and compared for unenhanced ultrasound, CEUS, and DCT. Sensitivity
and specificity were calculated for correct classification of lesions as
malignant or benign. Degree of confidence in the diagnosis was compared
between unenhanced ultrasound and CEUS. For evaluation of detection efficacy,
the numbers of patients in whom the number of lesions detected by blinded
reviewers was less than, equal to, or more than that detected with the
reference standard were calculated for unenhanced ultrasound, CEUS, and DCT
and compared. In addition, the numbers of lesions detected by blinded
reviewers were used to compare efficacy between methods. Efficacy in terms of
detection of different types of lesions and of detection of lesions in various
size categories was evaluated in a similar manner. In the cases of patients
whose treatment strategy was changed on the basis of information from CEUS,
the reasons for doing so were recorded.
Safety Evaluation
Safety was evaluated by the onsite investigators. Clinical chemistry
variables and vital signs were assessed immediately before and within 24 hours
after injection. Patients were observed for adverse events for 72 hours after
injection, and the severity and causes of the events were assessed. Serious
adverse events were observed for 7 days. Severity criteria were as follows:
mild, temporary and easily tolerable; moderate, interfering with normal
activities; and severe, completely preventing normal activities.
Statistical Analysis
For assessment of characterization efficacy, the McNemar test was used to
compare the rates of correct diagnosis of lesions for unenhanced ultrasound,
CEUS, and DCT. For assessment of detection efficacy, Wilcoxon's signed rank
test was used to compare the lesion detection rates obtained with unenhanced
ultrasound, CEUS, and DCT. For all tests, p < 0.05 was considered
to indicate a statistically significant difference. A statistical software
package (SAS version 8.2, SAS) was used for the statistical analyses.
Results
Characterization
Different types of focal lesions had different patterns of enhancement on
vascular phase images. Typical enhancement patterns of HCC, metastasis, and
hemangioma on CEUS and DCT images are shown in Figures
1A,
1B,
1C,
1D,
1E,
1F,
2A,
2B,
2C,
2D,
2E,
2F,
3A,
3B,
3C,
3D,
3E, and
3F. In all cases, CEUS images
were adequate for assessment. In no case was lesion contrast missing owing to
artifacts from the microbubbles.
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Fig. 1D —75-year-old man with hepatocellular carcinoma. Scale bar = 4
cm. Late vascular phase perflubutane-enhanced ultrasound image shows
homogeneously enhanced perfusion in tumor 20 seconds after contrast
injection.
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As shown in Table 1, the
overall rate of correct diagnosis of lesions by the blinded reviewers
significantly improved from 68.4% for unenhanced ultrasound to 88.9% for CEUS
(p < 0.001). In addition, the overall rate of correct diagnosis
with CEUS was significantly higher than that with DCT (80.5%) (p =
0.008). In classification of the lesions into the five types, the rates of
correct diagnosis of HCC, metastasis, and hemangioma were significantly higher
for CEUS than for unenhanced ultrasound (p < 0.001, p =
0.002, and p = 0.025). In particular, all 17 cases of hemangioma were
correctly diagnosed with CEUS (100%). The performance of CEUS in the correct
diagnosis of metastasis was superior to that of DCT, but no significant
differences were evident for other types of lesions.
In terms of correct classification of lesions as malignant or benign, the
overall accuracy and sensitivity significantly improved from 86.3% and 89.0%
for unenhanced ultrasound to 97.4% and 98.8% for CEUS (both p <
0.001) (Table 2). In contrast,
no significant differences in accuracy, sensitivity, or specificity were found
between CEUS and DCT.
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Fig. 4A —Degree of confidence scored by blinded reviewers. Graphs show
degree of confidence in diagnoses made with unenhanced ultrasound (A)
and contrast-enhanced ultrasound (CEUS) (B). Disagreement
(black) indicates that diagnosis by blinded reviewers was not
correct. Agreement (white) indicates diagnosis by blinded reviewers
was correct.
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Fig. 4B —Degree of confidence scored by blinded reviewers. Graphs show
degree of confidence in diagnoses made with unenhanced ultrasound (A)
and contrast-enhanced ultrasound (CEUS) (B). Disagreement
(black) indicates that diagnosis by blinded reviewers was not
correct. Agreement (white) indicates diagnosis by blinded reviewers
was correct.
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The level of diagnostic confidence scored by the blinded reviewers was
compared between unenhanced ultrasound and CEUS (Figs.
4A, and
4B). The degree of confidence
in diagnoses made with unenhanced ultrasound was scored definite in four of
189 cases (2.1%), and one of these diagnoses was incorrect. The number of
diagnoses scored definite with CEUS increased to 132 of 189 (69.8%), and 126
of these diagnoses (95.5%) were correct.
Detection
Metastatic lesions were clearly depicted as contrast defects on CEUS
Kupffer phase images (Figs.
5A,
5B, and
5C).
Table 3 shows the number of
patients in whom more, an equal number of, and fewer lesions were detected by
the blinded reviewers than by the onsite readers using the reference standard.
Using DCT, the blinded reviewers detected more or fewer lesions than were
found with the reference standard in similar numbers of patients. Using CEUS,
the blinded reviewers detected more lesions approximately twice as often as
they detected fewer lesions. The percentages of patients in whom more lesions
were detected by the blinded reviewers than were found with the reference
standard were 31.9% (61 patients), 18.8% (36 patients), and 13.1% (25
patients) for CEUS, DCT, and unenhanced ultrasound
(Table 3). The detection rate
with CEUS was significantly higher than that with unenhanced ultrasound and
DCT (p < 0.001 and p = 0.008).
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TABLE 3 : Comparison of Numbers of Patients With Lesions Identified by Blinded
Reviewers and Those Identified With Reference Standard (n =
191)
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The number of lesions detected with unenhanced ultrasound, CEUS, and DCT
compared with the reference standard was determined for the five types of
lesions, and the results are shown in Table
4. The number of lesion detected with CEUS was larger than that
with unenhanced ultrasound and DCT. The number of lesions detected with CEUS
(464 lesions) was larger than the number detected with the reference standard
(375 lesions). It was particularly evident that the number of metastatic
lesions detected with CEUS was significantly larger than the number detected
with unenhanced ultrasound (p < 0.001) and the number detected
with DCT (p < 0.001).
In classification of lesions according to size, the number of small lesions
(
1 cm) detected with CEUS was significantly larger than the number
detected with unenhanced ultrasound (p < 0.001) and DCT
(p = 0.008) (Fig. 6).
Furthermore, in classification of metastatic lesions according to size, the
number of lesions 1 cm in diameter or smaller detected with CEUS was
significantly larger than the number detected with DCT (p <
0.001). No significant difference was found between CEUS and DCT in the
detection of lesions larger than 1 cm
(Fig. 7).
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Fig. 6 —Graph shows number of lesions classified according to lesion
size detected by blinded reviewers using unenhanced ultrasound
(gray), contrast-enhanced ultrasound (CEUS) (striped), and
dynamic CT (white) and by onsite investigators using reference
standard (black). Wilcoxon's signed rank test for lesions 1 cm or
smaller, CEUS vs dynamic CT, p = 0.008; CEUS vs unenhanced
ultrasound, p < 0.001; CEUS vs reference standard, p =
0.001.
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Fig. 7 —Graph shows number of metastatic lesions classified according
to lesion size detected by blinded reviewers using unenhanced ultrasound
(gray), contrast-enhanced ultrasound (CEUS) (striped), and
dynamic CT (white) and by onsite investigators using reference
standard (black). Wilcoxon's signed rank test for lesions 1 cm or
smaller, CEUS vs dynamic CT, p < 0.001; CEUS vs unenhanced
ultrasound, p < 0.001; CEUS vs reference standard, p <
0.001.
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Follow-Up of Newly Detected Lesions and Influence on Treatment Strategy
Among patients with newly visible lesions detected only with CEUS, 16
patients were available for follow-up, and the lesions in 12 patients were
confirmed to be true lesions. Confirmation was verified at surgery in four
cases, follow-up CT in four cases, follow-up MRI in two cases, follow-up
angiography in one case, and needle biopsy in one case. All lesions in the
other four patients were benign. Therefore, 75% (12 of 16) of cases were
correctly diagnosed with CEUS. Table
5 shows the cases in which treatment strategy was changed on the
basis of the diagnosis reached by the onsite investigators using CEUS. On the
basis of information obtained on vascular or Kupffer images, the treatment
strategy changed for 13 patients (6.8%).
Safety
No deaths, serious or severe adverse events were found in this study. The
incidence of adverse events was 49.2% (95% confidence limits, 42.2%, 56.3%)
(95 of 193 cases). Events with an incidence greater than 2% are shown in
Table 6. The incidence of
adverse drug reactions was 10.4% (95% confidence limits, 6.1%, 14.7%) (20 of
193 cases (Table 7). All
adverse drug reactions were mild.
Discussion
The efficacy of CEUS with perflubutane microbubbles in the characterization
and detection of lesions was assessed and compared with that of unenhanced
ultrasound and DCT. Characterization of focal liver lesions relies on
well-known vascular enhancement patterns at DCT and dynamic MRI, which are the
standard methods of diagnosis
[20]. Contrast enhancement
with perfluorochemical microbubble agents in nonlinear ultrasound imaging,
such as phase-modulation harmonic mode, has been found to be efficacious in
various studies [21]. Because
of the high temporal and spatial resolution of sonography, CEUS can depict the
arterial perfusion characteristics of liver lesions and depict fine tumor
vasculature. DCT has poorer performance than CEUS.
Differences in contrast enhancement patterns among lesion types have been
well studied with several perfluorochemical microbubble agents, and CEUS has
had high accuracy in characterization of lesions
[22,
23]. Because contrast effects
similar to those of other perfluorochemical agents are observed at CEUS with
perflubutane microbubbles, it is not surprising that the accuracy of CEUS is
higher than that of DCT. For example, although the number of cases was
limited, the accuracy of CEUS in the diagnosis of hemangioma was 100%.
Real-time CEUS depicted the typical enhancement pattern of
hemangioma—namely, peripheral globular pooling of contrast material
(cotton-wool appearance) followed by gradual perfusion of the entire lesion.
Compared with unenhanced ultrasound, CEUS not only had approximately 20%
greater overall accuracy but also was associated a higher degree of diagnostic
confidence. Therefore, CEUS with perflubutane microbubbles is likely to be
useful as a standard method of diagnosis and one that is comparable with
DCT.
In terms of lesion detection, CEUS depicted more lesions than did DCT, many
of which were small metastatic lesions ( 1 cm). Because of the high
specificity of uptake of perflubutane microbubbles by Kupffer cells in normal
parenchyma
[16-18],
malignant lesions that lack Kupffer cells are negatively enhanced. This
characteristic, coupled with the higher spatial resolution of ultrasound, may
explain the increased efficacy of CEUS in the detection of small lesions. SH U
508A (Levovist, Bayer Schering Pharma), an air-based microbubble agent, has
been reported to have a parenchyma-specific contrast effect similar to that of
perflubutane microbubbles, and this effect has been useful in detecting
lesions [24,
25]. The parenchyma-specific
contrast effect of SH U 508A is observed several minutes after injection, but
it is effective only when imaging is performed at high acoustic power, and the
effect is transient. Because imaging with SH U 508A entails destruction of
microbubbles, visualization of the whole liver is limited to a single scan
[26]. In contrast, because
imaging with perflubutane microbubbles is performed at lower acoustic power
without destruction of microbubbles, repeated scanning of the whole liver can
be accomplished, as in our study. This capability may help operators reduce
the number of missed lesions. Another technique that entails the use of
Kupffer phase imaging is contrast MRI with superparamagnetic iron oxide, which
is also taken up by Kupffer cells
[27,
28]. Although further studies
are needed to compare CEUS with perflubutane microbubbles and MRI with
superparamagnetic iron oxide, CEUS has the advantage of higher temporal and
spatial resolution.
Most malignant tumors of the liver are HCC and metastatic lesions. HCC is
one of a few malignant tumors in which the etiologic and pathogenic processes
are understood and groups at high risk are well known. Chronic viral hepatitis
leads to cirrhosis, which is a predisposing factor for HCC
[29,
30]. This course is
predominant in Asia. For early detection and treatment, it is recommended that
these high-risk groups undergo ultrasound and DCT every 3 and 6 months,
respectively [31]. Other
groups at high risk are patients with alcoholic liver disease and,
increasingly, those with fatty infiltration (non-alcoholic steatohepatitis)
[32], which predominate in
other parts of the world. Thus the need for early diagnosis of HCC is
increasing. The liver also is a frequent site of metastasis. Strategies for
the management of primary tumors and the prognosis are influenced by the
absence or presence of hepatic metastasis, and early detection of these
lesions is important.
Although it is the standard method of diagnosis of both types of liver
tumors, DCT has limitations. First, radiation-induced cancer from CT
examinations is becoming a major issue
[33], and fewer CT
examinations are being recommended. CT should be used only when the benefits
outweigh the risks. Second, the sensitivity of DCT with helical CT in the
detection of small metastatic lesions of the liver ( 1 cm) is 30-50%
[34]. DCT with MDCT at
collimation less than 5 mm does not have greater sensitivity for lesions 1.5
cm or smaller [35]. In this
study, CEUS with perflubutane microbubbles was superior to DCT in both
characterization and detection of focal liver lesions, especially in the
detection of small hepatic metastatic lesions. The treatment of 13 of 191
patients (6.8%) was changed on the basis of the CEUS diagnosis. This finding
suggests that current diagnostic procedures have room for improvement and that
CEUS with perflubutane microbubbles may be an alternative to DCT.
In this study, patients with unenhanced ultrasound images of adequate
quality were enrolled, and all the lesions imaged with unenhanced ultrasound
were enhanced at CEUS without artifacts such as shadowing. This finding
suggests that perflubutane microbubbles cause fewer artifacts. This effect may
be attributed to the fact that the higher mechanical index can be applied for
perflubutane microbubbles than for other perfluorochemical microbubbles, such
as aqueous suspension of phospholipid-stabilized micro bubbles filled with
sulfur hexafluoride (SonoVue, Bracco) and perflutren (Definity, Lantheus
Medical Imaging) owing to higher resistance to pressure
[14].
The incidences of adverse events and adverse drug reactions were
self-limited over the period of observation and were 49.2% and 10.4%,
respectively. The relatively high incidence of adverse events can be
attributed to adverse events caused by the primary disease, cancer, itself and
by treatments and examinations after administration of perflubutane
microbubbles. All adverse drug reactions were mild in intensity, and none was
peculiar to perflubutane microbubbles. Therefore, the findings suggest that
perflubutane microbubbles is a safe contrast agent.
A limitation of this study was potential bias affecting the blinded
readings of DCT images because DCT was part of the reference standard. Despite
this possible bias in favor of DCT, CEUS was more accurate than DCT in lesion
characterization. This finding suggests that CEUS has potential as a
diagnostic alternative to DCT for lesion characterization. Other limitations
regarding DCT were that MDCT was not used at all centers and the slice
thickness varied from 2 to 10 mm among the centers and was not standardized,
although all were within routine CT protocols.
Another limitation was that not all newly detected lesions were followed
up. Compared with the reference standard, 89 new lesions were detected only
with CEUS in 61 patients. The onsite investigators tried to conduct follow-up,
and 12 of 16 cases were confirmed to be true lesions. This finding suggests
that CEUS has high potential in the detection of new true lesions. An
additional limitation was the extent of the overall safety assessment.
Although no serious adverse reactions, such as anaphylactic reaction or shock,
were observed with perflubutane microbubbles in the 193 patients in this study
or in more than 2,000 patients in clinical trials in the United States and
Europe (unpublished data), further careful safety assessments are needed.
We conclude that compared with unenhanced ultrasound and DCT, CEUS with
perflubutane microbubbles had better diagnostic efficacy in the
characterization and detection of focal liver lesions with no substantial
adverse drug reactions. CEUS with perflubutane microbubbles has potential as a
diagnostic alternative to DCT in the care of patients with known or suspected
focal liver lesions.
Acknowledgments
We thank K. Koito, T. Iwasaki, K. Sasaki, Y. Mizuguchi, N. Izumi, N. Ueno,
T. Kumada, H. Gotoh, F. Urano, Y. Horiguchi, Y. Matsuda, S. Tanaka, Y.
Kinoshita, M. Sata, S. Matsutani, M. Kudo, T. Hirai, A. Kono, A. Tanimoto, and
T. Ichikawa, for data collection and assessment.
The 15 enrolling centers were Sapporo Medical University Hospital, Sapporo;
Tohoku University Hospital, Sendai; National Cancer Center, Tokyo; Showa
University Hospital, Tokyo; Tokyo Medical University, Tokyo; Musashino Red
Cross Hospital, Musashino; Yokohama City University Hospital, Yokohama; Nagoya
University Hospital, Nagoya; Fujita Health University Hospital, Toyoake;
Toyohashi Municipal Hospital, Toyohashi; Ogaki Municipal Hospital, Ogaki;
Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; Otemae
Hospital, Osaka; Shimane University Hospital, Izumo; and Kurume University
Hospital, Kurume.
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Abstract
Introduction
