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Combined Percutaneous Radiofrequency Ablation and Ethanol Injection for Hepatocellular Carcinoma in High-Risk Locations

¹ Liver Research Unit, Department of Hepatogastroenterology, Chang Gung Memorial Hospital and Chang Gung University, 199, Tunghwa Rd., Taipei, Taiwan.
² Section of Gastroenterology, University of Santo Tomas Hospital, Manila, Philippines.

Received May 9, 2007; accepted after revision September 19, 2007.

 
Address correspondence to S. M. Lin (lsmpaicyto{at}cgmh.org.tw).

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Abstract

Top Abstract Introduction Subjects and Methods Results discussion References

 
OBJECTIVE. The purpose of this study was to investigate whether combining percutaneous ethanol injection (PEI) with radiofrequency ablation in the management of hepatocellular carcinoma (HCC) in high-risk locations improves treatment outcomes.

SUBJECTS AND METHODS. We compared the outcome of management of high-risk tumors with PEI and radiofrequency ablation (n = 50) or radiofrequency ablation alone (n = 114) with the outcome of radiofrequency ablation of non-high-risk tumors (n = 44). We also compared the survival rates of patients with and those without high-risk HCC. PEI was performed into the part of the tumor closest to a blood vessel or vital structure before radiofrequency ablation.

RESULTS. The study included 142 patients with 208 HCCs managed with radiofrequency ablation. Despite larger tumor sizes (2.8 ± 1 cm vs 1.9 ± 0.7 cm vs 2.5 ± 0.1 cm for the high-risk radiofrequency plus PEI, non-high-risk radiofrequency, and high-risk radiofrequency groups, respectively; p < 0.001), the primary effectiveness rate of high-risk radiofrequency ablation and PEI (92%) was similar to that of non-high-risk radiofrequency ablation (96%). The primary effectiveness rate of high-risk radiofrequency ablation and PEI was slightly higher (p = 0.1) than that of high-risk radiofrequency ablation (85%). The local tumor progression rates (21% vs 33% vs 24% at 18 months) of the three respective groups were not statistically different (p = 0.91). Patients with and those without high-risk tumors had equal survival rates (p = 0.42) after 12 (87% vs 100%) and 24 (77% vs 80%) months of follow-up. Independent predictors of primary effectiveness were a tumor size of 3 cm or less (p = 0.01) and distinct tumor borders (p = 0.009). Indistinct borders (p = 0.033) and non-treatment-naive status of HCC (p = 0.002) were associated with higher local tumor progression rates. The only predictor of survival was complete ablation of all index tumors (p = 0.001).

CONCLUSION. The combination of radiofrequency ablation and PEI in the management of HCC in high-risk locations has a slightly higher primary effectiveness rate than does radiofrequency ablation alone. A randomized controlled study is warranted.

Keywords: efficacy • ethanol • hepatocellular carcinoma • radiofrequency ablation

Introduction

Top Abstract Introduction Subjects and Methods Results discussion References

 
Since the introduction of radiofrequency ablation for hepatocellular carcinoma (HCC) in 1983 [1], the procedure has steadily become first-line ablative management of small- to intermediate-sized ( 5 cm) HCC at many centers. Radiofrequency ablation has a primary effectiveness rate of 88–99% in the management of HCC [2–7]. The efficacy varies, however, depending on the proximity of the tumor to various structures. A location close to blood vessels, liver capsule, and vital structures is considered at high risk of treatment failure and complications [8–10]. These tumors are often difficult to approach percutaneously because of restriction of the needle insertion angle by the ribs, sonographic interference by air in the lungs, or less than optimal positioning of the radiofrequency ablation electrode because of fear of injuring a vital structure. The increased incidence of complications has prompted some investigators [9, 11–13] to classify these tumors as relative contraindications to radiofrequency ablation. Other investigators [2, 14, 15], however, have suggested that treatment outcome after radiofrequency ablation is unaffected by tumor location, although direct comparisons between patients with and those without high-risk HCC have been few.

The effect of nearby vessels 3 mm or larger in diameter in dissipating heat away from tissues during radiofrequency ablation, the so-called heat-sink effect, has been well documented. The result has been significantly smaller diameter and volume of radiofrequency ablation–induced coagulation and lower complete ablation rates [10, 16]. One technique that may diminish the heat-sink effect is performance of percutaneous ethanol injection (PEI) immediately before radiofrequency ablation. PEI induces coagulation and obliteration of small intratumoral vessels [17], cooling the tissue to be ablated. In combination with radiofrequency ablation, PEI may have the additional effect of being heated by radiofrequency energy and extending tissue necrosis through the effects of hot ethanol [18]. Clinical studies [19, 20] have shown that the performance of PEI before radiofrequency ablation produces a larger area of coagulation necrosis than obtained with radiofrequency ablation alone.

We aimed to compare treatment outcome in terms of complete ablation and local tumor progression and complication rates for three treatment groups: HCC in non-high-risk locations managed with radiofrequency ablation alone, HCC in high-risk locations managed with radiofrequency ablation alone, and HCC in high-risk locations managed with combined PEI and radiofrequency ablation. We also aimed to compare the survival rates of patients with and those without high-risk tumors and to identify independent predictors of treatment outcome and survival.

Subjects and Methods

Top Abstract Introduction Subjects and Methods Results discussion References

 
Patients
The study included consecutively registered patients with cirrhosis and HCC with no evidence of intrahepatic vessel invasion or distant metastasis who underwent radiofrequency ablation between January 1, 2004, and August 31, 2006. Patients who underwent transarterial chemoembolization (TACE) within 1 month before radiofrequency ablation and who underwent other forms of locoregional HCC treatment (TACE or PEI) before the first dynamic liver imaging study after radiofrequency ablation were excluded. HCC was diagnosed through cytologic or histopathologic findings or the presence of a hypervascular liver mass in the arterial phase of a dynamic imaging study (CT or MRI) with contrast washout during the portal or delayed phase plus angiographic confirmation of a hypervascular mass or an -fetoprotein concentration greater than 200 ng/mL. Before radiofrequency ablation, the following features were recorded: patient demo graphics, size of index tumor, tumor margin char acteristics (distinct vs indistinct), distance between outermost margin of the tumor and the liver capsule, sonographic or dynamic imaging evidence of nearby vital structures (gallbladder, lungs, heart, kidney, gastrointestinal tract), and sonographic or dynamic imaging evidence of nearby intrahepatic blood vessels 3 mm in diameter or larger. Whether the patient had undergone previous treatment of the index tumor (incompletely controlled vs treatment-naive HCC) also was recorded. The Edmondson and Steiner [21] classification was used to grade HCC. All patients gave written informed consent before radiofrequency ablation. The study was approved by our institutional review board.

Radiofrequency Ablation Techniques
Radiofrequency ablation was performed percutaneously under real-time sonographic guidance by three investigators who had 18, 10, and 9 years of experience in performing sonographically guided interventional procedures for liver tumors. One of the following three devices was used: internally cooled electrode with a 3-cm uninsulated tip (Cool-tip radiofrequency system, Radionics), expandable electrode with 10–12 tines extending to 2–4 cm in diameter with impedance monitoring (LeVeen electrode, RadioTherapeutics), and an expandable electrode with nine tines extending to 3–5 cm in diameter with temperature monitoring (Starburst XL, RITA Medical Systems). The select ion of the type of electrode was depend ent on operator or patient preference or health insurance restrictions. The internally cooled electrode and the expandable electrode with temperature monitoring were operated according to the manufacturers' instructions. The expandable elect rode with impedance monitoring was operated according to an interactive algorithm described elsewhere [22]. Multiple overlapping ablations were performed as needed to cover the whole tumor plus a 5- to 10-mm ablative margin around the tumor, when feasible. Electrode track thermocoagulation was routinely performed with a power of 20 W on withdrawal.

Radiofrequency Ablation of HCC in High-Risk Locations
Because we aimed for an ablative margin of 5–10 mm for all tumors, tumors within 10 mm of the capsule (subcapsular), a vital structure, or a blood vessel 3 mm in diameter or larger were considered in a high-risk location. To reduce the heat-sink effect caused by nearby large vessels and to avoid positioning the radiofrequency ablation electrode close to a vital structure, our unit started to perform PEI combined with radiofrequency ablation in January 2004. A 21- to 22-gauge, 15- to 20-cm-long needle was used to inject 1–10 mL of 99.5% ethanol into the tumor closest to the blood vessel or vital structure while the radiofrequency ablation electrode was positioned 5–10 mm away from the PEI needle and activated immediately after PEI. For all other HCCs in high-risk locations, only radiofrequency ablation was performed. The decision to perform either technique was left to the discretion of the operator.

Follow-Up Protocol
For assessment of the completeness of ablation, a dynamic imaging study (CT or MRI) was performed for all patients a median of 27 days (range, 14–56 days) after radiofrequency ablation. A completely ablated tumor was defined as an area of low attenuation on CT or low signal intensity on T2-weighted MRI that encompassed the area of the index tumor with no nodular peripheral enhancement on dynamic studies. Dynamic imaging studies, liver function tests, and -fetoprotein measurement were repeated every 3–6 months after the first post treatment study. All complications of the radio frequency ablation procedure were recorded accord ing to previously proposed criteria [23].

Study End Points
The primary end points of the study were the primary effectiveness, defined as complete ablation of the index tumor after one or more radiofrequency ablation sessions, and survival. Secondary end points were local tumor progression and local tumor progression–free survival. Local tumor progression was defined as the appearance of nodular enhancement contiguous with the ablated tumor on dynamic imaging or an increase in the size of the ablated area on follow-up imaging of a tumor that was previously completely ablated.

Statistical Analysis
All index tumors were assessed for complete ablation after one radiofrequency ablation session; primary effectiveness, complication and local tumor progression, and the findings for the three groups (non-high-risk radiofrequency, high-risk radiofrequency, and high-risk radiofrequency plus PEI) were compared. Cases of tumors in which complete ablation was achieved and in which at least one dynamic scan was performed after complete ablation were assessed for local tumor progression. The survival rates of two patient groups were compared. The high-risk group was patients with at least one index tumor in a high-risk location; the non-high-risk group was patients in whom all tumors were in a non-high-risk location. Patients with multiple index tumors in whom not all tumors were managed with radiofrequency ablation were excluded from the survival analysis.

The considerable influence of blood vessel size and the distance between a tumor and a vessel on the degree of heat-sink effect has not been studied, to our knowledge, in HCC managed with radiofrequency ablation. We therefore performed subanalyses dividing tumors according to distance between tumor and vessel ( 5 mm vs > 5 mm) and diameter of the adjacent vessel ( 5 mm vs > 5 mm) to determine whether these factors had a significant effect on treatment outcome.

Continuous and categoric variables were analyzed with the Mann-Whitney U test and the Fisher's exact test, respectively. Cumulative probability of survival and local tumor progression were estimated with Kaplan-Meier curves. Variables with p 0.1 were included in the multivariate analysis. Multiple logistic regression analysis was used to determine independent predictors of complete ablation, and Cox regression analysis with forward logistic regression was used to model independent predictors of local tumor progression and survival. A value of p < 0.05 was considered significant. All statistical analyses were performed with statistical software (SPSS v.13).

Results

Top Abstract Introduction Subjects and Methods Results discussion References

 
A total of 149 patients underwent radiofrequency ablation during the study period. Seven patients were excluded because TACE had been performed within 1 month before radio frequency ablation (n = 5) or other locoregional treatments were performed before the first dynamic imaging after radiofrequency ablation (n = 2). Primary effectiveness and complication rates were analyzed for 142 patients with 208 tumors. Ten patients were excluded from survival analysis because not all index tumors were managed with radiofrequency ablation (Fig. 1). There were 164 tumors in high-risk locations (Fig. 2). Thirty-eight (18.3%) of the 208 tumors were incompletely controlled with previous loco regional therapy (PEI in 29 cases, TACE in nine cases). The last treatment had been performed a median of 3.8 (range, 0.1–34.6) months before the first radiofrequency ablation treatment. Forty-one (31.1%) of the 132 patients included in the analysis had a history of treatment of the index HCC or HCC in a different segment.

View larger version (15K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1 —Schematic shows patient and tumor distribution in analyses of outcomes. TACE = transarterial chemoembolization, HR = high risk, PEI = percutaneous ethanol injection.

View larger version (13K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2 —Distribution of high-risk tumors. * = 44 tumors were located near both vessel/s and vital structure. PV = portal vein, HV = hepatic vein, IVC = inferior vena cava, GB = gallbladder, GIT = gastrointestinal tract.

Local Tumor Progression
Follow-up after the first radiofrequency ablation session was significantly longer for the non-high-risk radiofrequency (median, 14 months; range, 3.3–30.9 months) and high-risk radiofrequency (median, 11.6 months; range, 2.3–32.7 months) groups than for the high-risk radiofrequency plus PEI group (median, 7.2 months; range, 1.9–30.9 months) (p = 0.019). A total of 30 (19.7%) of the tumors had local progression a median of 7.6 months (range, 2.2–22.6 months) after the first radiofrequency ablation session. There was no significant difference in the cumulative probabilities of local tumor progression at 6, 12, and 18 months for the three groups (non-high-risk radiofrequency, 10%, 18%, and 33%; high-risk radiofrequency, 7%, 24%, and 24%; high-risk radiofrequency plus PEI, 7%, 21%, and 21%; p = 0.91) (Fig. 3). Indistinct tumor margins (Fig. 4A, 4B, 4C, 4D, 4E, 4F) and previous incomplete treatment were associated with higher local tumor progression rates in both univariate and multivariate analyses (Table 2).

View larger version (15K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3 —Graph compares local tumor progression rates for three treatment groups. HR = high-risk, RF = radiofrequency, NHR = non-high-risk, PEI = percutaneous ethanol injection.

View larger version (116K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4A —45-year-old man with hepatitis B virus–related cirrhosis and hepatocellular carcinoma. Indistinct tumor border is independent predictor of local tumor progression. Arterial phase CT scan before radiofrequency ablation shows enhancement of solitary tumor (arrows) at segment VII.

View larger version (123K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4B —45-year-old man with hepatitis B virus–related cirrhosis and hepatocellular carcinoma. Indistinct tumor border is independent predictor of local tumor progression. Portal phase CT scan before radiofrequency ablation shows contrast washout (arrows) at segment VII.

View larger version (134K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4C —45-year-old man with hepatitis B virus–related cirrhosis and hepatocellular carcinoma. Indistinct tumor border is independent predictor of local tumor progression. Sonographic image shows indistinct tumor borders (arrows), as in A and B.

View larger version (127K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4D —45-year-old man with hepatitis B virus–related cirrhosis and hepatocellular carcinoma. Indistinct tumor border is independent predictor of local tumor progression. Dynamic CT scan 1 day after radiofrequency ablation shows complete ablation of area of index tumor with peripheral enhancement due to postablation hyperemia.

View larger version (126K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4E —45-year-old man with hepatitis B virus–related cirrhosis and hepatocellular carcinoma. Indistinct tumor border is independent predictor of local tumor progression. Repeated CT scans 2 months after D show local tumor progression at posterior border of ablation zone with enhancement (arrowhead) in arterial (E) and washout in portal (F) phases.

View larger version (121K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4F —45-year-old man with hepatitis B virus–related cirrhosis and hepatocellular carcinoma. Indistinct tumor border is independent predictor of local tumor progression. Repeated CT scans 2 months after D show local tumor progression at posterior border of ablation zone with enhancement (arrowhead) in arterial (E) and washout in portal (F) phases.

Effect of Vessel Size and Distance
Table 3 shows that the diameter of the adjacent blood vessel and the distance between the vessel and the tumor did not affect treatment outcome. There was a trend, however, toward lower complete ablation rates after one session for tumors that were near vessels larger than 5 mm in diameter.

Survival
A higher proportion of patients in the nonhigh-risk group had disease in Child-Pugh class B or C (p = 0.036). The high-risk group had larger tumor sizes (p = 0.012) and was more likely to be treated with an internally cooled electrode (p = 0.003). The other baseline and treatment parameters and response to treatment were similar for the two groups (Table 4). After a median follow-up period of 9.8 months from the first radiofrequency ablation session (non-high-risk, 11.2 months [range, 0.7–29.5 months]; high-risk, 9.5 months [range, 0.5–32.7 months]; p = 0.69), 16 patients had died (non-high-risk, one [6.7%] patient; high-risk, 15 [12.8%] patients). No patient died as a direct result of radio frequency ablation, and none died within 30 days of the last radio frequency ablation session. The most common cause of death was liver failure due to sepsis (n = 8) or gastrointestinal bleeding (n = 3), followed by tumor progression (n = 2) and other diseases unrelated to the underlying liver disease (n = 3). Cumulative probabilities at 12 and 24 months were 100% and 80% (non-high-risk) versus 86.6% and 76.9% (high-risk) for survival (p = 0.42) and 82.5% and 66% (non-high-risk) versus 77.3% and 70.6% (high-risk) for local tumor progression-free survival (p = 0.83) (Fig. 5). The only independent predictor of survival was complete ablation of all index tumors (odds ratio, 5.6; 95% CI, 1.9–16.3; p = 0.001) (Table 2).

View larger version (9K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5 —Graphs compare survival (left) and local tumor progression-free survival (right) rates for patient groups. HR = high-risk, NHR = non-high-risk.

Complications
No major complications occurred in management of non-high-risk tumors. All major complications occurred in the management of tumors close to a vital organ or capsule, except in one patient, where the tumor was close to portal vein only. The complication rates of the patient (non-high-risk vs high-risk) and treatment (non-high-risk radiofrequency vs high-risk radiofrequency vs high-risk radiofrequency plus PEI) groups were not significantly different (Table 5). Most minor complications were detected within 30 days of the radiofrequency ablation session and spontaneously resolved within 1 month, except in patients with biliary tract injury, in whom complications were found a median of 112 days after the procedure. All cases of biliary tract injury manifested as mild intrahepatic ductal dilatation distal to the ablated tumor with no cholangitis. The one case of seeding, into the kidney capsule, was related to rupture of a subcapsular HCC after radiofrequency ablation and was confirmed at surgical resection 22 months after the ablation procedure. None of the patients died as a direct result of a complication of radiofrequency ablation.

discussion

Top Abstract Introduction Subjects and Methods Results discussion References

 
Our results confirm the safety and efficacy of radiofrequency ablation for patients with HCC in high-risk locations. The primary effectiveness rates of radiofrequency ablation in patients with high-risk tumors reported in the literature range from 88% to 100% [2, 10, 14, 15, 24, 25]. However, few studies have included a comparison group. In the largest series to date, Teratani et al. [2] compared data on 636 patients with 1,419 HCCs undergoing radiofrequency ablation and found that complete ablation was achieved in 99% of tumors within 5 mm of a large vessel or vital structure (high-risk location) compared with 100% for tumors not in those locations. Ablation of high-risk tumors, however, required a median of four sessions compared with 2.1 sessions for non-high-risk tumors, signifying that despite equivalent efficacy of treatment, HCC in high-risk locations was more difficult to completely ablate in only one radiofrequency ablation session. At most centers where the charges for one session of radiofrequency ablation are substantial, having a patient undergo multiple radiofrequency ablation sessions not only increases medical expenses but also can increase the risk of complications of the procedure [9]. It is therefore important that a strategy be devised whereby tumors can be safely and adequately managed in as few sessions as possible.

The combination of percutaneous ethanol injection and radiofrequency ablation has been used by other investigators for the management of large liver tumors and for tumors close to vital structures [20, 26, 27]. Percutaneous ethanol injection results in a larger volume of coagulation necrosis after radiofrequency ablation than does radiofrequency ablation alone [19, 20], probably because of the effect of hot ethanol in extending tissue necrosis, diffusion of ethanol into areas not reached by radiofrequency energy, and reduction of the heat-sink effect. This capability allowed Vallone et al. [27] to achieve complete ablation in 100% of 40 intermediate-sized to large (4–7 cm) tumors in their series. To our knowledge, however, in only one case series of five patients did the investigators [26] describe the effect of combined radiofrequency ablation and PEI on tumors in high-risk locations. We found that although the tumors were significantly large, the combination of PEI with radiofrequency ablation in the management of HCC in high-risk locations resulted in only slightly lower complete ablation rates after one session compared with tumors in non-high-risk locations (88% vs 93%) and in higher rates than similarly sized high-risk tumors managed with radiofrequency ablation only (81%). This trend in efficacy among the three treatment groups remained even after multiple radiofrequency ablation sessions (primary effectiveness rate) (Table 1).

The rate of major complications (5.3% of all patients) in our study is comparable to most clinical series on radiofrequency ablation. Despite the high proportion of tumors close to the liver capsule (62%), there was only one instance of seeding in our series. This favorable outcome may be related to our routine use of needle-track thermocoagulation and careful placement of the radiofrequency ablation electrode as described earlier, although longer follow-up may be needed to determine the true rate of seeding.

Consistent with the findings in previous studies [6, 22, 28], we found that complete ablation was more likely in smaller tumors. In addition, the imaging finding of an indistinct tumor border was an independent predictor not only of primary effectiveness but also of local tumor progression. Aside from infiltrating HCC (n = 8), nine previously managed HCCs in our series had indistinct borders on sonography because of echo artifacts in and around the tumor brought about by previous treatment. Studies [29, 30] have shown that infiltrating HCC, as opposed to nodular HCC, was associated with a lower probability of complete ablation after radiofrequency ablation. The poorer outcome of management of tumors with indistinct borders can be attributed to difficulty in achieving an adequate ablative margin owing to difficulty in discerning the outer boundaries of the tumor. The poorer outcome also can be attributed to lack of the oven effect produced by a tumor capsule, which concentrates the heat produced by radiofrequency ablation energy within its borders, in infiltrating tumors [29].

Tumors incompletely controlled with previous locoregional therapies were independently associated with local tumor progression. This association may be due to more aggressive biologic features of these tumors or to foci of viable tumor cells that did not become enhanced on dynamic imaging studies. A study [31] of explanted livers showed that dynamic imaging studies performed within 3 months before liver transplantation were only 33% sensitive in detection of foci of viable HCC, most of which were microscopic, after locoregional therapy. Because the lag time between the last imaging study and performance of radiofrequency ablation in our study was variable, viable tumor cells might have grown or spread and contributed to underestimation of the area to be ablated. Furthermore, in our study more tumors that were incompletely controlled with previous locoregional therapy than treatment-naive HCCs had indistinct margins (24% vs 5%) on sonography, which may make precise targeting of viable tumors a challenge. Our relatively higher local tumor progression rate of 22% after 12 months may be related to the inclusion of HCCs subjected to previous treatment; in most other studies [4, 5, 13], only treatment-naive HCC have been included. Our higher progression rate also may be attributed to exclusion of tumors recently managed with TACE, which has been shown to decrease local tumor progression rates in combination with radiofrequency ablation [8].

The only independent predictor of survival in our series was achievement of complete ablation of all index tumors, suggesting that technical success may translate into favorable clinically relevant end points in patients treated with radiofrequency ablation. This finding is corroborated by reports of patients treated with radiofrequency ablation [6] and other locoregional therapies [32]. In those studies, attainment of complete ablation was associated with a twofold to sixfold increase in survival rate over the rate among patients with treatment failure. The importance of achieving this technical end point is indirectly supported by results of studies [4, 7] in which radiofrequency ablation was compared with percutaneous ethanol injection. Those studies showed radiofrequency ablation consistently results in higher complete ablation rates with consequently higher survival rates among patients with HCC.

Inherent to studies that lack randomization, a few biases might have been introduced into our study. First, the preference of using radiofrequency ablation plus PEI versus radiofrequency ablation alone may be related to the experience and competence of the operator. This factor might not have been relevant in our study because there was no difference among the three operators in frequency of using either technique or in treatment outcomes (data not shown). Second, the amount of ethanol injected was not standardized. The volume of coagulation necrosis and possibly the risk of complications may be proportionally increased with the volume of ethanol injected. Last, because of the relatively short follow-up period, some late complications, such as seeding and biliary tract injury, might have been underreported. However, on the basis of our previous experience, the rate of these complications is not expected to be substantial [4, 22].

In conclusion, we found a trend toward a higher complete ablation rate with the use of the combination of radiofrequency ablation and PEI in the management of HCC in high-risk locations compared with the rate for radiofrequency ablation alone with no increase in the risk of complications. A randomized controlled study is warranted to clarify these results. We also confirmed that the survival and tumor progression-free survival rates among patients with and those without tumors in high-risk locations were comparable. That complete ablation of all index tumors managed with radiofrequency ablation was the only independent predictor of patient survival emphasizes the importance of persistence in trying to ablate all areas of residual tumor and perhaps the importance of refinement and development of novel techniques for further improvement of an already highly effective treatment of patients with HCC.

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