Analysis of factors predicting survival in patients with hepatocellular carcinoma treated with percutaneous laser ablation *

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1 Journal of Hepatology 44 (2006) Analysis of factors predicting survival in patients with hepatocellular carcinoma treated with percutaneous laser ablation * Claudio Maurizio Pacella 1, *, Giancarlo Bizzarri 1, Giampiero Francica 2, Giuseppe Forlini 4, Alessandra Petrolati 3, Dario Valle 1, Vincenzo Anelli 1, Antonio Bianchini 1, Stefano De Nuntis 1, Sara Pacella 1, Zaccaria Rossi 4, John Osborn 5, Roberto Stasi 6 1 Department of Diagnostic Imaging and Interventional Radiology, Ospedale Regina Apostolorum, Via San Francesco, , Albano Laziale, Rome, Italy 2 Department of Interventional Ultrasound, Presidio Ospedaliero Camilliani S. Maria della Pietà, Casoria, Naples, Italy 3 Department of Gastroenterology, University of Tor Vergata, Rome, Italy 4 Department of Gastroenterology, Ospedale Regina Apostolorum, Albano Laziale, Italy 5 Department of Public Health Science, University La Sapienza, Rome, Italy 6 Department of Medical Sciences, Ospedale Regina Apostolorum, Albano Laziale, Italy Background/Aims: The factors which predict the long-term outcome in patients with hepatocellular carcinoma who are treated with percutaneous laser ablation (PLA) are not well established. Methods: We prospectively analyzed treatment and survival parameters of 148 cirrhotic patients with nonsurgical hepatocellular carcinoma who had undergone PLA at a single institution during an 11-year period. Results: Single tumors were seen in 129 of 148 (87%) patients, and 2 3 nodules were seen in 19 (13%) patients, for a total of 169 tumors. The median overall time survival was 39 months (95% confidence interval [CI], months). The 1-, 2-, 3-, 4-, and 5-year cumulative survival rates were 89, 75, 52, 43, and 27%, respectively. From multiple regression analysis, the independent predictors of survival were found to be tumor grading (PZ02; risk ratio [RR] 7, 95% CI 0 0), bilirubin levels %2.5 mg/dl (PZ14; RR 1.58, 95% CI ), and the achievement of complete tumor ablation (PZ20; RR 3, 95% CI 1 0). An initial complete tumor ablation was the only factor associated with longer survival in patients with Child Turcotte Pugh class A cirrhosis (PZ12; hazard ratio [HR] 8, 95% CI 3 3). Conclusions: A complete tumor ablation results in improved survival in all patients with nonsurgical hepatocellular carcinoma. Ideal candidates for PLA are those with a well-differentiated histology, and normal bilirubin levels. q 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Lasers; Interstitial therapy Liver; Interventional procedures Liver neoplasms; Liver neoplasms; Therapy 1. Introduction Received 10 October 2005; received in revised form 15 January 2006; accepted 22 January 2006; available online 28 February 2006 * Author Contributions: CMP, GF and ZR designed the study and performed research; GB, DV, VA, AB, SDN and SP performed research; AP, GF, RS and JO, analyzed the data; RS contributed to writing the paper. * Corresponding author. Tel.: C ; fax: C addresses: cmpacel@katamail.com (C.M. Pacella), claudiomaurizio.pacella@fastwebnet.it (C.M. Pacella). Abbreviations: HCC, hepatocellular carcinoma; PLA, percutaneous laser ablation; TACE, transcatheter arterial chemoembolization. The most effective therapy for patients with unresectable hepatocellular carcinoma (HCC) remains a topic of much debate [1]. Several minimally invasive treatments have been developed that can achieve effective and reproducible tumor ablation. In the last decade, the most extensive clinical experience has been based on percutaneous ethanol injection (PEI) [2 5]. Recently, other interventional procedures such as radiofrequency [6,7], microwave, and percutaneous laser ablation, have been developed [8 11] /$32.00 q 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:1016/j.jhep

2 C.M. Pacella et al. / Journal of Hepatology 44 (2006) Percutaneous laser ablation (PLA) is a technique for local tumor destruction within solid organs that can be performed using various imaging methods. Optical fibers deliver high-energy laser radiation to the target tumor lesion. Neodymium:Yttrium Aluminum Garnet (Nd:YAG) lasers, with a wavelength of 1064 nm, are used for PLA because penetration of light is optimal in the near-infrared spectrum. The light scatters within the tissue and converts to heat, resulting in tumor coagulation. PLA has been shown to be effective in inducing complete necrosis in HCC [12 14]. However, studies describing the impact of this technique on the long-term outcome of patients and focusing on the major predictors of survival are lacking. The purpose of our analysis was to define these critical aspects, thereby identifying the subgroup of individuals that may benefit the most from therapy. 2. Materials and methods 2.1. Patients From 1994 to 2005, 384 patients with hepatocellular carcinoma were managed in our center. Percutaneous laser ablation was performed in 148 of these patients. Other treatments consisted of surgical resection in 28 cases, orthotopic liver transplantation in 12, transarterial chemoembolization (TACE) in 50, and a combination of PLA and TACE in 100. Palliative therapy was administered to the remaining 84 patients. The baseline characteristics of cases treated with PLA alone are summarized in Table 1. The diagnosis of hepatocellular carcinoma was confirmed via needle biopsy in 144 cases and by noninvasive criteria in 4 cases [15]. Tumors were classified with regard to the degree of differentiation (well, moderate, poor, and undifferentiated), cell arrangement, and histologic pattern (trabecular, pseudoglandular or compact) [16]. All patients were poor surgical candidates or did not fit into surgical criteria (solitary HCC, normal bilirubin and absence of significant portal hypertension) [17]. Eligibility criteria for PLA were the presence a single tumor %4 cm in diameter or one to three nodules each %3 cm in diameter, irrespective of their location. Exclusion criteria were age older than 85 years, evidence of extrahepatic metastases (based on the coincident findings of at least two imaging techniques) and/or local, segmental or lobar portal venous thrombosis, uncontrolled liver disease decompensation (gastrointestinal bleeding, encephalopathy, refractory ascites, bacterial infection), severe clotting impairment (platelet count less than 25!10 9 /L or prothrombin time with international normalized ratio (INR) greater than 1.99), renal failure, or Child Pugh class C cirrhosis. The size and number of lesions, their location in the liver, vascular and biliary ingrowth were established in all patients by US and CT before biopsy. The threedimensional size (three largest perpendicular diameters of the lesion multiplied by 25 [ellipsoid volume]) of each tumor was assessed on the basis of its CT image. Portal hypertension was defined as the presence of esophageal varices on upper endoscopy [18]. Treatment of patients was approved by the local institutional review board and a written informed consent was obtained from all patients Percutaneous laser ablation The PLA procedure has been reported in detail elsewhere [12,19]. Depending on the size, shape, and location of the lesions, from two to four 21-gauge needles were positioned under US guidance in the area to be treated, with interneedle spacing of cm (in a square configuration when four fibers were used). The needles were positioned one at a time through the single skin entry port. We used 2 fibers for lesions ranging in size from to cm, and 4 fibers for larger lesions. The optical fiber was inserted through each needle to the end of the sheath, which was then retracted, leaving at least cm of bare tip in direct contact with the lesion. Table 1 Baseline characteristics of patients No. of patients (M/F) 83/65 Age (years) 67.6G8.9 ECOG performance status (0/1) 132/16 Etiology HCV 124 HBV 12 Alcohol 8 Cryptogenetic 4 Child-Turcotte-Pugh class (A/B) 105/43 Okuda stage (I/II) 92/56 Ascites (yes/no) 11/137 Serum bilirubin (mg/dl) 1.38G4 Serum albumin (g/dl) 3.22G7 Serum creatinine (mg/dl) 3G2 Prothrombin activity % 76.6G12.9 INR 1.2G Platelet count (n!10 9 /l) 88G42 Alfa-Fetoprotein (ng/ml) 121.1G293.8 Barcelona clinic liver cancer stage No. A1 37 A2 54 A3 37 A4 20 Total no. of tumors 169 No. of patients with 1 tumor tumors 18 3 tumors 1 Tumor size (cm) 2.6G Tumor size no. (%) %3.0 (cm) 116 (69%) O3.0 (cm) 53 (31%) Differentiation degree (nz144) Well 33 Moderate 55 Poor 44 Undifferentiated 12 HCV, hepatitis C virus; HBV, hepatitis B virus. Tilting the US probe the arrangement of fibers can be suited to the lesion shape and the insertion of four needles in a sequential fashion increases the accuracy of the treatment. For each illumination the laser was turned on at a power of 5.0 W with an exposure time of 360 s (1800 J per fiber). Fibers were always activated simultaneously. In a single treatment the total energy delivered ranged from 3600 J (1800 J!2) with two fibers to 7200 J (1800! 4) with four fibers Assessment of treatment efficacy Assessment of response was based on modified WHO criteria [15]. A dynamic CT scan was performed h after each session. This allowed us to assess the extent of necrosis and plan a new treatment if needed, as well as to detect possible complications of the procedure. Tumor ablation was considered complete when no areas of enhancement were seen at the periphery of the target area(s). In these cases, the efficacy of PLA had to be confirmed by a CT scan at 3 months. For cases with incomplete necrosis, an additional PLA session was scheduled within 2 weeks of the first one. Initial treatment failure was defined as the presence of viable tumor at the end of treatment. Late treatment failure refers to the detection of viable tumor during follow-up either within the treated nodule or within 2 cm of the surrounding parenchyma, as reported by other groups [3,20]. Therefore, treatment failure includes early and late failure and represents the failure of

3 904 C.M. Pacella et al. / Journal of Hepatology 44 (2006) treatment to achieve local disease control. Disease recurrence was defined as the appearance of HCC foci beyond this area in the absence of failure Follow-up Patients were followed every 3 months by means of clinical examination and blood analysis, including alpha-fetoprotein. A clinical restaging with CT scan was performed three and six months after the first PLA session(s). After the first 6 months of follow-up, CT was performed every six months. All CT scans were analyzed in consensus by two radiologists. Upon detection of failure or recurrence, patients were considered for new treatment sessions Assessment of complications Complications of treatment were described using the reporting standards of the Society of Interventional Radiology [21] Statistical analysis The main end point of the study was survival. Secondary end points were treatment efficacy and recurrence. Baseline characteristics of patients are expressed as meangsd. Comparison among groups was performed using ANOVA for continuous variables and the chi-square test with Yates correction for categorical variables. Overall survival was computed as starting from the beginning of the treatment and was maintained until death or the last visit. Time to recurrence or late failure was calculated as the interval between no evidence of neoplastic disease at spiral CT after PLA was completed and the appearance of the tumor. Probability curves obtained via the Kaplan Meier method were compared using the Log-Rank test. The following variables were assessed for their impact on survival: sex; age; cause of underlying cirrhosis; Child Turcotte Pugh class; Okuda stage; Barcelona Clinic Liver Cancer (BCLC) staging classification [22]; ascites; portal hypertension; differentiation degree; tumor size; number of tumors; a-fetoprotein levels; prothrombin activity; platelet count; serum creatinine; serum bilirubin; serum albumin; and size of main tumor. For continuous variables, the cutoff level was chosen with a minimum P-value approach. A problem with this approach is the considerable inflation of the type I error rate with multiple testing. We, therefore, used the correction as proposed by Altman et al [23]: P corr zk1.63!p min (1Clog e P min ), and give both values. Significant variables (P!5) were included in a Cox regression analysis. Data collection was censored on June 30, Calculations were performed with SPSS software package (SPSS, Inc., Chicago, IL). 3. Results 3.1. Treatment efficacy We performed a total of 239 PLA sessions (range, 1 4; mean 1.4). Overall, 122 of 148 (82%) patients achieved an initial complete response. All complete responses observed by CT scan at h after treatment were confirmed by a CT scan at 3 months. The probability of achieving a complete tumor ablation was greater for lesions with a size %3.0 cm (103/116, 89%) than for larger lesions (39/53, 74%; PZ12). Treatment results in relation to size and number of tumors are reported in Table 2. There was no association between the achievement of an initial complete response and the other variables investigated. Predictors of late treatment failures are reported in Table 3. These were observed in 18 of 122 (15%) patients, with a cumulative incidence of 34.6%. Failures were more likely to occur in Table 2 Treatment efficacy according to tumor size and stage Complete ablation Initial failure Lesions % Lesions % Tumor size % (cm) 3 (75) 1 (25) (cm) 41 (95) 2 (5) (cm) 59 (85) 10 (15) (cm) 39 (74) 14 (26) Stage Single tumors 107 (83) 22 (17) Multinodular 17 (89) 2 (11) patients with a tumor size O3.0 cm than in patients with smaller tumors (Hazard Ratio [HR] 5.92, 95% confidence interval [CI] , P!01; Fig. 1). It is also relevant that none of the 28 cases with a well-differentiated histology relapsed, as compared to 18 of 72 relapses observed in cases with less differentiated tumors (HR, PZ08). The appearance of new lesions was observed in 73 of 148 (49%) patients, and the cumulative incidence of distance recurrence was 76.8%. Distant recurrences were not predicted by any variable. Forty-nine distant recurrences in 31 patients were treated, with new complete responses in 34/49 (69.4%). Overall, only 6 of the retreated patients remained free of disease at the end of follow-up Survival The median follow-up was 26 months (range 103 months). The median overall survival was 39 months (95% confidence interval [CI] months). The 1-, 2-, 3-, 4-, and 5-year cumulative survival rates were 89, 75, 52, 43, and 27%, respectively (Fig. 2). The 5-year survival rate was 30% for patients with Child Turcotte Pugh class A, and 17% for patients with Child Turcotte Pugh class B. At the time of the analysis, 91 of 148 (61%) patients had died, and 13 (9%) had been lost to follow-up. Death was due to hepatocellular carcinoma in 46 cases, to liver failure in 31 cases, and to other causes in 14 cases. There were 2 deaths within the first 30 days. One suffered from complications of Table 3 Predictors of late treatment failure (local recurrence) after complete tumor ablation Variable Recurrence P-value a Hazard ratio (95% CI) Yes No Tumor size %3.0 (cm) 6 77 O3.0 (cm) 12 27! ( ) Differentiation degree Well differentiated 0 28 Moderately to poorly differentiated a Log-Rank test of the differences in cumulative incidence.

4 C.M. Pacella et al. / Journal of Hepatology 44 (2006) Cumulative Incidence of Late Treatment Failure P < 01 Number at risk Tumor size < or = 3.0 cm Tumor size > 3.0 cm Fig. 1. Probability of late treatment failure by tumor size in patients in whom an initial complete response was obtained. the PLA procedure, and one suffered from progressive liver failure not related to treatment. Death related to liver failure was significantly more frequent in Child-Turcotte-Pugh class B patients (15/105, 35%) compared with Child- Turcotte-Pugh class A (16/105, 15%; PZ14). In univariate analysis, predictors of longer survival were serum levels of bilirubin %2.5 mg/dl (P corr!01, P min! 01; Fig. 3), an initial complete tumor ablation (PZ07, Fig. 4), the absence of ascites (PZ11), a Child-Turcotte- Pugh class A (PZ14), a-fetoprotein levels %200 ng/ml (P corr Z30, P min Z04), a BCLC stage A1 or A2 (PZ 32), and a well differentiated tumor grading (PZ44, Fig. 5). In multivariate analysis (Table 4), independent predictors of survival were tumor grading (PZ02; Risk Ratio [RR] 7, 95% CI 0 0), bilirubin levels %2.5 mg/dl (PZ14; RR 1.58, 95% CI ), and the achievement of a complete tumor ablation (PZ20; RR 3, 95% CI 1 0). Cumulative proportion surviving Number at risk Fig. 2. Overall survival in 148 patients with nonsurgical hepatocellular carcinoma. Cumulative proportion surviving When the 105 patients with Child Turcotte Pugh class A cirrhosis were singled out, the only factor associated with longer survival was an initial complete tumor ablation. The median survival was 50 months (95% CI months) for the 87 patients with complete ablation and 29 months (95% CI months) in the 18 patients with partial tumor ablation (PZ12; HR 8, 95% CI 3 3). There was no significant difference in the duration of survival in relation to tumor size when different cut-offs were used. Patients with Child Turcotte Pugh class A, a tumor size %3.0 cm, and a well-differentiated histologic pattern who achieved an initial complete tumor ablation had a median survival of 58 months (95% CI months) Treatment safety P < 01 Numberatrisk Fig. 3. Overall survival by bilirubin levels. Bilirubin<or=2.5mg/dl Bilirubin>2.5mg/dl Complications of treatment, classified according to the criteria of the Society of Interventional Radiology [21], are summarized in Table 5. One treatment-related Cumulative proportion surviving Number at risk P = Complete tumor ablation Partial tumor ablation Fig. 4. Overall survival by type of initial response.

5 906 C.M. Pacella et al. / Journal of Hepatology 44 (2006) Cumulative proportion surviving death, was observed in a 69-year-old woman 4 days after the PLA procedure. This patient, who had a Child Turcotte Pugh class B7 cirrhosis, suffered from an acute liver decompensation. There was one major complication: a patient with Child Turcotte Pugh class B9 disease had a transient decompensation of liver function that required medical therapy with prolonged hospitalization (O48 h). We observed asymptomatic pleural effusion that resolved after 1 3 weeks in 97 patients with lesions located in the dome of the liver beneath the diaphragm (segments 3, 4, 7, and 8). No case of tumor seeding along the PLA needletracks was observed. Apart from the patient who died, none of the patients who experienced any complication related to treatment required intensive care, surgical repair, or a radiologic interventional approach. 4. Discussion P = 30 Numberatrisk Welldifferentiated Moderatelytopoorly differentiated Fig. 5. Overall survival by tumor differentiation degree. We have reported the results of the largest prospective cohort study published to date evaluating the impact of Table 4 Results of Cox regression analysis Independent variable Risk ratio exp(b) Lower 95. 0% CL of exp (B) Upper 95. 0% CL of exp (B) Prob. level AFP (ng/ml) (NS) Ascites (yes/no) (NS) BCLC stagezal (NS) BCLC stageza (NS) BCLC stageza (NS) Bilirubin (mg/dl) Child-Turcotte (NS) Pugh class Complete ablation (yes/no) Tumor grading AFP, alfa-fetoprotein; BCLC, barcelona clinic liver cancer; NS, not significant. Table 5 Major complications of percutaneous laser ablation treatment Type of reaction No. of cases SIR a class Immediate (within 24 h) Vasovagal reaction 1 A Subcapsular hematoma in one patient 1 A Self-limiting variceal bleeding 1 A Perirenal inflammation 1 A Partial segmental infarction of contiguous 1 A kidney Abdominal pain 76 B Mild or moderate increase in body temperature 62 B Pleural effusion 97 B Periprocedual (within 30 days) Acute liver decompensation 1 F Transient decompensation of liver function 1 D Transient decompensation of liver function 5 B a SIR, Society of Interventional Radiology. percutaneous laser ablation on the survival of patients with hepatocellular carcinoma. The technique we used was highly effective in terms of local tumor control, thus confirming both our preliminary reports with laser ablation [12],as well as the results obtained with other hyperthermic methods such as radiofrequency [24,25]. As expected, small nodules (%3.0 cm) were easier to destroy than large ones. In addition to size, a recent systematic analysis identified tumor location as a critical variable for the success of treatment [19]. For some tumor locations the PLA technique presents limitations. In fact, some tumors are located in poorly accessible regions of the liver that do not allow the optimal placement offibers. This confounding factor may be the cause of incomplete ablation and can account both for the different response rates between primary lesions and distant recurrences, and for the lack of prognostic significance of tumor size. PLA was associated with acceptable morbidity (just one major complication, %) and a single treatment-related death (%). With this technique, Nd:YAG laser fibers can be inserted through 21-gauge needles, which reduce the size of puncture in patients who often have poor coagulation parameters. In fact, we managed to treat 9 cases with Child- Turcotte-Pugh class B8 e 14 cases with Child-Turcotte- Pugh class B9, for whom other ablation procedures are usually precluded. It is also noteworthy that no case of tumor seeding along the needle-tracks was observed. This compares favorably with the results of large series of radiofrequency ablation, showing an incidence of needle track seeding of % [26]. Cost-efficacy assessments may also tilt the balance in favor of PLA rather than RFA. For a single tumor ablation, the cost of disposable devices is Euros for PLA vs Euros for radiofrequency. This analysis is shared by other European investigators [10]. On the other hand, the costs of PEI are much cheaper than PLA or RFA, ranging from 40 to 85 Euros per session [13,27]. However, for a complete ablation to be achieved 3 6 sessions of PEI are usually necessary.

6 C.M. Pacella et al. / Journal of Hepatology 44 (2006) Because of differences in study designs and patient populations, direct comparisons of our results with those of other trials using percutaneous ablation should be considered cautiously. The 5-year survival rate of 27% in our series is superimposable to values reported by the Barcelona Clinic Liver Cancer group using various techniques [24]. Much better results (5-year survival rate of 50%) have been reported in a large Japanese series (1238 patients) treated between 1992 and 2003 with PEI, percutaneous microwave coagulation therapy, or RFA [2]. However, it should be noted that for these patients percutaneous ablation represented the first therapeutic option, while in our series and in the BCLC experience percutaneous ablation was the third option (after surgical resection and liver transplantation). Thus, this excellent outcome may result, at least in part, from an initial selection of patients with more favorable characteristics. Other long term studies using PEI indicate that Child Turcotte Pugh class A patients with successful tumor necrosis may achieve a 50% survival at 5 years [5,28]. This compares well with the outcome of our patients presenting with the same characteristics. Radiofrequency ablation offers the same response rates as PEI in tumors!2 cm, but is more effective in tumors O 2 cm [29 32]. In small randomized trials RFA provided better local control for small lesions in patients with cirrhosis than PEI [30 32], and resulted in a significantly longer 3-year or 4-year survival [31 33]. In a larger series of 206 patients treated with RFA the 5-year survival was 41%, but for those who had Child Turcotte Pugh class A cirrhosis with solitary HCC (nz116) the 5-year survival rate was 61% [34]. Only a few other investigators have used PLA for the treatment of HCC [13,14,35]. The complete ablation rates in these reports ranged from 70 to 84%, with no details about the 5-year survival. The prognostic value of liver function impairment, which in our study was by elevated bilirubin levels, is in keeping with the results of many recent studies [24,25,34,36]. It is generally assumed to reflect the fact that the natural history of liver cirrhosis is not changed by the results of tumor treatment [37]. On the other hand, this is the first time that tumor grading emerges as an independent prognostic factor in the nonsurgical treatment of HCC. However, the majority of previous studies did not report the results of tumor biopsy, either because it was not performed, or because it was not systematically investigated as a prognostic factor. Tumor grading is known to be closely associated with an increase in biological aggressivity and/or capacity to recur after tumor resection [38]. Furthermore, it has been shown to be highly correlated with microvascular invasion [39]. As a matter of fact, in our series a poorly differentiated histology was significantly associated both with a higher frequency of late treatment failures, and with a decreased survival. Therefore, it may be speculated that for patients with a poorly differentiated tumor we need an area of necrosis larger than the one planned according to conventional imaging. When we use PLA we usually try to destroy all of the tumor plus a 1 cm cuff of adjacent liver. The cuff of liver is destroyed in an attempt to create a tumor-free margin. In the case of poorly differentiated tumors, in which tumor emboli may spread at various distances from the tumor because of microvascular invasion, attempts should be directed at producing a thicker cuff. The fact that tumor grading was not found to be a significant prognostic factor in patients with Child Turcotte Pugh class A may be related to a smaller number of patients and thus insufficient statistical power. Despite screening programmes many patients present with tumors larger than 4.0 cm [40]. In our experience, these large tumors are not effectively treated with PLA. Combinations of selective transarterial chemoembolization and thermal ablation have been explored with some success in this group [41,42]. Although there have been many published studies using TACE, it has been difficult to demonstrate improved survival. A meta-analysis published in 2003 succeeded in showing a significant improvement in the 2-year survival, albeit short, of arterial embolization compared with control [43]. In addition, sensitivity analysis showed a significant benefit for chemoembolization with cisplatin or doxorubicin, but none with embolization alone. Therefore, a combined approach would appear to be reasonable. In conclusion, our results indicate that percutaneous laser ablation is a highly effective treatment that can improve the survival of patients with nonsurgical hepatocellular carcinoma with a diameter %4.0 cm. The best candidates to this treatment are those with a well differentiated histology and normal bilirubin levels. However, with the available data definite conclusions about the relative efficacy of the individual ablation techniques cannot be deduced. At the present time, PEI probably remains the standard treatment for tumors smaller than 2 cm, since it is safe, easy to perform, inexpensive, and achieves complete response rates greater than 90%. For larger tumors RFA offers better results than PEI, but it also has higher costs and a higher rate of adverse events. PLA seems to overcome some of the disadvantages of RFA while retaining the same efficacy. However, large randomized clinical trials comparing these techniques and primarily designed to assess survival are needed. Conflicts of interest statement The authors declare that they are not shareholders and do not have any financial interests in the companies mentioned in this paper that compromised the design of research, the safety and well-being of patients, the collection and interpretation of research data, as well as the dissemination

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