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(Radiology. 1999;211:643-649.)
© RSNA, 1999


Vascular and Interventional Radiology

Radio-frequency Ablation of Hepatic Metastases: Postprocedural Assessment with a US Microbubble Contrast Agent—Early Experience1

Luigi Solbiati, MD, S. Nahum Goldberg, MD, Tiziana Ierace, MD, Marina Dellanoce, MD, Tito Livraghi, MD and G. Scott Gazelle, MD, MPH

1 From the Department of Radiology, Ospedale Generale, Busto Arsizio (VA), Italy (L.S., T.I., M.D.); the Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston (S.N.G., G.S.G.); and the Department of Radiology, Ospedale Civile, Vimercate (MI), Italy (T.L.). Received March 20, 1998; revision requested April 27; revision received August 5; accepted November 5. Address reprint requests to G.S.G., MGH DATA Group, Zero Emerson Pl, Ste 2H, Boston, MA 02114.


    Abstract
 TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To evaluate contrast agent–enhanced ultrasonography (US) in the detection of untreated tumor after radio-frequency (RF) ablation of hepatic metastases.

MATERIALS AND METHODS: Twenty patients with solitary colorectal liver metastases underwent percutaneous RF tumor ablation. Pre- and postablation imaging was performed with nonenhanced and enhanced color and power Doppler US and contrast-enhanced helical computed tomography (CT). Initial follow-up CT and US were performed 24 hours after ablation. The findings at US and CT were compared.

RESULTS: Nonenhanced US demonstrated intratumoral signal in 15 of 20 metastases before ablation. This signal increased after contrast agent administration. Contrast-enhanced US performed 24 hours after ablation demonstrated residual foci of enhancement in three tumors, whereas no US signals were seen in any tumor on nonenhanced scans. CT demonstrated small (<3-mm) persistent foci of residual enhancement in these three tumors and in three additional lesions that were not seen at US (US sensitivity, 50%; specificity, 100%; diagnostic agreement with CT, 85%). All six patients with evidence of residual tumor underwent repeat RF ablation.

CONCLUSION: Contrast-enhanced US may depict residual tumor after RF application and thereby enable additional directed therapy. The potential reduction in treatment sessions and/or ancillary imaging procedures might increase the ease and practicality of percutaneous ablation of focal hepatic metastases.

Index terms: Liver neoplasms, secondary, 761.33 • Liver neoplasms, US, 761.12981, 761.12983, 761.12984, 761.12986, 761.12988 • Radiofrequency (RF) ablation • Ultrasound (US), contrast media, 761.12988 • Ultrasound (US), Doppler studies, 761.12983, 761.12984 • Ultrasound (US), power Doppler studies, 761.1299


    Introduction
 TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Induction of coagulation necrosis by using thermal energy sources such as radio frequency (RF) (15), microwaves (6,7), and lasers (8,9) has recently been promoted as a new, minimally invasive technique for percutaneous tumor ablation. The potential benefits of these techniques include the ability to ablate tumor in nonsurgical candidates, reduced morbidity compared with that associated with surgery, the ability to perform real-time imaging guidance, and the potential to perform the procedure on an outpatient basis. We and others (15) have used RF ablation for the treatment of small hepatic primary and secondary malignancies. For this procedure, a needle electrode is placed directly into the tumor with imaging guidance. This procedure most often is performed with ultrasonography (US), because this modality enables visualization and precise, accurate placement of the electrode.

The primary goal of percutaneous ablation is complete ablation of the entire tumor. Unfortunately, however, the US findings of gray-scale, color Doppler, and power Doppler scanning after ablation do not correlate well with the extent of induced coagulation necrosis (15,10). Specifically, it has been observed that US may either underestimate or overestimate the zone of RF-induced coagulation necrosis. Furthermore, the US appearance of the treated area after ablation changes rapidly such that the actual size of the necrosis is difficult to estimate with US. Therefore, contrast material–enhanced computed tomography (CT), magnetic resonance (MR) imaging, or both are generally required to determine the extent of induced coagulation. Experience to date with use of either modality suggests that tumors that fail to enhance after treatment can be considered to be necrotic and therefore successfully treated. Conversely, focal areas of persistent contrast enhancement that are seen after RF ablation generally require re-treatment to achieve complete tumor necrosis.

Recently, microbubble contrast agents have become available for clinical use with US (11,12). The increased echogenicity of these agents enables improved detection of parenchymal organ blood flow compared with the echogenicity with routine color Doppler and power Doppler US (13). As a result, previously undetected differences in vascularity between benign and malignant lesions can be detected (1418). Because the agents can be used to help differentiate perfused from nonperfused tissue, it has been hypothesized that their use might help to improve the accuracy of US in the detection of residual (ie, viable) tumor after RF ablation. Therefore, we performed this study to investigate the potential role of contrast-enhanced US in the examination of patients immediately after RF ablation and, specifically, to determine its accuracy in the detection of residual tumor.


    MATERIALS AND METHODS
 TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
All treatments were performed at the Ospedale Generale, Busto Arsizio, Italy. The study was performed with approval from the institutional ethics committee. Written and/or oral informed consent was obtained from all patients at enrollment.

Patient Population
Twenty consecutive patients (mean age, 66.3 years; age range, 51–76 years) who were referred for treatment of solitary liver metastases of colorectal origin with percutaneous application of RF by using internally cooled RF electrodes (19) were included in this study (Figs 13). The metastases were 2.0–4.3 cm in diameter (mean diameter, 2.6 cm ± 0.4). All patients had undergone surgical resection of their primary tumors 6–24 months before the RF ablation procedure. The patients were not considered candidates for operative resection and therefore were referred specifically for RF ablation therapy because of the following reasons: Four patients had a history of prior hepatic resection, three had other metastases, 10 had coexistent morbidity, and three refused to undergo surgery. Pathologic proof of malignancy of the hepatic lesions was obtained in every case by using US-guided fine-needle aspiration biopsy. No concurrent chemotherapy or other medical treatment was administered to these patients during the study.



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Figure 1a. Metastasis in liver segment 4. (a) Contrast-enhanced helical CT scan in the portal venous phase demonstrates a 1.5-cm-diameter colorectal metastasis in segment 4. Blood vessels (arrow) surround and cross the lesion. (b) Power Doppler US scan of the metastasis in a, obtained after drip infusion of SH U 508A, shows rich vascularity within and at the periphery of the otherwise hypoechoic tumor (arrows). (c) Power Doppler US scan of the same tumor, obtained after administration of SH U 508A 24 hours after RF ablation, demonstrates a 4.5 x 3.5-cm avascular region (arrows) devoid of flow signal. (d) Contrast-enhanced helical CT scan of the same tumor, obtained the same day as that in c, demonstrates a lack of enhancement in this region (arrow), which helped to confirm the diagnosis of complete necrosis of tumor.

 


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Figure 1b. Metastasis in liver segment 4. (a) Contrast-enhanced helical CT scan in the portal venous phase demonstrates a 1.5-cm-diameter colorectal metastasis in segment 4. Blood vessels (arrow) surround and cross the lesion. (b) Power Doppler US scan of the metastasis in a, obtained after drip infusion of SH U 508A, shows rich vascularity within and at the periphery of the otherwise hypoechoic tumor (arrows). (c) Power Doppler US scan of the same tumor, obtained after administration of SH U 508A 24 hours after RF ablation, demonstrates a 4.5 x 3.5-cm avascular region (arrows) devoid of flow signal. (d) Contrast-enhanced helical CT scan of the same tumor, obtained the same day as that in c, demonstrates a lack of enhancement in this region (arrow), which helped to confirm the diagnosis of complete necrosis of tumor.

 


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Figure 1c. Metastasis in liver segment 4. (a) Contrast-enhanced helical CT scan in the portal venous phase demonstrates a 1.5-cm-diameter colorectal metastasis in segment 4. Blood vessels (arrow) surround and cross the lesion. (b) Power Doppler US scan of the metastasis in a, obtained after drip infusion of SH U 508A, shows rich vascularity within and at the periphery of the otherwise hypoechoic tumor (arrows). (c) Power Doppler US scan of the same tumor, obtained after administration of SH U 508A 24 hours after RF ablation, demonstrates a 4.5 x 3.5-cm avascular region (arrows) devoid of flow signal. (d) Contrast-enhanced helical CT scan of the same tumor, obtained the same day as that in c, demonstrates a lack of enhancement in this region (arrow), which helped to confirm the diagnosis of complete necrosis of tumor.

 


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Figure 1d. Metastasis in liver segment 4. (a) Contrast-enhanced helical CT scan in the portal venous phase demonstrates a 1.5-cm-diameter colorectal metastasis in segment 4. Blood vessels (arrow) surround and cross the lesion. (b) Power Doppler US scan of the metastasis in a, obtained after drip infusion of SH U 508A, shows rich vascularity within and at the periphery of the otherwise hypoechoic tumor (arrows). (c) Power Doppler US scan of the same tumor, obtained after administration of SH U 508A 24 hours after RF ablation, demonstrates a 4.5 x 3.5-cm avascular region (arrows) devoid of flow signal. (d) Contrast-enhanced helical CT scan of the same tumor, obtained the same day as that in c, demonstrates a lack of enhancement in this region (arrow), which helped to confirm the diagnosis of complete necrosis of tumor.

 


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Figure 2a. Metastasis in liver segment 4. (a) Contrast-enhanced power Doppler US scan obtained after RF ablation of a 2.9 x 2.1-cm colorectal metastasis in segment 4 shows the persistence of many parenchymal blood flow signals (solid arrow) in the anterior portion of the lesion (open arrows). (b) Contrast-enhanced helical CT scan of the lesion in a obtained in the portal venous phase demonstrates wide residual unablated tumor (arrow) in the same area. Targeted re-treatment of the lesion with RF was performed 20 days later; blood flow signals obtained with contrast-enhanced power Doppler US were used as guidance. (c) Contrast-enhanced power Doppler US scan of the same tumor, obtained after the second ablation procedure, shows complete disappearance of blood flow signals (arrows). (d) Contrast-enhanced helical CT scan of the same tumor helped to confirm the diagnosis of complete necrosis (arrows).

 


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Figure 2c. Metastasis in liver segment 4. (a) Contrast-enhanced power Doppler US scan obtained after RF ablation of a 2.9 x 2.1-cm colorectal metastasis in segment 4 shows the persistence of many parenchymal blood flow signals (solid arrow) in the anterior portion of the lesion (open arrows). (b) Contrast-enhanced helical CT scan of the lesion in a obtained in the portal venous phase demonstrates wide residual unablated tumor (arrow) in the same area. Targeted re-treatment of the lesion with RF was performed 20 days later; blood flow signals obtained with contrast-enhanced power Doppler US were used as guidance. (c) Contrast-enhanced power Doppler US scan of the same tumor, obtained after the second ablation procedure, shows complete disappearance of blood flow signals (arrows). (d) Contrast-enhanced helical CT scan of the same tumor helped to confirm the diagnosis of complete necrosis (arrows).

 


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Figure 2b. Metastasis in liver segment 4. (a) Contrast-enhanced power Doppler US scan obtained after RF ablation of a 2.9 x 2.1-cm colorectal metastasis in segment 4 shows the persistence of many parenchymal blood flow signals (solid arrow) in the anterior portion of the lesion (open arrows). (b) Contrast-enhanced helical CT scan of the lesion in a obtained in the portal venous phase demonstrates wide residual unablated tumor (arrow) in the same area. Targeted re-treatment of the lesion with RF was performed 20 days later; blood flow signals obtained with contrast-enhanced power Doppler US were used as guidance. (c) Contrast-enhanced power Doppler US scan of the same tumor, obtained after the second ablation procedure, shows complete disappearance of blood flow signals (arrows). (d) Contrast-enhanced helical CT scan of the same tumor helped to confirm the diagnosis of complete necrosis (arrows).

 


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Figure 2d. Metastasis in liver segment 4. (a) Contrast-enhanced power Doppler US scan obtained after RF ablation of a 2.9 x 2.1-cm colorectal metastasis in segment 4 shows the persistence of many parenchymal blood flow signals (solid arrow) in the anterior portion of the lesion (open arrows). (b) Contrast-enhanced helical CT scan of the lesion in a obtained in the portal venous phase demonstrates wide residual unablated tumor (arrow) in the same area. Targeted re-treatment of the lesion with RF was performed 20 days later; blood flow signals obtained with contrast-enhanced power Doppler US were used as guidance. (c) Contrast-enhanced power Doppler US scan of the same tumor, obtained after the second ablation procedure, shows complete disappearance of blood flow signals (arrows). (d) Contrast-enhanced helical CT scan of the same tumor helped to confirm the diagnosis of complete necrosis (arrows).

 


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Figure 3a. Colorectal metastasis in liver segment 4. (a) Helical CT scan shows a 3.0 x 3.0-cm metastasis (arrow) from colon cancer in segment 4. (b) Contrast-enhanced color Doppler US scan of the tumor in a clearly shows blood flow signals (arrows) within the lesion. (c) Contrast-enhanced color Doppler US scan of the same tumor, obtained after a single session of RF ablation, shows a large (3.5 x 3.5-cm) avascular area (arrows), which is suggestive of complete necrosis. (d) Contrast-enhanced helical CT scan of the same tumor, obtained the same day as that in c, however, demonstrates a 1-cm-thick peripheral portion of unablated tumor tissue (arrow) along the medial margin of the lesion.

 


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Figure 3b. Colorectal metastasis in liver segment 4. (a) Helical CT scan shows a 3.0 x 3.0-cm metastasis (arrow) from colon cancer in segment 4. (b) Contrast-enhanced color Doppler US scan of the tumor in a clearly shows blood flow signals (arrows) within the lesion. (c) Contrast-enhanced color Doppler US scan of the same tumor, obtained after a single session of RF ablation, shows a large (3.5 x 3.5-cm) avascular area (arrows), which is suggestive of complete necrosis. (d) Contrast-enhanced helical CT scan of the same tumor, obtained the same day as that in c, however, demonstrates a 1-cm-thick peripheral portion of unablated tumor tissue (arrow) along the medial margin of the lesion.

 


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Figure 3c. Colorectal metastasis in liver segment 4. (a) Helical CT scan shows a 3.0 x 3.0-cm metastasis (arrow) from colon cancer in segment 4. (b) Contrast-enhanced color Doppler US scan of the tumor in a clearly shows blood flow signals (arrows) within the lesion. (c) Contrast-enhanced color Doppler US scan of the same tumor, obtained after a single session of RF ablation, shows a large (3.5 x 3.5-cm) avascular area (arrows), which is suggestive of complete necrosis. (d) Contrast-enhanced helical CT scan of the same tumor, obtained the same day as that in c, however, demonstrates a 1-cm-thick peripheral portion of unablated tumor tissue (arrow) along the medial margin of the lesion.

 


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Figure 3d. Colorectal metastasis in liver segment 4. (a) Helical CT scan shows a 3.0 x 3.0-cm metastasis (arrow) from colon cancer in segment 4. (b) Contrast-enhanced color Doppler US scan of the tumor in a clearly shows blood flow signals (arrows) within the lesion. (c) Contrast-enhanced color Doppler US scan of the same tumor, obtained after a single session of RF ablation, shows a large (3.5 x 3.5-cm) avascular area (arrows), which is suggestive of complete necrosis. (d) Contrast-enhanced helical CT scan of the same tumor, obtained the same day as that in c, however, demonstrates a 1-cm-thick peripheral portion of unablated tumor tissue (arrow) along the medial margin of the lesion.

 
RF Technique
Seventeen patients were treated by using conscious sedation (ie, neuroleptoanalgesia), and three were treated with general anesthesia. The conscious sedation technique was as follows: An anesthetic cream containing prilocaine and xylocaine (EMLA; Astra, Sweden) was applied to the skin surface 1 hour before treatment. Then, an anesthesiologist intravenously administered both the neuroleptic agent droperidol (1.25–2.5 mg) (Sintodian; Farmitalia, Milan, Italy) and the analgesic agent fentanyl (50–100 µg) (Fentanest; Farmitalia) with continuous cardiovascular and respiratory monitoring. General anesthesia with endotracheal intubation was administered to patients with subcapsular tumors, which are associated with increased pain during RF application.

RF ablation was performed by using a 500-kHz, monopolar RF generator (model 3E; Radionics, Burlington, Mass) and internally cooled electrodes with 2–3-cm tips (Radionics) (19). Grounding was achieved by attaching two large grounding pads (400 cm3) to the patient's thigh. Tissue impedance was monitored continuously by using circuitry incorporated within the generator. A peristaltic pump (Watson-Marlow, Medford, Mass) was used to infuse 0°C normal saline into the cooling lumen of the RF electrode at a rate sufficient to maintain a tip temperature of 20°–25°C.

For each treatment, a single electrode was placed within the tumor by using real-time US guidance. For nine tumors with diameters greater than 2.5 cm, up to three insertions of the electrode were performed within different areas of the tumor during the same ablation session. For each RF application, energy was delivered for 12–15 minutes at the maximum current achievable while maintaining the circuit impedance at within 10 {Omega} of the baseline (1,300–1,500 mA). Purposeful reduction in generator output for short intervals (<10 seconds) toward the end of the treatment was performed, in response to observed rises in tissue impedance (>10 {Omega}), to permit completion of the treatment session.

Imaging
Imaging-based pretreatment evaluation of metastases with nonenhanced and contrast-enhanced US and contrast-enhanced CT was performed in all patients: CT scans were obtained within 1 week before the procedure, and US scans were obtained immediately before RF ablation. In all patients, follow-up CT and US were performed 24 hours after ablation to permit direct comparison of these imaging modalities and accurate correlation of the regions of enhancement between both modalities. In four (20%) patients, contrast-enhanced US was performed 10–15 minutes after RF ablation because the area of increased echogenicity surrounding the RF electrode at the completion of the treatment session was substantially smaller than that usually observed, which suggested that these tumors may have been inadequately treated. Follow-up CT was also performed 6 months after the procedure to detect local tumor recurrence. These 6-month follow-up scans were used to determine treatment success.

Gray-scale (ie, B-mode), color Doppler, and power Doppler US were performed by using either a Sequoia (Acuson, Mountain View, Calif) or model AU5 (Esaote Biomedica, Genoa, Italy) scanner with 3.5–5.0-MHz curved-array multifrequency transducers. Harmonic imaging was not used in this study. The power and gain settings were maintained at optimized parameters, including the highest level of color gain before observing artifacts, which were determined during the initial nonenhanced color Doppler US examination performed before ablation. Gain settings were not changed from this baseline for any of the pre- or postablation US examinations in a given patient. The pulse repetition frequency was maintained at 1 kHz in all studies.

We used the US contrast agent SH U 508A (Levovist; Schering, Berlin, Germany) (300 mg/mL) in all studies. This agent was approved for use and commercially available in Italy before the initiation of this study. SH U 508A is a suspension of D-galactose (99.9%) stabilized with 0.1% palmitic acid. The contrast agent was reconstituted immediately before use in sterile distilled water. Tiny microbubbles, which are produced by vigorously shaking the ampule before use, adhere to the galactose microparticle and thereby induce an increase in Doppler signal enhancement of approximately 25 dB. A total of 5 g (17 mL) of SH U 508A was injected into an antecubital fossa vein. A bolus of the agent was injected for 1 minute in the first seven patients. In the remaining 13 patients, a drip infusion at 1 mL/min was used to prolong the duration of enhancement to 6–7 minutes and to reduce or eliminate initial blooming artifact, which can limit lesion conspicuity.

During and after the contrast agent administration, US was performed by using a combination of color Doppler and power Doppler. These two imaging techniques were not specifically compared in a controlled manner because the intent of this study was not to evaluate the relative merits of color Doppler and power Doppler techniques but rather to evaluate the potential role of contrast-enhanced US in the treatment of patients undergoing RF ablation of liver tumors. In general, however, we began by using color Doppler US and scanned predominantly with this technique unless insufficient color Doppler enhancement was identified. In all patients, however, both color Doppler and power Doppler imaging were used.

CT was performed with Xpress (Toshiba Medical Systems, Tokyo, Japan) and model 5000 (Picker, Twinsburg, Ohio) imaging units by using a helical technique with 7-mm collimation, a 1:1 pitch, 120 or 140 kVp, and 280–300 mA. These data were used to reconstruct contiguous 5-mm axial images. Both nonenhanced and dual-phase contrast-enhanced scans were obtained (with 30- and 70-second image acquisition delay) during the power injection of 200 mL of 60% iopamidol (Iopamiro; Bracco, Milan, Italy) at a rate of 3 mL/sec.

Assessment of Treatment Efficacy
Treatment efficacy was assessed on the basis of posttreatment contrast-enhanced CT scan findings. The areas of hypoattenuation that did not enhance after contrast agent administration were considered to represent necrotic, ablated tissue, whereas the tumor regions that displayed enhancement were considered to represent untreated tumor. Prior studies (1,5) have documented close correlation of these imaging findings to pathologically proved coagulation necrosis and residual tumor. In cases in which residual tumor was identified by using CT, a second RF treatment session was performed within 2 weeks of diagnosis. The efficacy of this re-treatment was assessed 6 months later at follow-up CT.

Analysis
The pre- and postablation US findings were compared, and the US findings were compared with the results of contrast-enhanced CT performed 24 hours after ablation. The sensitivity and specificity of contrast-enhanced US in the detection of residual tumor were calculated; CT was used as the standard of reference.


    RESULTS
 TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
All patients tolerated the US contrast agent without signs of adverse reactions or side effects. In addition, all US scans were considered to be of diagnostic quality.

Without contrast agent enhancement, color Doppler signal was present in three tumors (15%) before ablation (Table). Scattered power Doppler signal was present within these tumors and in an additional 12 metastases (15 of 20 metastases [75%]) at nonenhanced US performed before ablation. Increased Doppler signal was observed throughout the tumor in all cases after contrast agent administration.


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Results of Pre- and Postablation Imaging Studies
 
Twenty-four hours after RF ablation, no residual enhancement was evident at nonenhanced color Doppler or power Doppler US. Contrast-enhanced US, however, enabled the identification of residual foci of contrast enhancement in a small peripheral portion of three of the 20 (15%) tumors (<10% of the initial tumor volume). In two of these tumors, this enhancement was seen with both color Doppler and power Doppler US, whereas in one tumor, the focal enhancement was seen only with power Doppler US. These foci were confirmed as untreated tumor at CT. CT depicted a thin (<3-mm) focal rim of residual disease in three additional lesions. Thus, the sensitivity of contrast-enhanced US was 50%, and the specificity was 100%. Diagnostic agreement with CT was achieved in 17 of 20 cases (85%).

All four patients who underwent contrast-enhanced US immediately after ablation were found to have residual foci of enhancement at one margin of the metastasis. Although the importance of this finding cannot be known with certainty on the basis of these results, we nevertheless used this finding to guide a second application of RF selectively to the focus of enhancement during the same treatment session. Subsequently, at 24 hours after ablation, no enhancement was seen in any of these four lesions with either contrast-enhanced US or CT.

CT enabled the detection of residual tumor in six patients 24 hours after ablation. Of the 14 patients with negative findings at both contrast-enhanced US and CT, 12 (86%) had no CT evidence of local tumor recurrence at 6-month follow-up. The two patients with residual local disease were successfully re-treated and had no evidence of local tumor recurrence 6 months after re-treatment. Four of the six patients that showed residual tumor at initial postablation CT performed 24 hours after ablation had successful tumor ablation with repeated RF treatments. Thus, taking into account the successful re-treatment of six of eight patients (four of six patients treated after the initial postablation imaging and both patients treated at 6 months), local control of disease was achieved with RF in 18 (90%) of the 20 patients.


    DISCUSSION
 TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Percutaneous RF tumor ablation has been used in clinical trials for the treatment of hepatic (15), cerebral (20), and bone (21) malignancies. The success of this technique in the treatment of focal liver tumors depends on the complete destruction of the entire tumor. To accomplish this, diagnostic imaging is required for precise lesion targeting as well as to determine the extent of induced coagulation necrosis. In the past, we have predominantly used gray-scale US to guide electrode placement while relying on posttreatment contrast-enhanced CT and MR imaging to help differentiate between avascular, nonenhancing coagulated tumor and residual unablated foci that display tumoral enhancement (1,2,4). Although this strategy facilitated efficacious therapy, the multiple imaging studies and repeated treatment sessions necessary to ensure tumor eradication was cumbersome and expensive. The results of the current study suggest that contrast-enhanced US may enable both immediate imaging of the ablation procedure and detection of residual unablated tumor in many cases. As a result, the use of US contrast agents may prove to be a useful adjunct for percutaneous ablation therapies.

US with microbubble contrast agents has been shown to increase the detection of microvasculature and parenchymal organ blood flow compared with nonenhanced color Doppler and power Doppler US (11,13). This increased sensitivity to blood flow with US contrast agent administration has enabled detection of abnormal enhancement from malignant deposits in lymph nodes (14) and the liver (15). In addition, these contrast agents have enabled the differentiation between malignant and benign microvascularity in the liver (16) and breast (17) and between inflammatory and malignant pancreatic disease (18). The notion of using US contrast agents to direct therapy has also been advanced by Hashimoto et al (15), who used carbon dioxide microbubbles to help differentiate hypervascular hepatocellular carcinomas, for which transarterial chemoembolization was indicated, from hypovascular tumors, which were treated with percutaneous ethanol instillation.

In our study of RF ablation of focal colorectal liver metastases, 15 (75%) of 20 tumors had detectable signal at nonenhanced color Doppler and power Doppler US immediately before ablation; all tumors showed diffuse enhancement after the administration of the microbubble contrast agent. The areas of enhancement at both color Doppler and power Doppler US were similar before RF ablation. Twenty-four hours after RF ablation, no color Doppler or power Doppler signal was demonstrated at any examination performed without contrast agent administration despite the fact that six (30%) patients were found to have evidence of residual tumor at CT. The administration of the microbubble contrast agent increased the sensitivity in the detection of these small rests of residual tumor; it enabled the identification of untreated tumor in three (50%) of these six patients. This enhancement was seen with both color Doppler and power Doppler US in two patients but with only power Doppler US in one patient. No intratumoral contrast enhancement was seen at US in any case in which the 24-hour postprocedural CT scan failed to depict residual tumor (specificity, 100%). Thus, the use of this US contrast agent to direct further RF therapy would not have resulted in inappropriate treatment of adequately ablated tissue in any case.

During the course of this study, we performed an additional contrast-enhanced US examination immediately after RF ablation in four patients. Contrast material was administered in these cases because the extremely limited extent of hyperechogenicity surrounding the electrode at the completion of the RF application raised sufficient concern that the tumors had been inadequately treated. In each of these cases, we detected persistent enhancement at the tumor periphery and therefore targeted these regions for a second RF application during the initial treatment session. Unfortunately, because enhancement was detected in each of these lesions and we did not perform immediate posttreatment contrast-enhanced US in the remaining 16 patients, it is difficult to determine the importance of residual, focal peripheral enhancement on scans obtained immediately after ablation treatment. After targeted reapplication of RF, however, enhancement was not seen in any of these lesions with either US or CT at 24 hours. Thus, this finding suggests that contrast-enhanced color Doppler US might enable unablated tumor to be identified immediately after treatment. If this is confirmed with further experimental or clinical studies, US contrast agents may ultimately be of further use by enabling a reduction in the number of treatment sessions owing to the targeting of residual untreated tumor during the initial treatment session without requiring posttreatment CT.

If we take into account the successful re-treatment (immediately after ablation) of four of six lesions found to have residual local disease on posttreatment follow-up scans, then the 6-month follow-up CT results showed local control of disease in 80% of patients. Additional RF treatments in incompletely treated tumors enabled local control of disease in 90% of patients 6 months after the second course of RF treatment. These results exceed those that we previously reported (4) and are probably attributable to improvements in RF delivery technique.

The use of US contrast agents offers potential benefits over other imaging strategies. Although conventional gray-scale US has been extremely useful for directing real-time placement of RF electrodes, US findings after ablation (eg, hyperechogenicity surrounding the electrode) are variable and do not correlate well with overall necrosis shape and volume. The results of our current study also demonstrated that nonenhanced color Doppler and power Doppler US were not useful for detecting residual disease: They failed to depict residual unablated foci in any of the tumors. Contrast-enhanced US, however, enabled the detection of residual disease in three of six patients.

Even though contrast-enhanced CT has been shown to depict foci of residual unablated tumor after RF ablation (15), it does not enable real-time documentation of electrode placement. Contrast-enhanced US performed immediately after ablation is clearly more convenient and probably less expensive than is a combined approach with both US and CT to treat and evaluate tumors in patients. The use of intravascular US contrast agents may also be beneficial compared with iodinated CT contrast agents, because the US contrast agents do not distribute into the extracellular space and therefore should permit more accurate demonstration of persistent blood flow to untreated tumor. Interventional MR imaging also has shown promise for enabling both real-time guidance and assessment of induced tumor necrosis (22); however, it is expensive and is not widely available.

One potential limitation of our study was the use of contrast-enhanced CT 24 hours after ablation as the standard of reference in the assessment of complete ablation of tumor, particularly because CT scans obtained 6 months after ablation demonstrated residual or locally recurrent tumor in two patients that was missed at the initial CT examination. Nevertheless, clinical decisions, such as the decision to re-treat a specific lesion, must be made as early as possible. The goal of this study was to determine whether US contrast agents have clinical use compared with the currently used methods for detecting residual tumor. Clearly, the improved detection of residual rests of tumor with any imaging modality is desirable and a major focus of percutaneous ablation research. Newer US contrast agents, several of which are currently being developed, or advances in US technology may ultimately improve our results by enabling greater sensitivity in the detection of residual regions of untreated tumor.

In light of the results of this study, we have adopted the strategy of performing US with a microbubble contrast agent within 24 hours after RF ablation in all patients who are able to receive this agent. If foci of persistent enhancement are identified within the treated tumor, an additional RF treatment is performed without performing CT. We perform follow-up CT only when no persistent contrast enhancement is identified at US. Therefore, even though all patients still undergo CT after the completion of RF therapy, the number of CT scans obtained is reduced by eliminating at least one posttreatment scan in patients found to have residual tumor at US. It is not yet possible, on the basis of these preliminary results, to estimate the potential effect this strategy will have on either the cost or cost-effectiveness of RF ablation therapy, as these are both substantially affected by a number of complex and interrelated factors that were not specifically evaluated in this study. Nevertheless, we believe that the results of further analysis may demonstrate that, depending on the perspective taken, a strategy that involves contrast-enhanced US as the initial posttreatment imaging study may be more cost-effective than are other approaches for imaging patients after RF tumor ablation.

In conclusion, the use of a microbubble contrast agent as part of the initial posttreatment assessment of US-guided RF ablation in liver metastases may offer distinct benefits over current imaging protocols. Residual unablated tumor can be seen as persistent color enhancement by using US with microbubble US contrast agents after RF application. This may lead to the reduced use of intervening diagnostic imaging studies (eg, contrast-enhanced CT or MR imaging), which are currently required to adequately assess complete treatment of a given tumor. Nevertheless, further development of these contrast agents and US technology is probably necessary to achieve a tumor detection sensitivity that approaches that of CT or MR imaging.


    Footnotes
 
Abbreviation: RF = radio frequency

Author contributions: Guarantor of integrity of entire study, L.S.; study concepts and design, L.S., S.N.G., G.S.G.; definition of intellectual content, L.S., S.N.G., G.S.G., T.L.; literature research, L.S., S.N.G., M.D.; clinical studies, L.S., T.I., M.D.; data acquisition, L.S., T.I., M.D.; data analysis, L.S., S.N.G., G.S.G.; statistical analysis, S.N.G., G.S.G.; manuscript preparation, S.N.G., G.S.G. manuscript editing, L.S., S.N.G., G.S.G.; manuscript review, L.S., S.N.G., G.S.G., T.L.


    References
 TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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