Radiofrequency ablation for hepatocellular carcinoma

Abstract

Introduction

Radiofrequency ablation (RFA) has been applied to clinical practice since the early 1990s and rapidly disseminated to become the first-choice locoregional treatment. Less than a decade after its introduction, RFA was resulting in a higher rate of complete necrosis and required fewer treatment sessions than percutaneous ethanol injection (PEI) in small (≤3 cm) hepatocellular carcinoma (HCC) lesions.1 However, at about the same time, the diminishing effectiveness of RFA in achieving tumor necrosis with increasing tumor size was apparent.2 In addition to tumor size, blood flow and tumor location affect the antitumor effect.3,4

Attempts have been made to overcome these limitations and increase the antitumor effect.5–13 Furthermore, some measures have been developed to avoid RFA-related complications, resulting in marked improvement in the safety of liver RFA.14,15 These efforts have lead to improved therapeutic outcomes, and 10-year survival rates have been reported recently.16,17

The current status of liver RFA is reviewed in this manuscript.

Indication for liver RFA

The need for liver RFA is generally determined by taking into account patients’ performance status, liver function, and tumor background. Based on the Barcelona Clinic Liver Cancer staging system, RFA is applied for the treatment of patients having very early (Stage 0) and early stage (Stage A) HCC. Patients with performance status of 0, Child-Pugh class A or B liver profile, and three or fewer HCC nodules ≤3 cm are indicated for RFA.18 However, these indication criteria also point out the limitation of RFA. Small ablation zone size obtained in a single treatment session limits the indication of RFA. RFA is applied in <30–40% of HCC patients in Europe and the USA, and 30.6% in Japan.18,19 According to the report from the Liver Cancer Study Group of Japan, HCCs were found at a maximum size of ≤3 cm and 3.1–5 cm in 57.5% and 21.5% of HCC patients, respectively.19 If the indication for RFA is expanded to include a maximum size up to 5 cm, more HCC patients can benefit from RFA.

Exclusion criteria were determined by taking into account complications. Hemorrhage is one of the most frequent severe complications. Patients with abnormal coagulability, even after its correction, are usually excluded. In general, platelet counts <40–50 × 10⁹/L and/or international normalized ratio exceeding 1.5 are benchmarks of abnormal coagulability.

When the targeting tumor is adjacent to the critical organs, such as the gastrointestinal (GI) tract, the risk of collateral damage is high. The risk of liver abscess also becomes higher when there is a past history of biliary surgery.20

Local therapeutic effect

Local tumor control is important in HCC patients because it is significantly linked with survival.21 Local tumor progression is usually evaluated by contrast-enhanced computed tomography or magnetic resonance imaging. Livraghi et al evaluated the initial therapeutic effect of RFA on HCC based on tumor size by evaluating the disappearance of tumor enhancement following RFA.1,2 The anticancer effect was stronger as the tumor size became smaller. Tumor enhancement completely disappeared in 90% of small HCCs (≤3 cm), 60% of medium-sized HCCs (3.1–5 cm), and 24% of large HCCs (>5 cm; Table 1).1,2 The local tumor progression rate has been reported to be 2.4–19.5% at 3 years when the maximum tumor size is ≤ 3 cm (Table 1).6,17,22,23 Infiltrating tumor morphology, previous treatment history, subphrenic tumor location, vicinity to the vessels, and ablative margin may significantly worsen local tumor progression.6,22–25

Some of these limitations can be overcome. When the tumor is in the liver dome, it is sometimes difficult to depict the whole tumor by ultrasonography, and almost half of the subphrenic tumors recur at 3 years after RFA.26 The usefulness of artificial pleural effusion, artificial ascites, and real-time virtual sonography has been reported to depict tumors that are invisible by conventional ultrasonography.27–29 By contrast, there is no blind spot when using computed tomography as an image guide; in particular, iodized-oil accumulates in the tumor after chemoembolization (Fig. 1).30 The local tumor progression rate is as low as 3% at 5 years after the combination therapy of RFA and chemoembolization.30

The ablative zone is limited by blood flow (heat-sink effect), causing a small ablative margin.3–9,31 An ablative margin of at least 5 mm is required to avoid local tumor progression, because microsatellite lesions are frequently present surrounding the HCC nodule.25 Sasaki et al measured the distance of microsatellites from the main HCC nodule in resected specimens.32 Most of the microsatellite lesions were present within 5 mm of the main tumor when the tumor size was ≤25 mm.32 The overall survival rate of patients with a microsatellite distance exceeding 5 mm was lower than that of patients with a microsatellite distance < 5 mm.32

Overlapping insertions of RF electrodes sometimes fail to produce large ablation zones relative to the number of ablations.25,33 A decrease in blood flow in the liver causes expansion of the ablative zone size.5,31,34 Balloon occlusion of the hepatic artery, chemoembolization of the hepatic artery, portal venous embolization, and hepatic venous balloon occlusion have been combined with RFA in an attempt to expand the ablative zone size.5–9 RFA following chemoembolization is the most popular combination therapy among these options (Fig. 1).

Takaki et al performed RFA following chemoembolization and reported a 5-year local tumor progression rate of 8% in patients with small (≤3 cm) HCCs, 25% in those with HCCs measuring 3.1–5 cm, and 32% in those with HCCs measuring 5.1–10 cm maximum diameter.6,8 Morimoto et al compared the local tumor progression in HCC lesions measuring 3.1–5 cm between RFA alone and combination of RFA and chemoembolization.35 The 3-year local tumor progression rate was significantly lower in combination therapy than RFA alone (6% vs. 39%, P = 0.012).

Recently, microwave ablation has emerged as a valuable alternative to RFA in the treatment of hepatic malignancies.36 Microwave ablation is a promising heat-based thermal ablation modality that has particular applicability in treating hepatic malignancies; the ability to generate very high temperatures in a very short time can potentially improve treatment efficiency and larger ablation zones with less heat-sink effect.36 Comparison of local tumor progression between RFA and microwave ablation is required.

Survival after RFA

Superiority of RFA to PEI in prolonging patient survival has been shown in a randomized controlled trial.37 The 3-year survival rates were 48–67% following PEI and 63–81% following RFA. Chen et al performed a randomized control trial between RFA and hepatectomy in patients who had HCC ≤5 cm, and found the same overall and recurrence-free survival between the two patient groups.38

Combination therapy of RFA and chemoembolization also provides HCC patients the same survival as surgical intervention does. Yamakado et al retrospectively compared overall and recurrence-free survivals between this combination therapy and hepatectomy in Child-Pugh grade-A patients who had HCC lesions within the Milan criteria.7 There were no significant differences found in the 5-year overall survival rate (75% vs. 81%) or recurrence-free survival rate (27% vs. 26%). Combination therapy of RFA and chemoembolization is useful in treating HCC nodules larger than 5 cm. Takaki et al performed combination therapy in 20 patients who had three or fewer HCC nodules with a maximum diameter of 5.1–10 cm and reported a 5-year survival rate of 41%, which was almost equal to that following hepatectomy (Table 1).8 The 5-year survival rates following hepatectomy was reported as 43.8% in patients who had HCC nodules with maximum diameter 5.1–10 cm.39

Recently, survival rates up to 10 years have started to be reported.16,17 Shiina et al treated 1170 patients by RFA and reported 5-and 10-year survival rate of 60.2% and 27.3%, respectively (Table 1).16 They combined chemoembolization in patients with four or more tumors or those with even one tumor larger than 3 cm. Age, hepatitis C, Child–Pugh grade, tumor diameter, tumor number, des-γ-carboxy-prothrombin, and lectin-reactive α-fetoprotein level ere significant prognostic factors. Fujimori et al performed combination therapy of RFA and chemoembolization in 277 naïve HCC patients, and reported a 5- and 10-year survival rate of 56.3% and 23.5%, respectively (Table 1).17 Those results were almost comparable to those following hepatectomy.

Complications

Livraghi et al reported complications in 2,320 patients with 3,554 liver tumors.40 The mortality rate was 0.3%. The causes of death were bowel perforation, peritonitis, tumor rupture, and liver failure due to biliary stricture. The major complication rate was 2.2%. The most frequent major complications were hemorrhage and tumor seeding, with an incidence of 0.5% each, followed by liver abscess (0.3%), bowel perforation (0.2%), hemothorax (0.1%), and liver failure (0.1%). An increased number of RF sessions were related to a higher rate of major complications (P < 0.01), whereas the number of complications was not significantly different when tumor size or electrode type were compared. Minor complications that did not require treatment developed in <5% of patients. Takaki et al41 evaluated complications following 1500 treatment sessions of combination of RFA and chemoembolization, and reported the same mortality (0.1%) and major complication (2.8%) rates as those reported by Livrghi et al.40 The content of complications were also same between the two studies. From these studies, hemorrhage and bowel perforation are most frequent severe complications.

To prevent hemorrhagic complications, patients with abnormal coagulability should be excluded as mentioned in the indication section. Combined use of chemoembolization is useful in avoiding hemorrhagic complications.41

The liver is sometimes adjacent to the stomach, ascending colon, and duodenum. When the liver tumor is close to the GI tract, the GI tract should be moved away from the tumor to avoid collateral damage from RFA. Based on empirical observations, most tumors can be moved away from the GI tract by changing the patient’s body position, injecting saline solution into the peritoneal cavity, or aspirating intrabowel air and fluid. If the liver neoplasms could not be moved away from the GI tract by the above measures, the placement of a balloon between the tumor and the GI tract appears to be a practical, safe, and effective technique for separating the tumor from the adjacent bowel.14 Recently, the usefulness of hyaluronic acid gel injection between the tumor and the GI tract in separating the bowel from the tumor has been reported (Fig. 2).15

Conclusions

Development of both technique and technology of RFA has expanded the indication of RFA and improved local control of HCC. Development of techniques and accumulation of knowledge to prevent complications have established the safety of hepatic RFA. The good local tumor control and safety provide a longer survival to patients with HCCs.

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