Introduction
Hepatocellular carcinoma (HCC) represents approximately 90% of primary liver cancers and ranks as the sixth most common carcinoma globally, with a dismal prognosis [1]. Ablation therapy, notably radiofrequency ablation (RFA), is the standard treatment for patients diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage 0 and A tumors [2].
Despite its widespread adoption, concerns arise from sporadic reports, detailing the rapid recurrence of HCC post-RFA [3-6], thereby necessitating judicious patient selection. The precise mechanism behind this swift progression remains elusive, though it is believed to involve the popping phenomenon, characterized by the scattering of tumor cells around the resection zone [4]. This phenomenon likely arises from a sudden surge in internal tumor pressure induced by RFA. To mitigate this risk, modified ablation techniques employing low-power [7] or multi-step RF power [8] have emerged.
Conversely, in cases where conventional abdominal ultrasound fails to visualize tumors, a perfluorobutane microbubble contrast agent (Sonazoid, GE Healthcare, Tokyo, Japan), is employed. Sonazoid utilization during RFA for HCC leads to an expanded ablation zone and reduced popping incidence [9].
Experimental investigations using in vivo rabbit liver models have further supported these findings, demonstrating minimal or absent popping occurrences [10].
Based on this clinical background, our study aimed to explore whether RFA for HCC, supplemented with Sonazoid in routine clinical practice, effectively suppresses the popping phenomenon and impacts local recurrence rates.
Material and methods
Study population
A total of 135 patients with HCC, comprising 308 nodes, underwent RFA using a unipolar needle electrode from December 2019 to December 2023. The diagnosis of HCC was made using dynamic contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI), in which the contrast medium was rapidly injected through a vein, and the same area was imaged multiple times after the contrast medium reached the target area at the right time. Tumor diameters ranged from 10 to 30 mm, with procedures conducted using the arfa RF ablation system (Japan Lifeline Co. Ltd., Tokyo, Japan) with adjustable electrode needle devices, equipped with variable electrodes and a 30 mm cautery electrode length. All RFA sessions were performed via a percutaneous approach under ultrasound guidance (LOGIQ E9 XDclear 2.0, GE Healthcare, Chicago, IL, USA). During RFA, intravenous conscious sedation was performed, and vital signs were monitored. The treatment protocol involved initiating ablation at 30 W. The output of the arfa system was increased at a rate of 1 W/6 s (linear mode) until the so-called “roll-off” or “break” point (i.e., cessation of delivery of the RFA system) was attained.
The popping rate during ablation was compared between two groups: those receiving RFA with Sonazoid and those without Sonazoid.
Measured outcomes
Various parameters, including impedance, maximum power, energy value, intra-tumor temperature, ablation time, local recurrence rate after RFA, and popping rate during ablation, were compared between the Sonazoid and non-Sonazoid groups. Selection criteria for RFA included: 1) solitary or multiple HCC nodules < 3 cm (≤ 3 nodules, each < 3 cm); 2) Child-Pugh class A or B; 3) absence of macrovascular invasion and extrahepatic metastases during pretreatment imaging evaluation; and 4) normal prothrombin time and platelet count ≥ 50,000.
Ethics statement
This study was approved by the Institutional Review Board of Saiseikai Niigata Hospital and conducted in accordance with the principles of the Declaration of Helsinki. Prior to participating in this study, written informed consent was obtained from all patients.
Statistical analysis
The two groups were compared using the chi-square test. Normally distributed continuous data were expressed as mean ± standard deviation and compared using t-tests. The differences in parameters were analyzed using a one-way repeated measures analysis of variance. Statistical significance was set at p < 0.05. All statistical analyses were performed using EZR (Saitama Medical Centre, Jichi Medical University, Shimotsuke, Japan), a graphical user interface for R version 3.2.2 (The R Foundation for Statistical Computing, Vienna, Austria) [11].
Results
The study included 99 male and 36 female participants, with an average age of 72 (range: 35-93) years. Among the 135 enrolled patients, 21 patients were seropositive for hepatitis B surface antigen, 44 patients were seropositive for hepatitis C virus antibody, and 70 patients were seronegative for both hepatitis B surface antigen and hepatitis C virus antibody (Table 1). The group without Sonazoid had 267 nodes, whereas the Sonazoid group had 41 nodes.
Table 1
Patient and lesion characteristics at the time of enrollment
| Baseline characteristic | Value |
|---|---|
| Age (years) | 72.0 [35.0-93.0] |
| Sex ratio (male : female) | 99 : 36 |
| Etiology (HBV/HCV/non-HBV/HCV) | 21/44/70 |
In terms of energy-related comparisons, the Sonazoid group demonstrated significantly lower values than did the non-Sonazoid group for impedance (59.00 [38.00, 103.00] vs. 64.00 [33.00, 117.00], p = 0.002), maximum power (87.0 [43.0, 120.0] vs. 95.0 [38.0, 200.0], p = 0.039), energy value (24,954 [8,500, 48,571] vs. 29,906 [3,194, 100,000], p = 0.013), and ablation time (445 [216, 879] vs. 490 [113, 1248], p = 0.021) (Table 2).
Table 2
Radiofrequency ablation parameters with/without Sonazoid
However, no significant differences were observed between the groups regarding tumor diameter and localization (Table 2). The popping rate during ablation was markedly lower in the Sonazoid group than in the non-Sonazoid group (12.2% vs. 28.8%, p = 0.023) (Table 3). Notably, there was no significant difference in the local recurrence rate between the two groups.
Discussion
Devices used in RFA for HCC can be categorized into two types based on the shape of the electrode needle tip: monopolar needle electrode type and the expanded type. While the monopolar needle electrode is favored for its ease of puncture manipulation, it often leads to popping. Mitigating popping is crucial for ensuring safe RFA treatment, particularly in minimally invasive procedures.
The phenomenon of popping during RFA for HCC was initially documented by Livraghi et al. [12], with a previous study reporting a relatively high incidence of approximately 58% [13]. In our study, the use of Sonazoid proved effective in reducing the popping phenomenon during RFA for HCC treatment. Typically, the accumulation of RFA energy can be substantial, especially in the treatment of large tumors, leading to elevated intra-tumor pressure and an increased risk of popping phenomena.
Radiofrequency ablation under Sonazoid conditions was observed to reduce power output, enabling ablation at lower energies, reducing ablation time, and mitigating popping during the procedure. These findings align with the results of prior in vivo experimental studies utilizing a rabbit model [10]. During ablation, numerous microbubbles were noted surrounding the RF electrode, indicating a potential pressure-regulating mechanism that releases accumulated pressure, thus suppressing tissue pressure escalation. Additionally, the authors noted that gas-containing microbubbles exhibit significantly low electrical conductivity, inversely affecting tissue impedance.
Iida et al. reported that the popping phenomenon arises from a sudden and rapid decline in tissue impedance, potentially triggered by elevated tissue temperature and vaporization of tissue fluid [14].
Hence, it was deduced that maintaining relatively high tissue impedance with Sonazoid microbubbles during RFA could reduce the occurrence of popping events. The use of Sonazoid might decrease within the ablation zone due to heightened tissue impedance. Consequently, while there exists a risk of incomplete ablation due to reduced RF energy delivery, our study did not observe a decrease in local recurrence.
Angonese et al. and Kotoh et al. proposed that tumor recurrence following RFA of HCC may be attributed to increased intra-tumor pressure, leading to intravascular tumor spread [8, 15]. However, the definition of the popping phenomenon in these studies was not explicit, complicating comparisons with other research outcomes.
In this study, the occurrence of the popping phenomenon did not significantly impact the local recurrence rate. This suggests that popping may solely represent a physical consequence of thermal ablation and may not significantly influence treatment outcomes. Conversely, considering the heightened risk of peritoneal dissemination resulting from tumor rupture during RFA treatment of subcapsular HCC [16], the utilization of Sonazoid during RFA may potentially mitigate this risk by suppressing the popping phenomenon.
There are some limitations to this study. First, the number of patients was limited. Second, we believe it is necessary to investigate a large number of patients in various stages of the disease. Third, the retrospective design of this study may introduce bias in the selection of patients for HCC treatment. Finally, the data are from a single center. More extensive prospective clinical trials are thus needed to confirm these findings with greater accuracy.
Conclusions
The study findings imply that combining RFA with Sonazoid enables ablation with decreased power and energy, resulting in shorter ablation times and potential reduction of the popping phenomenon. Ablation at lower power levels without compromising clinical outcomes, such as local recurrence rates, suggests that RFA is a viable minimally invasive treatment option. Future studies should expand the sample size to validate these results, including assessment of treatment efficacy in prospective comparative studies.
