Original Article

Monopolar Radiofrequency Ablation for Medium-sized Hepatocellular Carcinoma: Preliminary Experience with Single-Electrode Overlapping Ablation and Multiple-Electrode Switching System

Shen-Yung Wang1,5,6*, Tsang-En Wang1,5,8, Ching-Chung Lin1,5,7, Chia-Yuan Liu1,5,8, Horng-Yuan Wang1, Jiunn-Chang Lin3,5, Yu-Chung Hong4, Shu-Jung Tsai1, Chih-Jen Chen1, Wen-Chi Chao2, Jaw-Ching Wu6, Shou-Chuan Shih1,7,8

1 Division of Gastroenterology, Mackay Memorial Hospital, Taipei, Taiwan 2 Division of Chest Medicine, Department of Medicine, Mackay Memorial Hospital, Taipei, Taiwan 3 Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan 4 Department of Radiology, Mackay Memorial Hospital, Taipei, Taiwan 5 Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan 6 Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan

7 Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan 8 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan

Abstract. Background: Radiofrequency ablation (RFA) has been regarded as an effective treatment for early and small hepatocellular carcinoma (HCC). In vivo porcine studies showed a multiple- electrode switching system could create larger necrotic areas than single-electrode or cluster- electrode ablations. Some recent studies demonstrated a multiple-electrode RFA system could achieve local control of medium-sized HCCs. This study aimed to evaluate the treatment re-sults of monopolar RFA with either single-electrode overlapping ablations or a multiple- electrode switching system in treating medium-sized (3-5 cm) HCC. Methods: A total of 20 patients with medium-sized hepatocellular carcinomas were included in this study. Nine patients (6 males and 3 females) were treated with single- electrode mono-polar RFA. Eleven patients (4 males and 7 females) were treated with multiple- electrode switching monopolar RFA. Twelve patients (60%) included in this study had multi- nodular HCCs at the time of treatment. The tumor size was slightly larger in the multiple- electrode group (4.6 ± 0.3 cm) compared to that in the single-electrode group (3.6 ± 0.6 cm). CT or MR imaging studies were performed at 1 month after RFA to evaluate treatment effectiveness. Thereafter, local tumor progression, treatment effectiveness and survival after RFA were evaluated. Results: Overall, 18 of 20 patients (90%) showed satisfactory ablation of HCCs 1 month after their RFA procedures. Treatment effectiveness was achieved in 8 patients (88.9%) with single- electrode overlapping ablation and 10 (90.9%) patients with multiple-electrode switching sys-tem. The mean follow-up periods were 14.9 (range, 2-26) months in the single-electrode group, and 20.2 (range 4-41) months in the multiple-electrode group. Among the 18 patients who achieved primary tumor control, 2 patients (1 in the single-electrode group and 1 in the multiple-electrode group) had local progression noted during follow-up examinations. Conclusions: Medium-sized hepatocellular carcinoma can be effectively ablated with mono-polar radiofrequency ablation by either single-electrode overlapping ablation or a multiple-

journal homepage:www.cos.org.tw/web/index.asp

台灣癌症醫誌 (J. Cancer Res. Pract.) 2(1), 12-21, 2015 DOI: 10.6323/JCRP.2015.2.1.02

Open access under CC BY-NC-ND license.

electrode switching system. Regarding mid-term treatment responses, both RFA approaches can achieve similar treatment effectiveness, local tumor progression rate, and survival proba-bilities. Multiple-electrode switching RFA can treat larger medium-sized HCC with compara-ble mid-term efficacy as smaller medium-sized HCC treated with single-electrode overlapping RFA. Keywords : monopolar RFA, overlapping ablations, switching system, thermoablation

原著論文

經皮單極射頻消融術於治療中型肝細胞癌：單針重疊消融與多針切換系統的經驗

王勝永 1,5,6* 王蒼恩 1,5,8 林慶忠 1,5,7 劉家源 1,5,8 王鴻源 1 林俊昌 3,5 洪猶崇 4 蔡樹榮 1

陳志仁 1 趙文綺 2 吳肇卿 6 施壽全 1,7,8

1馬偕紀念醫院 胃腸肝膽內科 2馬偕紀念醫院 胸腔內科 3馬偕紀念醫院 一般外科 4馬偕紀念醫院 放射科 5馬偕紀念醫院 肝臟醫學中心 6國立陽明大學 臨床醫學研究所 7馬偕醫護管理專科學校 8馬偕醫學院 醫學系

中文摘要 背景：射頻消融術在治療早期小型肝細胞癌俱有相當好的療效。動物實驗發現多針電極

切換系統能夠產生較傳統單針電極或集束電極系統消融更大的體積。最近有些研究使用

多針電極射頻消融術證實能達到局部控制中型肝細胞癌。本研究的目的在評估單極射頻

消融術使用單針重疊消融或多針切換系統治療 3 至 5 公分大小的中型肝細胞癌的治療成

效。 方法：本研究共收入 20 位中型肝細胞癌的患者。9 位患者(6 位男性與 3 位女性)接受單針

重疊單極射頻消融術。11 位患者(4 位男性與 7 位女性)接受單針單極多針切換系統射頻消

融術。本研究收入的患者中，有 12 位(60%)患者在接受治療時肝細胞癌為多發結節。多

針切換系統治療患者的腫瘤大小(4.6 ± 0.3 公分)較單針重疊消融(3.6 ± 0.6 公分)為大。接受

治療一個月後以電腦斷層或核磁共振評估治療成效。本研究評估患者接受射頻消融術後

之治療成效、局部腫瘤復發、總和存活。 結果：總和來說，18 位(90%)中型肝細胞癌患者接受射頻消融術後一個月評估達到腫瘤完

全消融。細分來說，8 位患者(88.9%)接受單針重疊單極射頻消融術達完全消融，10 位患

者(90.9%)接受單針單極多針切換系統射頻消融術達完全消融。接受單針重疊單極射頻消

融術患者之平均追蹤時間為 14.9 個月(總範圍 2 至 26 個月)，而接受單極多針切換系統射

頻消融術為 20.2 個月(總範圍 4 至 41 個月)。在 18 位達到腫瘤完全消融的患者，2 位患者

(一位接受單針重疊消融，另一位接受多針切換系統消融)在追蹤期間有局部腫瘤復發。 結論：中型肝細胞癌可以有效地使用單極射頻消融術治療，在本中期追蹤研究中顯示，

不論是使用單針重疊消融或是多針切換系統消融皆能夠達到類似的腫瘤完全消融率、局

部腫瘤復發率、與總和存活率。多針切換系統治療較大的中型肝細胞癌與單針重疊術式

S. Y. Wang et al./JCRP 2(2015) 12-21 13

消融較小的中型肝細胞癌的治療效果相當。

關鍵字: 單極射頻消融、單針重疊消融、多針切換系統、熱消融 INTRODUCTION

Radiofrequency ablation (RFA) can effectively treat hepatocellular carcinoma (HCC) smaller than 2 cm [1,2]. Ablation, resection, and transplantation were considered as effective treatments for early-stage HCC [3]. Local ablation was suggested as first-line treat-ment for HCC less than 3 cm in size [3]. Among local ablation therapies, RFA was one of the most com-monly applied treatment because of its low probability of local recurrence and favorable long-term outcomes [4]. RFA was suggested by prospective randomized studies to have comparable outcome to surgical resec-tion treating single small HCC [1]. Therefore, RFA was recommended as one of the curative treatments for early-stage HCC [2].

RFA was less effective against medium and large HCCs [5]. By using a single electrode for HCC be-tween 3 to 4 cm and a triple electrode cluster placed 5 mm apart for HCC larger than 4 cm, RFA can achieve complete ablation in 61% of medium-sized HCC and only 24% in large-sized HCC [5]. A computational analysis suggested that overlapping multiple ablation was required by single-electrode RFA to achieve sat-isfactory ablation [6]. In vivo porcine studies testing a prototype of multiple-electrode switching system (ValleyLab) could create larger necrotic areas than single-electrode or cluster-electrode ablations [7]. Some recent studies demonstrated a multiple-electrode RFA system could achieve local control of medi-um-sized HCCs between 3 and 5 cm [8]. However, the effects of monopolar single-electrode system with

multiple sequential ablation in managing intermediate sized HCCs have remained unclear.

The effectiveness of RFA in treating medium- sized HCCs remains controversial and has been min-imally reported. The purpose of this study was to in-vestigate the technique effectiveness of the monopolar RFA system using single-electrode or a multiple- electrode switching control system in treating inter-mediate sized HCC. The technique effectiveness and outcome of treatment were compared between the monopolar single-electrode system and the monopolar multiple-electrode switching control system. MATERIALS AND METHODS Patients

From Dec. 2009 to Dec. 2013, patients who re-ceived RFA procedures for hepatocellular carcinomas were retrospectively evaluated and included into this study using the following criteria: (1) the malignan-cies were diagnosed by pathological studies, or HCC fulfilled the criteria of the guidelines of the American Association for the Study of Liver Diseases published in 2010 (typical vascular pattern in computed tomog-raphy scan or magnetic resonance imaging study) [2], (2) diameter of the largest tumor size between 3 cm to 5 cm, (3) platelet count was more than 40,000/mm3, (4) Child-Pugh class A or B, and (5) no radiographic evidence of HCC invading major vessels including the main portal vein or hepatic veins. Radiofrequency Ablation

The single electrode RFA procedure was per-formed as followed: an internally cooled 17-gauge monopolar radiofrequency electrode (Valleylab) with an electrically active tip was placed by percutaneous punctures through the intercostal space or upper ab-

*Corresponding author: Shen-Yung Wang M.D.

*通訊作者：王勝永醫師

Tel: +886-2-28094661

Fax: +886-2-28094679

E-mail: sywang@mmh.org.tw

14 S. Y. Wang et al./JCRP 2(2015) 12-21

domen to the liver. The electrode was inserted using the freehand technique under real-time sonographic guidance by a 1-5 MHz convex probe (C5-1, Philips) in conjunction with a iU22 ultrasound system (Philips). The radiofrequency energy was delivered to each electrode with a 480-kHz power generator (Series CC-1, Valleylab) with a maximum power of 200 watts. Energy output from the power generator was regulated using a feedback algorithm related to tissue imped-ance. The electrode was subsequently re-inserted by freehand puncture to pre-procedurally planned posi-tions, 1 to 2 cm distant from each of the ablation tracts. The immediate response was assessed by the presence of a hyperechoic rim beyond the border of target tu-mors to be ablated the electrode was reinserted and re-ablation was performed at the location around the tumor with incomplete hyperechoic rim.

The multiple-electrode switching control system RFA procedure was performed as followed: Two or three internally cooled 17-gauge monopolar radiofre-quency electrodes (Valleylab) with an electrically ac-tive tip were placed percutaneously by freehand punctures through the intercostal space or upper ab-domen to the target ablation area comprising HCCs. The distances between the electrically active tips of electrodes were 1 to 2 cm. The procedures were per-formed using the same ultrasound system mentioned

in previous sections (the probe was C5-1, Philips, and the ultrasound system used was the iU22, Philips). The switching control system power generator was the same as the one used in the single ablation system. The power generator was capable of delivering a maximum power of 200 watts in 480-kHz (Series CC-1, Valleylab). An additional switching control generator was used to alternate the ablation between either duo or triple electrodes (Valleylab). Only one electrode was utilized to deliver RF energy into the target tissue at the same time. The ablation was per-formed in the following order: the first phase of abla-tion was performed using maximum power regulated by a feedback algorithm based on tissue impedance for 3 minutes to each electrode sequentially. The se-cond phase of ablation was performed using the switching system such that radiofrequency energy was delivered to each electrode for 30 seconds unless the tissue impedance had abruptly risen when the energy delivery was switched to the next electrode. We as-sessed response to ablation based upon the presence of a hyperechoic rim as previously described. Additional ablations were performed at locations with incomplete hyperechoic rim around the tumors.

A single operator performed all of the RFA pro-cedures in this study. The electrodes used in the sin-gle-electrode or multiple-electrode switching control

Table 1. Characteristics of patients and tumors at the baseline of RFA treatment Single-electrode (n=9) Switching system (n=11) P-value Age (year) 60.4 ± 16.5 (42.5-81.7) 70.3 ± 9.4 (59.5-89.8) 0.201 Gender (M/F) Male 6 4 0.370 Female 3 7 Liver cirrhosis Child-Pugh class (A/B) 5/4 8/3 0.642 Multinodularity 5 (55.6%) 7/11 (63.6%) 1.000 Size of largest tumor (cm) 3.6 ± 0.6 (3.1-4.5) 4.6 ± 0.3 (3.9-5.0) 0.020 Follow-up since RFA (mo) 14.9 ± 9.8 (2-26) 20.2 ± 12.0 (4-41) 0.261 Note. Data presented with plus–minus values are means ± SD. HCC: hepatocellular carcinoma; RFA: radiofrequency ablation

S. Y. Wang et al./JCRP 2(2015) 12-21 15

system had inflow and outflow connectors for contin-uous circulation of chilled distilled water maintained by a system pump (model PEPM, Valleylab) to keep the temperature of the active tip of the electrode with-in 0-10°C. Tract ablation was performed at the end of the procedure to remove the electrodes. Intravenous sedation was induced with meperidine in addition to midazolam, or an anesthesiologist performed intrave-nous general anesthesia. Neither endotracheal intuba-tion nor mechanical ventilation was required in this study. The subject’s vital signs, electrocardiogram, and oxygen saturation were monitored during the RFA procedure. Evaluation of Treatment Response and Follow-up

One month after the procedure, alpha-fetoprotein and liver biochemistries were evaluated. A multi- phase CT or MR imaging (unenhanced, arterial, portal, and venous phases) was performed to evaluate the primary technique effectiveness. Non-enhanced area in portal phase was considered as the necrosis zone. Complete ablation was defined as the necrosis zone incorporating the target tumors. The patients were then regularly followed up every 3 months. Arterial enhancing soft tissue densities or signals around the margin of the necrosis zone related to treatment were defined as local tumor progression. Newly developed intra-hepatic soft tissue densities or signals with radi-ographic features of HCC but remote to treated nod-

ules were defined as remote recurrence. Statistical Analysis

Patient age, numbers and sizes of tumors, and total ablation time were compared between the treatment sessions with and without recurrence after RFA using the Wilcoxon rank sum test. Gender, multi-nodularity of HCC, and treatment effectiveness at 1 month were evaluated using Fisher’s exact test. The cumulative survival rate and local progression rate were analyzed using the Kaplan-Meier method. The difference of the survival and local progression rate between single- electrode overlapping ablation and multiple-electrode switching system was assessed with the log-rank test. All statistical analyses described were performed us-ing the IBM SPSS Statistics for Windows, Version 20.0. Statistical significance was defined at a two- tailed probability value of less than 0.05 in all anal-yses. RESULTS Patient Characteristics

There was a total of 20 patients (10 male and 10 female) included in this study. Nine patients (6 males and 3 females) were treated with single-electrode monopolar RFA. Eleven patients (4 males and 7 fe-males) were treated with multiple-electrode switching monopolar RFA. The age of patients at baseline ranged from 42.5 to 89.8 years (mean 65.9). Patients

Table 2. Characteristics and outcomes of RFA treatment Single-electrode (n=9) Switching system (n=11) P-value Ablation time (minutes) 48.6 ± 27.6 (18-87) 59.4 ± 18.5 (27-95) 0.295 Effectiveness at 1 month 88.9% (8 of 9) 90.9% (10 of 11) 1.000 Local progression1 1 of 8 1 of 10 1.000 Rapid tumor progression 12 13 1.000 Note. 1. Patients who achieved RFA effectiveness at 1 month were included

2. This patient had local tumor progression and distant metastasis 3. This patient had distant metastasis

16 S. Y. Wang et al./JCRP 2(2015) 12-21

Figure 1. Cumulative incidence of local tumor progression: (A) all patients in this study, and (B) two individual

groups of RFA approaches (solid line: all patients, dotted line: single-electrode overlapping ablation, dashed line: multiple-electrode switching system)

in the multiple-electrode group were slightly but not significantly older than those in the single-electrode group (60.4 ± 16.5 vs 70.3 ± 9.4). Five patients in the single-electrode group belonged to Child-Pugh class A and 4 patients belonged to Child-Pugh class B. Within the multiple-electrode group, 7 patients were designated Child-Pugh class A, and 4 patients were designated Child-Pugh class B. Twelve patients had multi-nodular HCCs at the time of RFA treatment (5 in single-electrode, 7 in multiple-electrode). The tu-mor size was larger in the multiple-electrode group (mean 4.6 cm, standard deviation 0.3 cm) comparing to that in the single-electrode group (mean 3.6 cm, standard deviation 0.6 cm) (Table 1). RFA Treatment and Effectiveness of Treatment

CT or MR imaging studies were performed 1 month after RFA to evaluate treatment effectiveness, which was defined as complete necrosis of target ab-lation tumor. Among the 20 patients, treatment effec-tiveness was achieved in 18 patients (90%) at 1 month. For patients where different approaches were used, 8 patients (88.9%) in single-electrode group and 10

(90.9%) patients had effective treatment. One patient that belonged to the multiple-electrode

group in this study had a bile duct injury with biloma and required drainage. One patient with local progres-sion in the single-electrode group received 2 follow- up RFA interventions to treat locally progressed HCC. However, the deterioration of liver reserve including intractable ascites and aggravated coagulopathy lim-ited the effectiveness of the follow-up RFA proce-dures and caused intraperitoneal hemorrhage and re-gional peritoneal tumor seeding. No immediate or periprocedural mortality was associated with RFA in this study.

Rapid tumor progression was observed in 2 pa-tients. These patients were found to have HCC sys-temic metastases within 1 month after the procedure. One patient’s outcome in the single-electrode group who did not achieve treatment effectiveness suggested that 1 of 3 target tumors had rapid local progression, portal vein thrombosis, and metastasis to bone and brain within one month after treatment. One patient in the multiple-electrode group showed metastasis to the lymph nodes within 3 weeks after treatment and sub-sequent brain and spinal metastasis despite complete

A B

S. Y. Wang et al./JCRP 2(2015) 12-21 17

Figure 2. Overall survival of (A) all patients in this study, and (B) two individual groups of RFA approaches (solid

line: all patients, dotted line: single-electrode overlapping ablation, dashed line: multiple-electrode switching system).

necrosis of the 4 targeted HCCs. This patient received RFA for recurrent HCCs, which occurred only 3 months after primary resection of HCC. Pathological studies for the initial HCC specimen revealed micro-scopic vascular invasion that is reported to be associ-ated with early recurrence and poor prognosis [9]. Local Tumor Progression and Survival

The mean follow-up period after ablation for HCC was 17.8 (range from 2 to 41) months. The mean follow-up periods were 14.9 (range, 2-26) months in the single-electrode group, and 20.2 (range 4-41) months in the multiple-electrode group. Among the 18 patients who achieved primary local tumor control, one patient in the single-electrode group had local progression 6 months after the first treatment and one patient in the multiple-electrode group had local pro-gression 10 months from the initial RFA treatment. Figure 1 showed the cumulative incidence of local tumor progression after initial RFA treatment in all patients and corresponding RFA treatment groups.

Overall, a total of 6 patients died during follow-up. The cause of death in all of these patients was related to liver cancer. Two patients died of rapid tumor pro-

gression, one patient died of local tumor progression, one patient had local progression controlled but died of intrahepatic remote recurrence, and two patients died of intrahepatic remote recurrence. The overall cumulative probabilities of survival at 1-year and 2-year were 77% and 63%, respectively. The proba-bilities of survival in the single-electrode and multi-ple-electrode group at 1-year were 73% and 81%, re-spectively. Figure 2 showed the overall survival after initial RFA treatment. DISCUSSION

Medium-sized HCC can be effectively ablated us-ing either the single-electrode overlapping ablation or the multiple-electrode switching system. Monopolar single-electrode RFA overlapping ablation achieved 88.9% (8 of 9) complete ablation of the target HCC, whereas the multiple-electrode switching system achieved 90.9 % (10 of 11) complete ablation. Overall, monopolar RFA achieved 90% effectiveness in treat-ing medium-sized HCC. The local progression rates in the single-electrode and multiple-electrode groups at 1-year were 17% and 12%, respectively. The probabil-ities of survival in the single-electrode and multiple-

A B

18 S. Y. Wang et al./JCRP 2(2015) 12-21

electrode groups at 1-year was 73% and 81%, respec-tively.

A single radiofrequency ablation with a single in-ternally cooled electrode was not satisfactory for treating medium-sized HCC. Livraghi et al. reported that RFA induced 61% complete necrosis rate for 3 to 4 cm HCC with a single electrode in one ablation, 4 to 5 cm HCC with a triple electrode cluster in one abla-tion or a single electrode in 2 to 4 ablations [5]. Re-garding the expandable electrode RFA system, com-plete necrosis was observed in 93.0 to 97.8% in ablat-ing HCC less than 3 cm [10,11]. RFA with an ex-pandable electrode was less effective against medi-um-sized HCC, in which the complete necrosis rate was 64.7% [11]. Overlapping RFA alone with a single internally cooled electrode was reported to reach 94% technique effectiveness in ablating medium-sized HCC [12]. Insertion of a single electrode was gener-ally not unduly demanding even in patients with a small window allowed for needle pass. However, single-electrode overlapping ablation would be diffi-cult to perform due to the presence of microbubbles from preceding ablations which obscured the path for placing the electrode in subsequent target positions.

Multiple-electrode switching RFA showed favora-ble short-term and mid-term outcomes in treating medium-sized HCC [4,8,13]. The major advantage of this system was reported to be the creation of a larger necrosis volume than either the single-electrode or multiple-electrode cluster RFA [7]. Thus, a wider tumor-free margin can be theoretically achieved. Pre-vious RFA studies of small HCC suggested that tumor-free margin was related to local tumor progres-sion [14]. In fact, the local tumor progression rate of medium-sized HCC treated by multiple-electrode switching RFA was lower than that rate reported in previous studies with single-electrode multiple abla-tions [13]. Without ultrasound artifacts related to pre-ceding ablations, the placement of electrodes in the switching system can be placed in more desirable lo-cations. However, the insertion of multiple needles

can be challenging especially in patients with narrow intercostal spaces. The treatment time required by switching RFA system was reported to be shorter than that of single-electrode overlapping ablation [15]. Time savings can be significant as a dozen ablations may be required for a single-electrode system to ablate substantially larger tumors [6].

Rapid growth of residual HCCs or early diffuse recurrence after RFA was uncommon [16,17]. Ill- defined tumor margin and large-size HCC were sug-gested as risk factors for early diffuse HCC recurrence [16]. This intrahepatic recurrence pattern was associ-ated with poor prognosis [17]. Rapid tumor progres-sion observed in our study was defined as multiple intrahepatic or systemic metastases within 1 month after RFA. The 2 patients with rapid tumor progres-sion after RFA had more ominous courses and had survived only 2 and 4 months after RFA, respectively. In vitro studies mimicking suboptimal RFA with heat treatment found that the residual tumors had enhanced tumor growth and angiogenesis through HIF-1a/ VEGFA pathway [18]. Epithelial-mesenchymal tran-sition (EMT), a process related to cancer invasion or metastasis, was promoted in HCC cell lines after sub-lethal heat treatment [19]. These in vitro studies sug-gested that heat treatment might promote the growth and metastasis of HCC. These studies may imply po-tential mechanisms for the rapid tumor progression observed in our study. One hypothesis is that those recurrent or metastatic HCCs may have earlier existed as microscopic metastasis undetectable by preproce-dural studies and RFA promotes the growth of those microscopic metastasis despite complete ablation of the target tumors. Another hypothesis is that RFA ab-lated the tumor incompletely and the residual tumor cells may exert elevated malignant potential and me-tastasis.

The current study was limited by several factors. First, the patient number was small and the study de-sign was retrospective. The selection of RFA treat-ment with either single-electrode overlapping ablation

S. Y. Wang et al./JCRP 2(2015) 12-21 19

or multiple-electrode switching system was not ran-domized. Second, the patient population was hetero-geneous. Half of the patients (10 of 20, 50%) had pri-or HCC treatments in diversified modalities. One pa-tient of the single-electrode group received intrave-nous sedation due to patient preference, whereas the others in this study received intravenous general an-esthesia. Finally, the lack of ultrasound contrast lim-ited the immediate real-time evaluation of ablation zones after RFA procedures. We used the develop-ment of a hyperechoic rim around the HCC under conventional ultrasound to guide our ablations. In vi-vo porcine studies using an expandable electrode sug-gested that the presence of hyperechoic rim was relat-ed to complete necrosis of liver tissue [20]. RFA in HCC patients with an internally cooled electrode (Cool-Tip) or expandable electrode showed that the hyperechoic rim correlated well with perfusion defects detected on contrast-enhanced ultrasound and on fused images from contrast-enhanced CT and ultrasound performed 3-4 days after RFA [20].

In summary, medium-sized hepatocellular carci-noma can be effectively ablated with monopolar ra-diofrequency ablation by using either the single- electrode overlapping ablation or a multiple-electrode switching system. Regarding mid-term treatment re-sponses, both RFA approaches can achieve similar treatment effectiveness, local tumor progression rate, and survival probabilities. Multiple-electrode switch-ing RFA can treat larger medium-sized HCC with comparable mid-term efficacy as smaller medi-um-sized HCC treated with single-electrode overlap-ping RFA.

REFERENCES 1. Chen MS, Li JQ, Zheng Y, et al. A prospective

randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 243: 321-8, 2006.

2. Bruix J, Sherman M, American Association for

the Study of Liver D. Management of hepatocel-lular carcinoma: an update. Hepatology 53: 1020- 2, 2011.

3. Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut 63: 844-55, 2014.

4. Lin SM. Local ablation for hepatocellular carci-noma in Taiwan. Liver Cancer 2: 73-83, 2013.

5. Livraghi T, Goldberg SN, Lazzaroni S, et al. Hepatocellular carcinoma: radio-frequency abla-tion of medium and large lesions. Radiology 214: 761-8, 2000.

6. Dodd GD 3rd, Frank MS, Aribandi M, et al. Ra-diofrequency thermal ablation: computer analysis of the size of the thermal injury created by over-lapping ablations. Am J Roentgenol 177: 777-82, 2001.

7. Laeseke PF, Sampson LA, Haemmerich D, et al. Multiple-electrode radiofrequency ablation cre-ates confluent areas of necrosis: in vivo porcine liver results. Radiology 241: 116-24, 2006.

8. Woo S, Lee JM, Yoon JH, et al. Small- and medium-sized hepatocellular carcinomas: mono-polar radiofrequency ablation with a multiple- electrode switching system-mid-term results. Ra-diology 268: 589-600, 2013.

9. Sumie S, Kuromatsu R, Okuda K, et al. Micro-vascular invasion in patients with hepatocellular carcinoma and its predictable clinicopathological factors. Ann Surg Oncol 15: 1375-82, 2008.

10. Shibata T, Shibata T, Maetani Y, et al. Radiofre-quency ablation for small hepatocellular carcino-ma: prospective comparison of internally cooled electrode and expandable electrode. Radiology 238: 346-53, 2006.

11. Solmi L, Nigro G, Roda E. Therapeutic effec-tiveness of echo-guided percutaneous radiofre-quency ablation therapy with a LeVeen needle electrode in hepatocellular carcinoma. World J Gastroenterol 12: 1098-104, 2006.

12. Kim JH, Won HJ, Shin YM, et al. Medium-sized

20 S. Y. Wang et al./JCRP 2(2015) 12-21

(3.1-5.0 cm) hepatocellular carcinoma: transarte-rial chemoembolization plus radiofrequency abla-tion versus radiofrequency ablation alone. Ann Surg Oncol 18: 1624-9, 2011.

13. Lee J, Lee JM, Yoon JH, et al. Percutaneous ra-diofrequency ablation with multiple electrodes for medium-sized hepatocellular carcinomas. Korean J Radiol 13: 34-43, 2012.

14. Komorizono Y, Oketani M, Sako K, et al. Risk factors for local recurrence of small hepatocellular carcinoma tumors after a single session, single application of percutaneous radiofrequency abla-tion. Cancer 97: 1253-62, 2003.

15. Laeseke PF, Frey TM, Brace CL, et al. Multi-ple-electrode radiofrequency ablation of hepatic malignancies: initial clinical experience. Am J Roentgenol 188: 1485-94, 2007.

16. Lee HY, Rhim H, Lee MW, et al. Early diffuse recurrence of hepatocellular carcinoma after per-cutaneous radiofrequency ablation: analysis of

risk factors. Eur Radiol 23: 190-7, 2013. 17. Kotoh K, Enjoji M, Arimura E, et al. Scattered

and rapid intrahepatic recurrences after radio fre-quency ablation for hepatocellular carcinoma. World J Gastroenterol 11: 6828-32, 2005.

18. Kong J, Kong J, Pan B, et al. Insufficient radiof-requency ablation promotes angiogenesis of re-sidual hepatocellular carcinoma via HIF-1alpha/ VEGFA. PLoS One 7: e37266, 2012.

19. Yoshida S, Kornek M, Ikenaga N, et al. Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma. Hepatology 58: 1667- 80, 2013.

20. Uehara T, Hirooka M, Kisaka Y, et al. Usefulness of the hyperechoic rim for assessing the therapeu-tic efficacy of radiofrequency ablation in hepato-cellular carcinoma patients. Hepatol Res 39: 954- 62, 2009.

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