2022 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for Local Ablation Therapy of Hepatocellular Carcinoma: What’s New?

Local ablation therapies for HCCs are generally indicated for patients with a single HCC ≤ 5 cm or up to three nodules ≤ 3 cm. Although local ablation therapies have been attempted for larger HCCs, treatment outcomes are closely associated with tumor size. The larger the tumor size, the higher the local tumor progression (LTP) rate. Therefore, combined transcatheter arterial chemoembolization (TACE) and ablation therapy are recommended for HCCs 3–5 cm in diameter. Many studies have reported that, compared with RFA or microwave ablation (MWA) alone, combined treatment with TACE and RFA or MWA increases local tumor control and survival rate for patients with HCCs measuring 3–5 cm that are not amenable to surgical resection [3, 4].

Percutaneous thermal ablation can cause collateral thermal injury to the surrounding organs. Traditionally, artificial ascites or pleural effusion has been used to overcome this risk. Use of artificial ascites also helps enhance sonographic windows, especially in hepatic dome lesions.

Another technical challenge of RFA is that HCCs < 2 cm are not always sufficiently conspicuous on conventional US [5]. Sometimes mistargeting is encountered and a pseudolesion is ablated [6]. However, CEUS and fusion imaging with real-time US and pre-acquired CT/MRI scans improve the detection and technical success rates of local ablation therapy for HCCs < 2 cm [7, 8]. In particular, the HCC detection rate is higher when CEUS is performed with fusion imaging than when it is used alone. Although fusion imaging helps localize small HCCs, the incidence of mistargeting after fusion imaging-guided RFA is 1.3%, likely because of registration errors between image sets [9]. Therefore, caution should be exercised when ablating subcapsular HCCs ≤ 1.5 cm, especially in patients with hepatitis B-related liver disease [9].

The initial complete tumor necrosis rate after RFA has been reported to exceed 95% on the basis of post-RFA CT/MRI. If RFA is repeated for residual unablated tumors, complete tumor necrosis can be achieved in almost all cases. However, the 3-year LTP rate after RFA ranges from 0.9% to 21.4% [10, 11]. The 5-year overall survival rates were 83.7%–85.1% in recent RFA studies of Korean patients with HCC within the Milan criteria [12, 13]. The independent factors associated with overall survival after RFA include initial complete tumor necrosis, Child–Pugh score, number and size of tumors, and preoperative serum alpha-fetoprotein level.

Patients with a single HCC < 2 cm and Child–Pugh class A liver function can achieve the best treatment outcomes after RFA. If the tumor location is ideal for RFA, its efficacy is comparable with that of hepatectomy. Hence, RFA is considered the primary treatment for single HCC < 2 cm [11, 14]. According to randomized controlled trials (RCTs) and meta-analyses [15, 16], compared with hepatic resection, RFA has an equivalent survival rate, higher LTP rate, and lower complication rate in patients with a single nodular HCC ≤ 3 cm in diameter.

Tumor location affects treatment outcomes after RFA for HCC. The best results can be expected when the tumor is separated from the hepatic capsule, intrahepatic blood vessels, and central bile duct [17]. Subphrenic HCCs are challenging to treat with US-guided RFA and thus have a high risk of LTP and peritoneal seeding after treatment [12, 18]. Laparoscopic RFA can help overcome the technical difficulties of US-guided RFA for subphrenic HCCs if the tumor is accessible under laparoscopic guidance [19, 20]. When the tumor is in contact with the portal or hepatic vein ≥ 3 mm in diameter, RFA may be ineffective because of the heat-sink effect and result in complications due to blood vessel or bile duct damage [12, 21].

In addition to tumor location, tumor biology is associated with treatment outcomes after RFA. MRI findings such as peritumoral arterial enhancement or peritumoral hypointensity in the hepatobiliary phase, serum tumor marker levels, and tumor size are related to microvascular invasion (MVI) in HCC. In general, HCCs with a high risk of MVI show poor prognosis after RFA [22]. However, to our knowledge, no RCT or meta-analysis investigating the effect of MVI on treatment outcomes is available in the literature; therefore, more evidence is needed to reach a solid conclusion.

No-touch RFA refers to an RFA performed after the placement of multiple electrodes outside the tumor rather than within the tumor. It has gained attention because of its theoretical advantages over conventional tumor-puncturing RFA, including the creation of a sufficient ablative margin [23]. In addition, the risk of tumor spread around the tumor is low because the electrodes are not in direct contact with the tumor. Moreover, tumor feeding and draining vessels are destroyed in the earlier period of RFA, preventing tumor spread via the blood vessels. In two recent RCTs and a prospective multicenter clinical trial, compared with conventional tumor-puncturing RFA, no-touch RFA provided a lower LTP rate [24, 25, 26]. However, further investigation is warranted to evaluate whether no-touch RFA enhances survival outcomes after treating patients with small HCCs.

Limited attention has been paid to PEI since the 2018v guidelines. Generally, compared with PEI, RFA has a lower LTP rate and a higher survival rate. However, the survival rate was not significantly different among subgroups of HCCs < 2 cm [27]. Therefore, PEI may be considered for treating HCCs < 2 cm if RFA is not feasible. However, previous RCTs comparing PEI and RFA were conducted more than a decade ago, when RFA technology was not as mature as PEI technology. Currently, advanced RFA techniques are utilized with multiple or perfusion electrodes. In addition, centripetal ablation using no-touch RFA has been performed at many institutions. Given that local tumor control for HCCs < 2 cm is excellent with RFA, treatment outcomes between RFA and PEI may not be similar if an RCT is performed. This assumption is supported by PEI being largely replaced by RFA, even in HCCs < 2 cm.

The diffusion of injected ethanol may be blocked by the fibrous septum or tumor capsule. Consequently, obtaining a sufficient ablative margin using PEI is challenging and decreases its therapeutic effect. Conversely, the size of the ablation zone is more predictable with RFA than PEI. Therefore, a sufficient ablative margin can easily be obtained using RFA.

MWA has advantages over RFA because effective ablation can be expected, even for tissues with low electrical conductivity, and higher and faster heating over 100°C is possible. Therefore, theoretically, MWA is less affected by the heat-sink effect caused by blood vessels near the tumor, and the ablation zone is larger. Therefore, MWA is frequently used for HCCs ≥ 2 cm. However, no significant differences were observed in treatment outcomes, including overall survival, disease-free survival, and complication rates, between MWA and RFA for HCCs < 3 cm [28]. Despite the better physical properties of MWA, its therapeutic efficacy seems similar to that of RFA for HCCs < 3 cm. Meanwhile, as no-touch RFA provides excellent local tumor control, a comparative study between no-touch RFA and MWA is warranted for HCCs > 2 cm.

Cryoablation has several advantages over thermal ablation. An ice ball created by cryoablation shows a clear margin under various guidance modalities: US, non-enhanced CT, or MRI. Therefore, monitoring of the ablation zone during the procedure is relatively easy. Moreover, cryoablation causes less procedure-related pain than does thermal ablation. Cryoablation is advantageous because it results in a lower complication rate than does RFA when treating HCCs near the bile duct or intrahepatic vessels [29, 30].

However, the size of the ablation zone with a single cryoprobe is relatively small and usually requires multiple cryoprobes. The procedure time is longer with cryoablation than with other thermal ablation therapies. In patients with one or two HCCs ≤ 4 cm, a multicenter RCT showed no significant difference in the 1-, 3-, and 5-year overall survival, disease-free survival, and major complication rates between RFA and cryoablation [31]. Cryoablation is expected to be comparable with RFA in terms of survival, recurrence, and complication rates.