Comparison of Contrast Enhanced Ultrasound and Contrast Enhanced CT or MRI in Monitoring Percutaneous Thermal Ablation Procedure in Patients with Hepatocellular Carcinoma: A Multi-Center Study in China

Ultrasound in Med. & Biol., Vol. 33, No. 11, pp. 1736 –1749, 2007 Copyright © 2007 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/07/$–see front matter

doi:10.1016/j.ultrasmedbio.2007.05.004

● Original Contribution COMPARISON OF CONTRAST ENHANCED ULTRASOUND AND CONTRAST ENHANCED CT OR MRI IN MONITORING PERCUTANEOUS THERMAL ABLATION PROCEDURE IN PATIENTS WITH HEPATOCELLULAR CARCINOMA: A MULTI-CENTER STUDY IN CHINA MING-DE LU,* XIAO-LING YU,† AN-HUA LI,‡ TIAN-AN JIANG,§ MIN-HUA CHEN,储 BAO-ZHEN ZHAO,¶ XIAO-DONG ZHOU,# and JIN-RUI WANG** *The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; †General Hospital of PLA, Beijing, China; ‡Sun Yat-sen University Cancer Center, Guangzhou, China; §The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; 储School of Oncology, Peking University, Beijing, China; ¶ Changhai Hospital, The Second Military Medical University, Shanghai, China; #Xijing Hospital, The Fourth Military Medical University, Xi’an, China; and the **Peking University Third Hospital, Beijing, China (Received 24 January 2007; revised 20 March 2007; in final form 1 May 2007)

Abstract—To evaluate the ability of contrast enhanced ultrasound (CEUS) in monitoring percutaneous thermal ablation procedure in patients with hepatocellular carcinoma (HCC) in comparison with contrast enhanced computed tomography (CECT) and/or magnetic resonance imaging (CEMRI). A total of 151 patients were enrolled in the study. Before the radio-frequency (RF) or microwave ablation treatment, tumor vascularity was assessed in 139 patients with three imaging modalities i.e., US (139 exams), CEUS (139 exams) and CECT (103 exams)/CEMR (36 exams). CEUS examination was performed using a sulphur hexafluoride-filled microbubble contrast agent (SonoVue®, Bracco, Milan, Italy) and real-time contrast-specific imaging techniques. Within 30 ⴞ 7 d after the ablation procedure, 118/139 patients were monitored to assess the tumor response to treatment. Before ablation, contrast enhancement within tumor was observed in 129/139 (92.8%) patients with CEUS and 133/139 (95.7%) patients with CECT/CEMRI. Compared with CECT/CEMRI, CEUS sensitivity and accuracy in detecting tumor vascularity were 97.0% and 94.2%, respectively. One month after treatment, no enhancement was seen in 110/118 (93.2%) both on CEUS and CECT/CEMRI. Concordance between CEUS and CECT/CEMR on the presence of residual vascularization was obtained in four patients (true positive). The specificity and accuracy of CEUS in detecting tumor vascularity were 98.2% and 96.6%, respectively. The periprocedural impact of SonoVue administration on the assessment of treatment extent was also evaluated in a subgroup of patients and CEUS showed its superiority compared with baseline US in defining treatment outcome. In conclusion, in the detection of HCC tumor vascularity and assessment of response to thermal ablation after 1 month, real time CEUS provided results comparable to those obtained with CECT/CEMRI. CEUS examination proved to be a safe and easy to access procedure, with potential for diagnostic impact in the clinical practice. (E-mail: [email protected]) © 2007 World Federation for Ultrasound in Medicine & Biology. Key Words: Hepatocellular carcinoma, Percutaneous thermal ablation, Contrast-enhanced US.

INTRODUCTION

options, less than 30% of cases are candidates to surgery at the time of diagnosis due to advanced tumor stage and underlying liver cirrhosis (Lau et al. 2003; Poon et al. 2002). Image-guided percutaneous ablation therapy for HCC has been used worldwide because of its minimal invasiveness, easy repeatability and cost-effectiveness (Lau et al. 2003; Goldberg et al. 2002; Dodd et al. 2000). In the past decade, thermal ablation therapy based on the use of energy sources has been increasingly accepted due to the advantages of a greater capacity to devitalize HCC with fewer treatment sessions compared with chem-

Hepatocellular carcinoma (HCC) is the second leading cause of death related to malignancies in China with more than 200,000 victims each year, which alone accounts for 53% of all liver cancer deaths worldwide (Zhao-You 2006). Although surgical resection and liver transplantation are considered to be potentially curative Address correspondence to: Ming-de Lu, MD, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhong Shan Road 2, Guangzhou, China. E-mail: [email protected] 1736

Monitoring of HCC percutaneous thermal ablation with CEUS ● M. LU et al.

ical ablation (Livraghi et al. 1999; Ikeda et al. 2001; Lencioni et al. 2003). Among them, microwave ablation and radio-frequency (RF) ablation are the most commonly used modalities in China (Dong et al. 2003; Lu et al. 2001; Chen et al. 2004). Thermal ablation for treatment of patients with small HCCs can achieve 80% to 95% of complete tumor necrosis and 33% to 57% of 5-y survival (Dong et al. 2003; Lu et al. 2001, 2005; Livraghi et al. 2001; Xu et al. 2004; Beppu et al. 1998; Buscarini et al. 2001). Image guidance plays a very important role in ablation therapy, being used for different purposes such as targeting the tumor, monitoring the ablative procedure and assessing treatment response (Goldberg et al. 2005). Baseline ultrasound is useful for guidance during the ablative procedure but is of little help in the assessment of treatment response after ablation because of its limitation in differentiating treated tissue from normal parenchyma (Goldberg et al. 1998, 2000; Choi et al. 2000; Solbiati et al. 1999). Contrastenhanced computed tomography (CECT) and magnetic resonance imaging (CEMRI) are currently used as standard imaging techniques to assess tumor response to ablation treatment and in the follow-up period. The recent development of newer ultrasound contrast agents and contrast specific imaging methods, produced a significant improvement in the diagnostic potential of contrast enhanced ultrasound (CEUS) in the characterization and detection of focal liver lesions, similar to that obtained by CECT or CEMRI (Solbiati et al. 2001; Quaia et al. 2004; Numata et al. 2001; Kim et al. 2005; Pompili et al. 2005; Choi et al. 2003). These developments prompted the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) to release, in 2004, guidelines (Albrecht et al. 2004) for the use of ultrasound contrast agents during US examinations of the liver. These guidelines stated that CEUS is complementary to CECT/CEMRI for pretreatment staging and assessment of lesion vascularity; it is recommended for guidance of needle positioning in case of insufficient lesion delineation by conventional US and immediate assessment of treatment ablation and, finally, for postablation follow-up. The present study was aimed to prospectively confirm the value of CEUS in comparison with CECT and/or

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CEMRI in monitoring of percutaneous thermal ablation procedure in patients with hepatocellular carcinoma in China. MATERIALS AND METHODS Patients This was a phase IV, multi-center, open label study conducted at eight hospitals in China. The study was performed in line with the latest amendments of the Helsinki declaration and national regulations. All patients provided informed consent for participation in the study and anonymous publication of data. The inclusion criteria were the following: male or female patients of at least 18 y of age with a suspected or known HCC. In case of single HCC, the maximum diameter was less than 6 cm. In case of multi-focal disease (no more than three lesions with a diameter ⬍3 cm), only the most conspicuous lesion was considered for the analysis. Study design A total of 151 patients were enrolled in the study between May 2004 and March 2005. There were 130 men and 21 women, with a mean age of 56 ⫾ 12 y (age range, 25 to 80 y). Efficacy population included 139 patients who underwent two evaluation sessions. One evaluation session was before treatment (within 14 d), using baseline US (139 exams), CEUS (139 exams) and CECT (103 exams)/CEMR (36 exams) for a complete imaging of the liver to better characterize and stage the lesion vascularization, and a further evaluation performed on 118 patients at 1-mo (30 ⫾ 7 d) after percutaneous thermal ablation to assess tumor response to treatment, with all three imaging modalities, US (118 exams), CEUS (118 exams), CECT (88 exams)/CEMR (30 exams) (Table 1). A secondary optional endpoint of the study was the evaluation of the periprocedural impact of SonoVue administration on the assessment of treatment extent immediately after the disappearance of gas from treated area, i.e., 5 to 10 min to 7 d after needle positioning (Table 1).

Table 1. Patients disposition Patients enrolled in the study

Patients evaluated with US, CEUS and CECT/CEMR before ablation treatment

Patients treated with percutaneous thermal ablation

Patients undergoing US & CEUS to assess immediate treatment outcome

Patients presenting at 1 mo follow-up

151 Session I

139 128

Session II Session III

90 118

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Table 2. Ultrasound equipment and contrast specific modes Mechanical index Center

Ultrasound equipment, manufacturer

1

HDI 5000; Advanced Technology Laboratories, (ATL/Philips) Bothell, WA, USA HDI 5000; Advanced Technology Laboratories, (ATL/Philips) Bothell, WA, USA Acuson Sequoia 512; Siemens, Mountain View, CA, USA Acuson Sequoia 512; Siemens, Mountain View, CA, USA Acuson Sequoia 512; Siemens, Mountain View, CA, USA Acuson Sequoia 512; Siemens, Mountain View, CA, USA Techonos MPX DU8; ESAOTE, Genoa, Italy Techonos MPX DU8 ; ESAOTE, Genoa, Italy Acuson Sequoia 512; Siemens, Mountain View, CA, USA Techonos MPX DU8; ESAOTE, Genoa, Italy

2 3 4 5 6

7 8

Contrast specific imaging technique

Transducer

Pre contrast Post contrast

Gen imaging contrast

Convex array (model C5-2), 2–5 MHz

1.00–1.10

0.09–0.12

Gen imaging contrast

Convex array (model C5-2), 2–5 MHz

1.00–1.10

0.10–0.11

Contrast pulse sequencing (CPS) Contrast pulse sequencing (CPS) Contrast pulse sequencing (CPS) Contrast pulse sequencing (CPS) Contrast tuned imaging (CnTITM) Contrast tuned imaging (CnTITM) Contrast pulse sequencing (CPS) Contrast tuned imaging (CnTITM)

Convex array (model 4C1), 2–4 MHz Vector array (model 4V1), 1–4 MHz Vector array (model 4V1), 1–4 MHz Vector array (model 4V1), 1–4 MHz Convex array (model CA430E), 2–7 MHz Convex array (model CA430E), 2–7 MHz Vector array (model 4V1), 1–4 MHz Convex array (model CA430E), 2–7 MHz

1.70–1.90

0.19–0.21

1.70–1.90

0.15–0.18

1.40–1.90

0.10–0.25

1.60–1.90

0.07–0.19

0.10–1.30

0.06–0.10

0.20–1.00

0.05⬃0.06

0.70–1.90

0.13–0.19

0.06–0.80

0.06–0.10

Imaging methods Ultrasound. Ultrasound examinations were performed using HDI 5000 (Philips/ATL Bothell, WA, USA), Technos MPX (Esaote, Genoa, Italy), Sequoia 512 (Siemens, Mountain View, CA, USA) equipments (Table 2). Baseline liver assessment was performed in each patient using conventional grey-scale US and color/ power Doppler to evaluate and record the number, location, size, shape, border, internal echogenicity of the lesion and the presence of intralesional blood supply. CEUS examinations were then carried out using low mechanical index (MI ⬍0.2) contrast dedicated methods (i.e., pulse inversion harmonic imaging [PIHI – Philips, Bothell, WA, USA], contrast pulse sequencing [CPS – Siemens, Mountain View, CA, USA], contrast tuned imaging [CnTI – Esaote, Genoa, Italy]). The contrast agent used in this study was SonoVue® (Bracco, Milan, Italy). It consists of an aqueous suspension of phospholipid-stabilized sulfur hexafluoride (SF6) gas microbubbles supplied as a lyophilized powder (Schneider et al. 1995). The solution is reconstituted before use by addition of 5 mL sterile saline. For each imaging session, a dose of 2.4 mL of SonoVue was injected as a quick bolus into the antecubital vein, followed by a flush of 5 mL of saline solution. After contrast injection continuous imaging of the liver parenchyma and the target lesion was performed to assess the vascular distribution of the contrast in the arterial (i.e., 8 to 30 s from contrast agent injection) portal-venous (i.e.,

31 to 120 s from injection) and sinusoidal phase (i.e., 121 to 360 s from injection). Unenhanced (color and power Doppler) and contrast enhanced images (all vascular phases) were acquired digitally on the hard disk of the US system in addition to the continuous imaging on sVHS and/or digital video tape and were evaluated in consensus by two expert sonographers blinded to clinical and imaging information of the patients and not involved in pre- and posttreatment examinations. CECT/CEMR CECT examinations were performed using dual/ multi- (four and sixteen) slices helical CT (Elscint, GE, Siemens, Philips, Toshiba) and iodinated Contrast Media (Ioversol/Optiray Mallinckrodt, Quebec, Canada; Iopromide/Ultravist, Schering, Berlin, Germany; Iohexol/Omnipaque, GE Healthcare Bio-Sciences (Princeton, NJ, USA), USA) (Table 3). After an unenhanced helical sequence scan through the liver, 80 to 100 mL of iodinated contrast material were administered via antecubital vein at a rate of 3 mL/s. The arterial phase sequence was obtained 25 to 30 s after injection, followed by a portal venous phase sequence beginning at 55 to 60 s after contrast injection. All images were obtained in the helical mode with 5-, 8- or 10-mm thickness sections, 5-, 8- or 10-mm collimation, a table speed adapted to image the entire liver within a single breath hold,120 to 140 kVp, 280 to 300 mA. For CEMR exams, 1.5 T Siemens or GE machines

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Table 3. CT/MRI equipment and contrast material CT contrast agent/ manufacturer

MRI equipment, manufacturer

MRI contrast agent/ manufacturer

Somatom Plus helical CT/ Siemens, Berlin, Germany HiSpeed NX/I/GE Medical Systems, Germany Somatom Plus 4 Volume Zoom helical CT/Siemens, Erlangen, Germany Aquillon 16 slice/ Toshiba, Tokyo, Japan

Ioversol/Mallinckrodt, Quebec, Canada Optiray/Mallinckrodt, Canada Ultravist/Schering, Berlin, Germany

/

/

/

/

5

X-Express helical CT/Toshiba, Tokyo, Japan

Ultravist/Schering, Berlin, Germany

6

ElscintTwin helical CT/Elscint, Israel

Ultravist/Schering, Berlin, Germany

Brilliance helical CT/Philips Medical System, Nederland Somatom Plus 4 Volume Zoom helical CT/Siemens, Erlangen, Germany LightSpeed 16 helical CT/ GE Healthcare Medical Systems, Berlin, Germany

Omnipaque/Amersham Health, NY, USA

Center

CT equipment/manufacturer

1 2 3 4

7 8

Ultravist/Schering, Berlin, Germany

Omnipaque/Amersham Health, NY, USA Ultravist/Schering, Berlin, Germany

were used with gadolinium based contrast media (Gd-DTPA) (Table 3). The MRI imaging technique was not standardized but had to fulfill the minimum requirements for inclusion of the MR imaging data into the data analysis: unenhanced T1- and T2-weighted sequences and dynamic T1-weighted contrast-enhanced sequences performed with gadolinium-based contrast agent (12 to 20 mL), administered via antecubital vein at a rate of 2 to 3 mL/s. The arterial phase sequence was obtained 20 to 25 s after injection, followed by a portal venous phase sequence beginning at 55 to 60 s after contrast injection. The section thickness was 5 to 8 mm and the intersection gap was up to 20% of the section thickness. Both spin-echo and gradient-echo sequences were allowed. The same imaging procedures were repeated for the different techniques at follow-up. Assessment of therapeutic efficacy The criteria used to determine tumor response to thermal ablation treatment at 1-mo follow-up were: (1) complete tumor necrosis if no foci of enhancement were seen within and in the peripheral ablated area on CECT and/or CEMRI imaging (Lim et al. 2001, 2002; Kim et al. 2003; Gazelle et al. 2000; Sironi et al. 1999; Dromain et al. 2002) or (2) presence of residual, inadequately treated tumor, if during the CECT and/or CEMRI arterial phase, the presence of a hyper-dense area was seen, becoming progres-

Symphony 1.5 T/ Siemens, Erlangen, Germany Signa Horizon LX 1.5 T/ GE Medical System, USA Symphony 1.5 T/ Siemens, Erlangen, Germany Signa CV/I/General Electric, Milwaukee, WI, USA

Gd-DTPA/Beijing, China

Signa EXCITE 1.5 T/ General Electric, Milwaukee, WI, USA Signa EXCITE 1.5 T and 3.0 T; General Electric, Milwaukee, WI, USA

Magnevist/Schering, Berlin, Germany

Magnevist/Schering, Berlin, Germany Magnevist/Schering, Berlin, Germany Dimeglumine Gadopentetate/ Consun, Guangzhou, China

Magnevist/Schering, Berlin, Germany

sively iso- and hypo-dense in respect to the surrounding parenchyma. The same criteria in the evaluation of tumor response to treatment were used with CEUS. Criteria used to determine immediate treatment outcome and changes in therapeutic (ablation) strategy were based on the following scales: 1 ⫽ Complete necrosis achieved; 2 ⫽ Incomplete necrosis; 3 ⫽ Residual central tumor areas; 4 ⫽ Residual peripheral tumor areas; 5 ⫽ Not applicable; 6 ⫽ Unable to determine. For CEUS an additional point was considered i.e., change in therapeutic management following contrast administration. Other efficacy parameters assessed pre- and postablation were: (1) border definition assessed according to the following scale: 1 ⫽ Sharp (margins are circumscribed with a clear transition between the lesion and the surrounding tissue); 2 ⫽ Diffuse (poor definition between the lesion and the surrounding tissue); 3 ⫽ Other; 4 ⫽ Indeterminate; (2) lesion shape evaluated by the following scale: 1 ⫽ Round (mass is circular); 2 ⫽ Elliptical (mass is egg shaped or oval); 3 ⫽ Lobular (mass demonstrates contour undulations); 4 ⫽ Irregular (not characterized by any of the above); 5 ⫽ Indeterminate; (3) lesion size measured as maximum diameter (mm). Image analysis Two experienced radiologists blinded to clinical and imaging information of the patients and not involved in the CECT or CEMRI scan and ablative treatment

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Table 4. RF/microwave equipment and anesthesia method Center 1 2 3 4

5 6 7 8

RF equipment, manufacturer Model WE-7568; Welfare Electronic, Beijing, China / Model RF2000; RadioTherapeuticus Corporation, Mountain View, CA, USA Model RITA1500; RITA Medical System, Inc., Mountain View, CA, USA Model WE-7568; Welfare Electronic, Beijing, China Model Hitt; Berchtold, Germany Model WE-7568; Welfare Electronic, Beijing, China Model RF2000; RadioTherapeuticus Corporation, Mountain View, CA, USA Model RITA1500; RITA Medical System, Inc., Mountain View, CA, USA /

Microwave equipment, manufacturer

Anesthesia method

/

Local anesthesia

Model UMC-I; Institute 207 of Aerospace Industry Company, Beijing, China, and PLA General Hospital, Beijing, China Model MTC-3; Forsea Microwave, Nanjing, China /

Local anesthesia

Model MTC-3; Forsea Microwave, Nanjing, China /

Local anesthesia with conscious sedation or general anesthesia Local anesthesia with conscious sedation Local anesthesia with conscious sedation Local anesthesia with conscious sedation

/ Model UMC-I; Institute 207 of Aerospace Industry Company, Beijing, China, and PLA General Hospital, Beijing, China

procedure evaluated the findings of pre- and posttreatment CECT or CEMRI in consensus. Unenhanced US and CEUS digital clips were retrospectively analyzed in consensus by two sonographers who were blinded to the ultrasound scan and the ablative treatment procedure, and were unaware of clinical and other imaging information of the patients. Percutaneous radio-frequency ablation and microwave coagulation techniques Radio-frequency ablation was performed by using different equipments (WE-7568, China; RF2000, USA; RITA1500, USA; Hitt, Germany) (Table 4). For microwave ablation, microwave UMC-I and MTC-3 (China) were used. All the procedures were performed with an insertion of one or multiple electrode(s) or antenna(s) to achieve a 0.5 to 1.0 cm safety margin surrounding the ablative zone. All the patients underwent local or general anesthesia, according to treatment protocols followed in the different institutions. Statistical analysis Demographics and other baseline characteristics were summarized for all patients dosed as mean ⫾ SD. Statistical significance in sensitivity and accuracy before and at posttreatment control between SonoVue-enhanced and unenhanced US using CECT and/or CEMRI as reference standards was tested by McNemar’s two-sided test with a level of significance equal to 0.05. The following definitions were used to calculate sensitivity and accuracy:

●

●

●

Local anesthesia or extradural anesthesia Local anesthesia

Sensitivity ⫽ (number of true positive identified with CEUS)/number of positive detected by CECT and/or CEMRI only. Accuracy ⫽ (number of true positive ⫹ number of true negative identified with CEUS)/N, where N is the number of patients with CECT and/or CEMRI assessment. The maximum diameter (mm) and area (cm2) of the target lesion were analyzed using paired t-test made by comparing the mean absolute differences between CEUS and unenhanced US versus CECT and/or CEMRI.

Safety Safety was assessed by the incidence of adverse events. Adverse events were monitored in the two study sessions starting 1 h before the administration of SonoVue and continuing for 2 h after.

Table 5. Pre-treatment evaluation: Diagnostic performance of unenhanced US and CEUS compared to CECT/CEMRI US CEUS CECT/CEMR p (pts ⫽ 139) (pts ⫽ 139) (pts ⫽ 139) value† Patients with typical vascular HCC pattern 104 (74.8%) 129 (92.8%) 133*(95.7%) — Sensitivity 78.2 97.0 — ⬍0.001 Accuracy 76.3 94.2 — ⬍0.001

* In 6/139 patients CECT/CEMR did not reveal any HCC. Four of these patients showed typical vascular HCC pattern at CEUS and were treated, while two patients did not present any lesion with both methods and were not treated. † McNemar’s test.

Monitoring of HCC percutaneous thermal ablation with CEUS ● M. LU et al.

RESULTS A total of 151 patients with previous diagnosis of suspected or known HCC were enrolled. Twelve of these patients, however, were not included in the efficacy population due to the lack of reference standard examination (seven patients) or indeterminate diagnosis (five patients) at reference standard.

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Unenhanced US was in agreement with CECT/ CEMRI on the presence of tumor vascularity within the target lesion in 104/139 patients (74.8%), while CEUS was in agreement in 129/139 (92.8%). CECT/CEMR demonstrated the presence of HCC in 133/139 (95.7%) patients. In 4/6 patients who did not show any vascularization at CECT/CEMR, CEUS showed typical

Fig. 1. HCC in a 46-y-old woman (preablation). (A) Baseline US image shows an iso-echoic nodule in the right lobe of the liver with a 4.1 cm diameter. (B) CEUS arterial phase at 12 s after contrast agent administration shows a heterogeneous hyper-enhancement of the lesion. (C) CEUS portal phase at 75 s. The nodule is hypo-echoic with respect to the surrounding liver. (D) CEUS late phase at 170 s. The HCC is hypo-echoic with respect to the surrounding liver. (E) Helical CT image shows a hypo-attenuation nodule in the right lobe of the liver. (F) CECT arterial phase image shows a heterogeneous hyper-enhancement of the lesion. (G) CECT portal phase. The nodule is hypo-enhanced with respect to the surrounding liver.

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vascular HCC pattern. These patients were treated on the basis of their clinical history and CEUS results. The remaining two patients did not present any lesion either with CEUS or CECT/ CEMRI and were not treated, thus, decreasing the total number of patients suitable for RFA to 137. Accuracy of tumor vascular detection of unenhanced US and CEUS compared with the CECT/CEMR was of 76.3% and 94.2%, respectively (p ⬍ 0.001). Sensitivity increased from 78.2% with unenhanced US to 97% with CEUS (p ⬍ 0.001) (Table 5). A total of 128/137 patients were treated with percutaneous thermal ablation. In fact, nine more patients were

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excluded from treatment. Reasons for not treating the nine patients are reported hereafter. Six patients were not treated due to CEUS diagnosis: in two cases, CEUS showed that the position of the lesion did not allow treatment; in four cases, CEUS showed that the lesion was not an HCC or the number of lesions was not compatible with the ablative treatment. In two other cases, discontinuation before the ablative treatment was due to the pathologic findings, which showed that the lesion was not an HCC. In another case, the treatment chosen was trans-catheter hepatic-arterial embolization (TAE) instead of local percutaneous thermal ablation.

Fig. 1. Continued.

Monitoring of HCC percutaneous thermal ablation with CEUS ● M. LU et al.

One mo after ablation, the evaluation of treatment outcome was performed with all imaging modalities on the patients who presented at follow-up visit, i.e., 118 out of 128 treated patients. The results at 1-mo follow-up showed complete tumor treatment in 110/118 patients

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both with CEUS and CECT/CEMR. Concordance between CEUS and CECT/CEMR on the presence of residual vascularization was obtained in four patients. Whilst in two patients residual vascularization was detected only by CEUS and not by CECT/CEMR, in other

Fig. 2. Residual tumor after partial ablation (same patient of Fig 1). (A) Baseline US image shows the ablative lesion in the right lobe of the liver with a 6.1 cm diameter. (B) CEUS arterial phase image at 14 s after contrast agent administration shows a nodular enhancement (arrow) at the lateral margin of the ablated area. (C) CEUS portal phase obtained at 40 s. The enhancing nodule (arrow) at the lateral margin of the ablated area is hypo-echoic with respect to the surrounding liver. (D) CEUS late phase obtained at 180 s. The enhancing nodule (arrow) is hypo-echoic with respect to the surrounding liver. (E) Transverse helical CT image shows a hypo-attenuation nodule (arrow) at the lateral margin of the ablated area. (F) CECT arterial phase shows a nodular enhancement (arrow) at the lateral margin of the ablated area. (G) CECT portal phase. The enhancing nodule is hypo-enhanced with respect to the surrounding liver. The enhancing nodule was considered as a residual viable tumor and treated with additional ablation.

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two patients, residual vascularization was detected by CECT/CEMR and not by CEUS. In comparison with CECT/CEMR, the accuracy of CEUS to correctly characterize the lesion after percutaneous thermal ablation was 96.6%. Periprocedural monitoring of treatment extent in a subgroup of patients showed that baseline US revealed a complete necrosis in 53/90 patients (58.9%), in 2/90 patients (2.2%) detected a residual peripheral tumor area and in remaining 35/90 (38.8%) was unable to make an evaluation, while CEUS demonstrated the achievement of complete necrosis in 87/90 patients (96.7%) and was

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able to change therapeutic management in five patients (5.5%). Lesion features Pretreatment. Pretreatment lesion feature evaluations showed that lesion size (mean diameter ⫾ SD) was 29.27 ⫾ 12.06 mm on unenhanced US, 29.31 ⫾ 12.02 mm on CEUS and 27.34 ⫾ 11.96 mm on CECT/CEMRI. Unenhanced US showed a sharp border lesion in 89/ 139 (64.1%) cases while CEUS in 122/139 (87.8%) and CECT/CEMRI in 112/139 (80.6%). Diffused border depic-

Fig. 2. Continued.

Monitoring of HCC percutaneous thermal ablation with CEUS ● M. LU et al.

tion of the lesion was observed in 50/139 (35.97%) lesions using unenhanced US, in 13/139 (9.3%) on CEUS and in 27/139 (19.4%) on CECT/CEMRI. A round lesion shape was depicted in 72/139 (51.8%) lesions on enhanced US, in 69/139 (49.6%) on CEUS and in 76/139 (54.7%) on CECT/ CEMRI; lesions with an elliptical shape on unenhanced US, CEUS and CECT/CEMRI were 42/139 (30.2%), 48/139 (34.5%) and 35/139 (25.2%) respectively; irregular shape was present in 19/139 (13.7%) lesions on unenhanced US,

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in 17/139 (12,2%) on CEUS and in 26/139 (18.7%) on CECT/CEMRI (Fig. 1). Posttreatment. The size of the posttreatment necrotic area (mean diameter ⫾ SD) was 38.42 ⫾ 10.92 mm on unenhanced US, 43.02 ⫾ 11.82 mm on CEUS and 41.99 ⫾ 12.14 mm on CECT/CEMRI. As to the depiction of lesion border, 23.7% of the lesions showed a sharp border on unenhanced US while both CEUS and CECT/CEMRI

Fig. 3. Successful ablation of HCC (same patient of Fig. 2). (A) Baseline US image shows the ablative lesion in the right lobe of the liver with a 6.3 cm diameter. (B) CEUS arterial phase at 24 s after contrast agent administration. (C) CEUS portal phase at 50 s. (D) CEUS late phase at 180 s. (E) Transverse helical CT image shows the ablated area in the right lobe of the liver. (F) CECT arterial phase. (G) CECT portal phase. All the contrast enhanced images show a nonenhancing oval ablated area suggesting a complete necrosis of the tumor.

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showed a sharp border in 95.8% of the lesions. On unenhanced US, 76.3% of the lesions had a diffuse border while CEUS and CECT/CEMRI showed a diffused border in 4.2% of the lesions. A round shape was evidenced in 8.5% of the lesions on unenhanced US, 11.0% of the lesions on CEUS and in 13.6% on CECT/CEMRI; an elliptical shape was shown on unenhanced US in 56.8% of the lesions, on CEUS in 55.1% and on CECT/CEMRI in 54.2%; irregular (lobular ⫹ irregular) shape appeared in 33.9% in 33.9% and 32.2% of the lesions on unenhanced US, CEUS and CECT/ CEMRI, respectively (Fig. 2 and Fig. 3).

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Safety SonoVue showed a good safety profile. No patient was discontinued from the study because of an adverse event. DISCUSSION Imaging plays an important role in the procedure of percutaneous ablation treatment of malignant focal liver lesions. US is the most used imaging modality to guide the treatment because of its real-time, easiness of use, wide availability and low cost. However, conventional US is of little help in the assessment of both pretreatment

Fig. 3. Continued.

Monitoring of HCC percutaneous thermal ablation with CEUS ● M. LU et al.

evaluation of patients for eligibility and posttreatment response. Conventional US examination during pretreatment evaluation is often insufficient in the detection and characterization of liver tumors and in the evaluation of their morphology (precise knowledge of lesion number, diameter, shape, border, location and vascularity) (Lencioni et al. 2002). Following tumor ablation, gray-scale US, in most cases, cannot help in differentiating viable tumor from necrotic tissue within the treated area because the treated lesion is often isoechoic with the surrounding parenchyma (Goldberg et al. 2000; 1999). Color/power Doppler also proved to be of limited added value in pre or postablation assessment of tumor vascularity because of its inadequate resolution of microcirculation (Goldberg et al. 1998; Choi et al. 2000; Solbiati et al. 1999). Contrast enhanced color/power Doppler has been reported to depict tumor vascularity in HCC better than unenhanced color and power Doppler and improve the detection of residual or recurrent tumor after RF ablation (Choi et al. 2000; Solbiati et al. 1999; Kim et al. 1998; Fiore et al. 2000) but still demonstrated low sensitivity in the detection of contrast agents in the microcirculation, thus, limiting the usefulness of contrast agents to the evaluation of the vascular architecture of focal lesions (Lencioni et al. 2002). The introduction of contrast dedicated imaging methods, working at low MI and in real-time has increased the sensitivity and the accuracy of ultrasound in the detection and characterization of focal liver lesions (Quaia et al. 2004; Dietrich et al. 2006; Hohmann et al. 2003). This new ultrasound modality for the monitoring of percutaneous ablation of focal liver lesions showed to be superior to contrast enhanced power Doppler in the detection of residual HCC after 4 mo of RF ablation as described in a paper by Meloni et al. (2001). Contrast enhanced pulse inversion harmonic imaging identified residual tumor in 23.3% of the treated lesions versus 9.3% of contrast enhanced power Doppler and compared with 27.9% of CECT examinations, with a sensitivity of 83.3% (p ⬍ 0.05) In the assessment of the response to ablation treatment, detection of vascularity in the ablated lesion is the most important imaging evaluation to perform to judge whether or not the tumor is completely destroyed. CECT/ CEMRI are the imaging modalities currently used as gold standard for the evaluation of the local effect of ablation therapy (Lim et al. 2001, 2002; Kim et al. 2003; Gazelle et al. 2000; Sironi et al. 1999; Dromain et al. 2002). The successfully ablated tumor does not show any contrast enhancement in the ablation zone on CECT or CEMRI imaging, while the residual viable tumor is recognized as an irregular, eccentric or nodular hyper vascular enhancement in the ablative area during the arterial phase with contrast washout in the late phase. Choi et al. (2003)

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reported that diagnostic agreement between CT and contrast-enhanced gray-scale harmonic ultrasonography in the assessment of therapeutic response to radio-frequency ablation of HCC at 1-mo follow-up was achieved in all 81 cases examined (100%), demonstrating the diagnostic efficacy of CEUS in the assessment of response to ablation treatment. These data have been confirmed by the experience of other groups (Choi et al. 2000; Solbiati et al. 1999; Kim et al. 1998, 2003; Solbiati et al. 2004a). The results of our study show that CEUS is comparable to CECT/CEMRI in the pretreatment workup of the patient. In particular, CEUS and CECT/CEMRI reported similar results in the evaluation of lesion features, i.e., size, shape and border delineation. Furthermore in the characterization of HCC microcirculation CEUS demonstrated a very high sensitivity (97.0%) and accuracy (94.2%) in comparison with CECT/CEMRI. The greatest advantage in the use of CEUS in monitoring percutaneous treatments is the possibility to evaluate the posttreatment response. In our study, CEUS showed a 96.6% accuracy in the evaluation of the tumoral area at 1-mo posttreatment, in comparison with CECT/CEMRI. In fact, CEUS detected residual viable tissue inside the necrotic area in four cases in agreement with CECT/ CEMRI. CEUS results were false positive in two and false negative in other two cases with respect to CECT/ CEMRI. The discordance between CEUS and reference imaging modalities we obtained, has been also observed in some literature papers (Dietrich et al. 2006; Rui Li et al. 2007; Giorgio et al. 2004) where CUES showed a better sensitivity in comparison with CECT/CEMRI in detecting small focal liver lesions, even if not statistically significant. This could be related to the use of the realtime technique which provides continuous information on the distribution of the contrast inside the liver and the US contrast agent which is fully intravascular. CEUS can also have a role during the percutaneous treatment procedure, guiding the correct positioning of the needle inside the lesion. CEUS can also allow early evaluation of treatment results, within a few minutes after the intervention, enabling the physician to immediately continue the treatment in case of incomplete tumor ablation (Solbiati et al. 2004b). Solbiati (2004a) reported that, in his center, with the routine adoption of CEUS in the ablative procedure, the rate of partial treated tumors detected on CT within 1 wk from treatment was reduced to 5.9% (17/289), in comparison with a 16.1% rate achieved from 1994 to August 2000 (before the introduction of contrast enhanced ultrasound for the real-time management of ablations) in 429 hepatocellular and metastatic lesions.

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Ultrasound in Medicine and Biology

The experience of Solbiati is confirmed by that of other groups using ablation therapy, either in Europe or in China (Varela et al. 2004; Vilana et al. 2005; Krix et al. 2005; Meloni et al. 2006). Chapter 4 of the ESFUMB guidelines (Albrecht et al. 2004) describes the clinical utility of the use of contrast ultrasound during the percutaneous ablative treatment of primary or secondary cancer liver lesions, using radio-frequency, microwave, alcohol, laser or HIFU. The guidelines recommend the use of contrast enhanced ultrasound for facilitating needle positioning in cases of incomplete or insufficient lesion delineation on unenhanced US and in the evaluation of postablation immediate treatment effect. The use of CEUS before treatment is considered complementary to CECT and/or CEMRI, while its use for assessment of tumor recurrence in the follow-up is suggested when CECT or CEMRI are contraindicated or not conclusive. CONCLUSION The sensitivity and accuracy of real-time CEUS in the detection of HCC vascularity and assessment of the response to thermal ablation after 1-mo have been shown to be comparable to those of CECT/CEMRI, suggesting that both contrast enhanced imaging modalities may have equal diagnostic efficacy, with the advantage that CEUS can be used also during the percutaneous treatment if required. Acknowledgments—This study was supported by Bracco Diagnostic Inc (Princeton, New Jersey).

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