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1 Division of Gastroenterology and Hepatology, Department of Internal Medicine,
Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511
Japan.
2 Abdominal Ultrasound Unit, Kinki University School of Medicine, Osaka-Sayama,
589-8511, Japan.
3 First Department of Surgery, Kinki University School of Medicine,
Osaka-Sayama, 589-8511, Japan.
Received July 1, 2002;
accepted after revision August 27, 2002.
Address correspondence to M. Kudo.
Abstract
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SUBJECTS AND METHODS. We studied 40 patients with 44 nodules measuring 1.5-11.0 cm in diameter (mean ± SD, 3.9 ± 2.0 cm) who underwent transcatheter arterial chemoembolization. Coded phase-inversion harmonic sonography, a technique based on a combination of phase-inversion harmonics and coded technology, was performed with a contrast agent approximately 1 week after chemoembolization. The results were compared with those obtained using dynamic CT (n = 44 lesions) and dynamic MR imaging (n = 20 lesions). We also evaluated the recurrence of hepatocellular carcinoma during clinical follow-up in 17 patients who did not undergo additional local therapy.
RESULTS. The detection rates of intratumoral vascularity of coded phase-inversion harmonic sonography, dynamic CT, and dynamic MR imaging were, respectively, 38 (86%) of 44 lesions, 19 (43%) of 44 lesions, and 10 (50%) of 20 lesions. Of 19 nodules of hepatocellular carcinoma treated only by transcatheter arterial chemoembolization, 17 nodules showed enhancement on coded phase-inversion harmonic sonography, suggesting incomplete responses. In all 17 nodules, apparent recurrence was noted on dynamic CT during clinical follow-up, even in nodules that had been observed to be completely filled with iodized oil 1 week after the chemoembolization.
CONCLUSION. We found coded phase-inversion harmonic sonography to be highly sensitive and accurate for evaluating the treatment response in patients with hepatocellular carcinoma even shortly after treatment. Consequently, it allows early recognition of the need for additional local ablation therapy and estimation of the risk of hepatocellular carcinoma recurrence.
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CT and MR imaging are commonly used to evaluate the efficacy of transcatheter arterial chemoembolization [4, 5, 6, 7, 8, 9]. However, evaluation using these modalities must be delayed by more than a month because tumor regression is rarely observed immediately after transcatheter arterial chemoembolization [4], and iodized oil may be washed out gradually, even if it filled the entire tumor immediately after treatment. Improvements have been made in both sonography equipment and contrast agents that allow more sensitivity in displaying tumor flow [10, 11, 12, 13, 14]. Coded phase-inversion harmonic sonography (LOGIQ 700 EXPERT; General Electric Medical Systems, Milwaukee, WI) is a technique based on a combination of phase-inversion harmonics and coded technology. When used with a contrast agent, this method can depict—without Doppler-related artifacts—signals from microbubbles with a slow flow. The purpose of our study was to assess the value of coded phase-inversion harmonic sonography in the evaluation of early-phase therapeutic response to transcatheter arterial chemoembolization in patients with hepatocellular carcinoma by comparing the effectiveness of the technique with those of dynamic CT and dynamic MR imaging.
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-fetoprotein
level, Lens culinaris agglutinin-reactive -fetoprotein level,
and des-gamma-carboxyprothrombin level. The characteristic findings of
hepatocellular carcinoma were positive enhancement during the arterial phase
CT and washout during the equilibrium phase of dynamic CT or hypervascularity
on hepatic angiography. All our patients had been examined by experienced
surgical staff and were considered to be unsuitable candidates for surgical
intervention. Patients older than 90 years were excluded from our study. We also excluded patients who had uncontrolled liver disease decompensation or an invasive pattern, such as portal vein thrombosis or extrahepatic spread; patients who exhibited any contraindication for an arterial procedure, such as impaired function related to clotting disorders (prothrombin activity of < 1.5, international normalized ratio; or platelet count of < 40 x 109/L), renal failure, or severe associated disease; and patients who had severe allergies to contrast media.
Contrast harmonic sonography was performed 4-8 days (median, 6 days) after transcatheter arterial chemoembolization, dynamic CT was performed 4-9 days (median, 7 days) after the procedure, and dynamic MR imaging was performed 4-10 days (median, 5 days) after the procedure to evaluate the effectiveness of the procedure. Because of difficulties in patient scheduling, only 20 lesions could be examined with dynamic MR imaging.
Twenty-three patients received additional treatment with radiofrequency ablation or percutaneous ethanol injection to improve their prognoses after transcatheter arterial chemoembolization. The other 17 patients were treated only by transcatheter arterial chemoembolization for poor hepatic function or for multiple liver nodules. These 17 patients (19 nodules of hepatocellular carcinoma) were followed up to allow us to compare the findings of coded phase-inversion harmonic sonography performed a week after transcatheter arterial chemoembolization with those of CT performed 2 months after the chemoembolization.
Therapeutic Procedure
Before transcatheter arterial chemoembolization, patients underwent hepatic
angiography. An emulsion of iodized oil and 30-50 mg of a chemotherapeutic
agent, epirubicine, was then injected, followed by the injection of a gelatin
sponge via a catheter. If the tumor was solitary, the tip of the catheter was
selectively placed into the segmental or subsegmental arteries feeding the
tumor [15,
16]. Otherwise, the tip was
placed into the right or left branch of the hepatic artery. The volume of the
injected emulsion was determined by the tumor volume (maximal volume of
emulsion, 10 mL).
Sonography
Coded phase-inversion harmonic sonography was performed using a LOGIQ 700
EXPERT unit and a 2-4 MHz curved array wide-band transducer. The acoustic
power of coded phase-inversion harmonic sonography mode was set at the default
setting with a mechanical index of 0.6-0.8. Microbubbles of the sonographic
contrast agent (Levovist; Schering, Berlin, Germany) stabilized in the
microparticle suspension (palmitic acid) had an average diameter of 1.3 µm
(range, 1-8 µm), which allowed the microbubbles to traverse the pulmonary
capillary bed and enhance the signal of blood. Through a 20-gauge cannula
placed in an antecubital vein, 2.5 g (concentration, 400 g/L) of the contrast
agent was injected manually at a speed of 1 mL/sec and was flushed by an
additional 10 mL of ordinary saline.
At the appearance of the first microbubble signal in the liver parenchyma, patients were requested to hold their breath. Real-time images in the optimal scanning plane were displayed by slightly changing the scanning slice showing the nodule. In addition to using real-time continuous imaging to reveal tumor vessels, we performed interval-delay scanning or flash imaging to depict tumor parenchymal flow in the vascular phase (< 5 min after injection of the contrast agent). All data were recorded continuously on videotape, and still images from cine loops were stored on magnetic optical disks. We avoided inter-operator variations by having all coded phase-inversion harmonic sonography performed by the same operator using the same examination protocol. Two physicians as well as the sonographer reviewed the videotapes of all contrast-enhanced harmonic studies of each lesion and prospectively assessed the therapeutic response without the knowledge of the dynamic CT study results.
Vascular findings on coded phase-inversion harmonic sonography included tumor vessel flow shown by continuous imaging in the early arterial phase (about 15-40 sec after injection of the contrast agent) and tumor parenchymal flow shown by interval-delay scanning during the late vascular phase (< 5 min after injection of the contrast agent). The positive enhancement of intratumoral vessels in continuous imaging or intratumoral parenchymal flow on interval-delay scanning was interpreted as viable tumor flow in nodules. In contrast, the negative enhancement of intratumoral vessel and intratumoral parenchymal flow (defined as no bubble signal within the tumor although the surrounding liver parenchyma was filled with bubble signals) was interpreted as complete tumor necrosis.
CT
Unenhanced CT scans were obtained, as well as three-phase dynamic CT scans
obtained 30, 60, and 180 sec after the initiation of the injection of contrast
medium with a 7.0-mm slice thickness. Dynamic CT was performed with 100 mL of
contrast medium (ioversol, Optiray 320; Yamanouchi Pharmaceuticals, Tokyo,
Japan) injected into the antecubital vein at a rate of 3 mL/sec. Areas in
tumors in which iodized oil accumulated after chemoembolization were regarded
as necrotic as were areas with persistent low density on both routine and
arterial phase dynamic CT scans. Areas in tumors that were enhanced on
arterial phase dynamic CT were regarded as viable and were supplied by feeding
arteries.
MR Imaging
MR imaging was performed with a superconducting imager (Toshiba, Tokyo,
Japan) operating at 1.5 T. We obtained T1-weighted gradient-echo images
(TR/TE, 500/15; slice thickness, 8 mm; number of excitations, 2; matrix, 160
x 384; field of view, 30 x 30 cm) and T2-weighted gradient-echo
images (3000/80; slice thickness, 8 mm; number of excitations, 2; matrix, 160
x 384; field of view, 30 x 30 cm). A multislice contrast-enhanced
study covering the entire liver parenchyma obtained with a breath-hold
T1-weighted spoiled gradient-echo sequence (170/4.0; flip angle, 70°;
slice thickness, 8 mm; number of excitations, 1; matrix, 128 x 320;
field of view, 28.0 x 35.0 cm) was performed before and 30, 50, and 130
sec after a bolus injection of 0.1 mmol/kg of gadolinium chelate
(gadopentetate dimeglumine, Magnevist; Berlex Laboratories, Wayne, NJ). If
treatment had been successful, the lesion on dynamic MR imaging no longer
showed enhanced areas after the administration of gadolinium, indicating tumor
necrosis. If the treatment had been unsuccessful, persistent neoplastic tissue
was depicted by residual hypervascular areas within the lesion.
Findings on dynamic CT and dynamic MR imaging were reviewed and determined through consensus by two hepatologists who were not aware of the results of contrast-enhanced harmonic sonography.
Statistical Analysis
Data were expressed as means ± standard deviations. Differences in
the detection rates of intratumoral blood flow after chemoembolization by
coded phase-inversion harmonic sonography, dynamic CT, and dynamic MR imaging
were compared with chisquare and Fisher's exact tests. A p value of
less than 0.05 was considered to be significant.
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For 25 of the 44 nodules, findings visualized on coded phase-inversion harmonic sonography of intratumoral blood flow agreed with findings seen on dynamic CT (Table 1). However, in 19 of 44 nodules, intratumoral blood flow was depicted only on coded phase-inversion harmonic sonography (Fig. 1A, 1B).
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In 13 of the 20 nodules examined with dynamic MR imaging, intratumoral blood flow was depicted both on coded phase-inversion harmonic sonography and on dynamic MR imaging (Table 2). However, intratumoral blood flow in seven of 20 nodules was depicted only on coded phase-inversion harmonic sonography (Fig. 2A, 2B, 2C, 2D, 2E). We found all nodules that displayed intratumoral blood flow on dynamic CT or dynamic MR imaging also displayed blood flow on coded phase-inversion harmonic sonography.
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In regard to the 17 patients with 19 nodules treated only with transcatheter arterial chemoembolization, two nodules with no enhancement on coded phase-inversion harmonic sonography showed no recurrence at 2 months after the chemoembolization (Table 3). The other 17 nodules with enhancing areas on coded phase-inversion harmonic sonography showed iodized oil washout and local recurrence on dynamic CT 2 months after chemoembolization, even those nodules that had been shown to be totally filled with iodized oil 1 week after chemoembolization (Fig. 3A, 3B, 3C, 3D). The areas of recurrence were compatible with the areas in which intratumoral flow was depicted on coded phase-inversion harmonic sonography performed 1 week after transcatheter arterial chemoembolization.
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Because iodized oil has little influence on signal intensity of MR imaging, dynamic MR imaging has been reported to have a specific advantage over CT in the assessment of the effectiveness of transcatheter arterial chemoembolization [5]. However, the signal intensity of some lesions of hepatocellular carcinoma sometimes changes from hypointense to hyperintense after treatment with transcatheter arterial chemoembolization. This fact may make it difficult to evaluate tumor enhancement even on dynamic MR imaging [6]. In our study, seven of the 20 nodules that showed no enhancement on dynamic MR imaging were shown as partially enhanced on coded phase-inversion harmonic sonography shortly after chemoembolization, but no nodule shown as unenhanced on coded phase-inversion harmonic sonography was shown as partially enhanced on dynamic MR imaging. These results clearly show the superiority of coded phase-inversion harmonic sonography over dynamic CT and dynamic MR imaging in depicting minute intratumoral residual flow in hepatocellular carcinoma after chemoembolization.
The iodized oil was gradually washed out from the viable area of the tumor in areas where residual intratumoral flow existed, and the tumors were viable even after transcatheter arterial chemoembolization. In nine nodules with no visualized intratumoral flow on dynamic CT scans obtained shortly after chemoembolization, the enhancing area—the area with recurrence—was depicted on dynamic CT scans obtained 2 months after chemoembolization. On the other hand, in all 17 nodules in which areas of intratumoral blood flow were depicted on coded phase-inversion harmonic sonograms obtained shortly after chemoembolization, areas of apparent recurrence were observed on dynamic CT scans obtained 2 months after chemoembolization.
This evidence strongly suggests that the residual vascularity shown on coded phase-inversion harmonic sonography 1 week after transcatheter arterial chemoembolization can be regarded as viable cancer cells without a risk of false-positive results. Thus, the sensitivity and specificity of coded phase-inversion harmonic sonography in the estimation of future recurrence were 100% when findings of dynamic CT at 2 months after chemoembolization were regarded as the gold standard. This evidence suggests that coded phase-inversion harmonic sonography can depict residual viable tumor with high sensitivity and accuracy. Therefore, coded phase-inversion harmonic sonography could permit accurate estimates of the treatment response of hepatocellular carcinoma and of the future risk of hepatocellular carcinoma recurrence approximately 1 week after transcatheter arterial chemoembolization.
To obtain complete necrosis on the first attempt at therapy, one must correctly evaluate whether additional treatment (e.g., percutaneous radiofrequency ablation or ethanol injection) is necessary, especially during the period shortly after transcatheter arterial chemoembolization. Our observations seem to indicate that patients who have a nodule with intratumoral blood flow visualized on coded phase-inversion harmonic sonography have a risk of future recurrence that may be as high as 100% and, therefore, should receive additional transcatheter arterial chemoembolization or local ablation treatment such as radiofrequency ablation. Moreover, coded phase-inversion harmonic sonography can be helpful in detecting viable areas of the tumor after transcatheter arterial chemoembolization and useful in guiding the needle puncture for radiofrequency ablation because the enhancing viable area can be imaged in the sonographic plane. Consequently, efficient treatment using coded phase-inversion harmonic sonography approximately 1 week after treatment may result in patients with hepatocellular carcinoma requiring a shorter period of hospitalization.
In patients with many nodules of hepatocellular carcinoma, evaluation of the efficacy of transcatheter arterial chemoembolization in all nodules is difficult. CT or MR imaging is considered to be superior to coded phase-inversion harmonic sonography for evaluation of the total therapeutic effect of chemoembolization in such patients, but coded phase-inversion harmonic sonography can complement CT and MR imaging in the evaluation of therapeutic response. For patients with a solitary hepatocellular carcinoma nodule, we highly recommend assessing residual intratumoral flow on coded phase-inversion sonography to determine the necessity of additional treatment or future risk of recurrence.
In conclusion, coded phase-inversion harmonic sonography performed with iodized oil is highly sensitive and accurate in revealing tumor vascularity in patients with hepatocellular carcinoma shortly after transcatheter arterial chemoembolization. In our study, depiction of tumor vascularity on coded phase-inversion harmonic sonography was far superior to the depictions on dynamic CT and dynamic MR imaging. Therefore, coded phase-inversion harmonic sonography allows recognition of the need for additional local ablation therapy or estimation of future recurrence of hepatocellular carcinoma to be made shortly after transcatheter arterial chemoembolization. Further study may be necessary to support our conclusion.
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