Locoregional therapies for hepatocellular carcinoma (HCC) have added flexibility in the patient care by accommodating various clinical issues that limit indication for surgical therapies and/or to enhance therapeutic benefit of other modalities. Percutaneous ablation such as radiofrequency and microwave ablation can achieve good local tumor control less invasively compared to surgical resection and therefore is applicable to inoperable cases due to impaired liver function and other reasons. Supporting techniques such as artificial fluid infusion can mitigate difficulty in ablating tumors close to hepatic hilum/dome and neighboring organs such as the intestine. New ablation modalities such as cryoablation have been developed as alternative options. New radiotherapeutic techniques such as stereotactic ablative radiotherapy and charged particle therapy have been utilized as additional options of locoregional treatment. Radiotherapies can expand treatment indication for locally advanced tumors with portal venous tumor thrombus and/or large size, which cannot be treated with surgical or percutaneous therapies. Immunomodulatory effects of locoregional therapies have rationalized clinical testing of combination with immuno-oncology agents such as immune checkpoint inhibitors to further enhance their antitumor effect. Locoregional therapies will remain the major components of HCC treatment algorithms that assist precision care of the patients optimized for each specific clinical scenario and geographic diversity in patient demographics with the recent technological development, identification of prognosis factors, and characterization of adverse effects.

Introduction

Hepatocellular carcinoma (HCC) generally arises from chronically diseased liver with impaired function, which often limits application of surgical therapies (see Chap. 8). In addition, even if regular HCC screening program is widely adopted as in Japan, only one-third of HCC patients are diagnosed at early stage and eligible for surgical resection. Thus, locoregional therapies have been developed to expand treatment options for locally limited but more advanced HCC tumors outside indication of surgical therapies and to improve outcome of surgical therapies. In this chapter, we overview the two major locoregional treatment approaches, percutaneous ablation and radiotherapy, with special focus on recent technical development to improve precision of the treatment and maximize therapeutic benefit (see Chap. 9 for interventional radiologic therapies).

Percutaneous Ablation

Percutaneous ablation is a method to destroy targeted tumor by chemical reaction, heat, freezing, or electric pulse using needle-like devices. Percutaneous ethanol injection is the first ablative method applied for HCC by Japanese hepatologists in the early 1980s. Since then, together with its successor techniques, percutaneous ablation has been widely used as a modality to achieve high local tumor control and incorporated in HCC treatment algorithms globally [1–3].

Ablative Methods

Radiofrequency Ablation

Radiofrequency ablation (RFA) is a thermal ablation method, using heat produced by electric current. RFA utilizes alternating current of 450 kHz, which is transmitted from the inserted electrode tip through patients’ body to the grounding pad pasted on the back or the thigh and induces heat coagulation of targeted tumor [8, 9]. RFA was introduced as a treatment modality for HCC, following ethanol injection and the first-generation microwave ablation. RFA overcome the limitation of ethanol injection, which is effective only for small tumors (e.g., <2 cm in diameter) with capsule and without intra-tumoral septa, by producing larger ablation zone independent of capsule and septa [10]. Multiple studies have demonstrated superior local tumor control and posttreatment survival for RFA compared to ethanol injection [11, 12]. RFA is currently the most widely used percutaneous ablation method.

There are two types of RFA electrode, single-needle and expandable electrodes (Fig. 10.1) [13]. An internal cooling system is equipped inside the single-needle electrode to prevent reducing ablation zone due to burnt tissue sticking on the surface of the needle. The expandable electrode equips four to nine small electrodes in the inner sheath that can be expanded near the target tumor to produce a wide ablation zone. The advantage of the expandable electrode over single-needle electrode is secured ablation zone inside the expanded small electrodes, which can reach 5 cm in diameter. Disadvantage of the expandable electrode is potential injury of the vasculature by the tip of small electrodes, which could also cause draining of electric power through the punctured vessels and incomplete ablation. In addition, its thicker outer sheath (15 gauge [G]) compared to the single-needle electrode (17 G) is another limitation that may increase the risk of bleeding and tumor cell seeding. To date, the second-generation microwave ablation can produce similar or even larger ablation zone to the expandable electrode, and as a consequence, the expandable electrode has been less frequently used. The multielectrode system is a variation of the single-needle electrode, where up to three single-needle electrodes are inserted in parallel to achieve larger ablation zone or to avoid direct puncture of targeted lesion [14]. Either of monopolar or bipolar electrodes are used in the system, and the latter is free from using grounding pads and associated complications [15].

Fig. 10.1

Various devices for radiofrequency ablation. (a) Single electrode with internal cooling. (b) Adjustable electrode with variable ablative zone with one electrode. (c) Multiple monopolar electrodes with switch controller to enable larger ablative zone. (more...)

Microwave Ablation

Microwave ablation (MWA) has been developed since the early 1990s [16]. An electrode connected to a microwave generator is inserted through a 14 G guide needle under ultrasonographic guidance. Microwaves of 2450 MHz are emitted from the tip of the electrode that can create an up to 1.5-cm-width ablation zone (Fig. 10.2). The first-generation microwave had a clear advantage over ethanol injection with the secured ablation zone, not affected by intra-tumoral septa that blocks ethanol penetration. On the other hand, the thick needle is a disadvantage that increases the risk of complications such as intraperitoneal hemorrhage and neoplastic seeding. The first-generation MWA was soon taken over by the single-needle RFA, which can achieve similar ablation zone with thinner needle (17 G) in the 2000s [17]. Recently developed second-generation MWA yields larger ablation zone than the single-needle RFA in a shorter ablation time. In addition, compared to RFA, MWA is less affected by “heat-sink effect,” which restricts ablation zone due to blood flow adjacent to the electrode, because microwave can propagate over surrounding vessels within the active zone [18]. These advantages of the second-generation MWA have helped revive it as a viable option of locoregional HCC treatment. Recent reports suggest that the second-generation MWA is superior to single-needle RFA in terms of local tumor control [19, 20].

Fig. 10.2

Various ablation technologies. (a) Microwave ablation. Microwaves of 2450 MHz are emitted from the tip of the electrode, which directly heat water in the surrounding tissue. Microwaves can propagate over surrounding vessels in the active zone. Passive (more...)

Ethanol Injection

Percutaneous ethanol injection is the precursor of all percutaneous ablation techniques, which was first described in 1983 [21]. In the original procedure, a 22 G hollow needle with stylet is inserted into the tumor under sonographic guidance, and then 2–8 mL of absolute ethanol is injected through the needle and infiltrates into the tumor via sinusoid-like structure and causes coagulation necrosis [4]. Ethanol injection is no longer performed at tertiary centers, where a high volume of HCC patients are treated. However, ethanol injection is an inexpensive procedure using readily available materials and with proven antitumor effect for small HCC tumors. Therefore, it still has a role in daily clinical practice when RFA and MWA are not accessible [22].

Cryoablation

In contrast to the heat or chemical ablation techniques, cryoablation uses low temperatures (< −20 °C) to induce tissue necrosis [23]. Tissue freezing is induced by Joule-Thomson effect via a probe using argon or helium gas. An ice ball around the probe is indicative of irreversible cellular damage with intracellular ice crystals. Small vascular vessels are frozen and occluded, whereas large vessels are maintained. The first-generation cryoablation required a thick (2.2 mm, approximately 11 G) probe and often caused bleeding complications and cryoshock, systemic inflammatory syndrome with multi-organ failure following large tissue freezing [24]. Recent technical development such as the thinner (17 G) probe and multi-probe system may advance cryoablation as an alternative strategy to RFA [25, 26].

Irreversible Electroporation

Irreversible electroporation (IRE) is a nonthermal ablation, using very high-intensity electric pulse between two electrodes that causes irreversible pore formation in cell membrane lipid bilayer and results in cell death [27]. Unlike other ablative methods, the connective tissue, basal membranes, and lumens of the vasculature are relatively preserved in IRE [28]. This feature will mitigate technical barrier to ablate tumor adjacent to bile ducts and hepatic hilum with RFA and MWA. On the other hand, general anesthesia is required with a muscular blockade to prevent muscle spasm. Cardiac arrhythmia and use of pacemakers are contraindications.

Techniques for Precision Percutaneous Ablation

The major limitations of percutaneous ablation include restricted applicability to difficult-to-access regions, such as hepatic hilum and dome, and visibility of target tumor under ultrasound to guide needle/probe insertion. Several techniques have been developed to address the challenges, most of which can be readily applicable in daily clinical care of the patients.

Artificial Pleural Effusion

Ultrasonographic visualization of HCC tumor located in hepatic dome right beneath the diaphragm is often challenging. Some tumors can be visualized by adjusting patient posture (e.g., head-up or sitting position) or tilting the operation table. Laparoscopic or CT-guided techniques can be employed, although these approaches are highly resource-intensive. Artificial pleural effusion is a simple alternative method to address the issue, which can be conveniently and inexpensively utilized in daily clinical practice. Five percent glucose solution, which is spontaneously absorbed, is infused into the pleural cavity via a 14 G and metallic needle with a stylet to create an acoustic window (Fig. 10.3) [29]. This procedure can be safely performed with low risk of respiratory insufficiency [30]. Artificial pleural effusion is contraindicated in patients who had left pneumonectomy and may not improve tumor visualization when pleural adhesion is present.

Fig. 10.3

Artificial pleural effusion technique. A 500 mL of 5% glucose solution is infused into the pleural cavity to achieve clear visualization of the tumor located beneath the diaphragm

Artificial Ascites

Artificial ascites is a similar fluid infusion-based method, injecting the fluid into the peritoneal cavity, to mainly improve therapeutic access to index tumor adjacent to other organs, especially the intestine, to avoid perforation (Figs. 10.4, and 10.5). Artificial ascites can also be used to improve visualization of tumors in the hepatic dome like artificial pleural effusion, although larger amount of fluid needs to be infused [31, 32]. Artificial ascites may not decrease the risk of intestinal perforation or penetration in a case there is adhesion between the liver and surrounding intestine.

Fig. 10.4

Artificial ascites technique. A 5% glucose solution is infused to create a space between the liver and adjacent organs to enable safe ablation

Fig. 10.5

Representative case with recurrent HCC treated with artificial ascites. (a) Enhanced CT before ablation. A small nodule in segment 6 adjacent to the gallbladder and the ascending colon (allow head). (b) An ultrasonographic image during ablation. An electrode (more...)

Contrast Ultrasonography

Besides tumor location, various factors such as coarse liver parenchyma, small tumor size, and scar created by previous treatment impede clear visualization of target tumor. Contrast agents for ultrasonography have been developed to obtain vascular images on B-mode or Doppler ultrasonography. Levovist, the first-generation contrast agent that contains a suspension of galactose microparticles, has improved differential diagnosis of liver tumors. However, Levovist is not suitable for percutaneous ablation because of short-lasting enhancement. Sonazoid, a second-generation sonographic contrast agent, contains a lipid-stabilized suspension of perfluorobutane gas microbubbles and yields long-lasting enhancement. In addition, the perfluorobutane microbubbles are taken up by Kupffer cells and enable parenchymal enhancement approximately 15 min after the injection (Kupffer phase), in which malignant liver tumors are visualized as defect in enhanced non-cancerous liver parenchyma (Fig. 10.6). The Sonazoid Kupffer phase image can be conveniently used to assist percutaneous ablation procedure since the phase lasts more than 30 min and is easily reproduced by another injection of the agent [33, 34].

Fig. 10.6

(a, b) A case with HCC treated with radiofrequency ablation using fusion imaging and contrast ultrasonography. (c) A fusion imaging before contrast ultrasonography. The left panel shows a virtual image of the tumor constructed from previously taken in (more...)

Fusion Imaging

Fusion imaging is a real-time construction of virtual sonographic image on the monitor of ultrasonographic equipment using CT or MRI images obtained in advance (Figs. 10.6 and 10.7) [35]. The system consists of an ultrasonographic apparatus, a magnetic field generator, and a magnetic sensor attached to the ultrasound probe. First, the digital data of CT or MRI images are uploaded to the ultrasonographic apparatus. After registration of specific points on the real ultrasonographic image to the virtual image, real-time virtual image synchronized with the movement of the ultrasound probe can be obtained. Fusion imaging significantly decreases the risk of mistargeting and sometimes enable accurate ablation of invisible tumor nodules on ultrasonography. The system can be combined with contrast ultrasonography, which enables more accurate and safe ablation in difficult-to-treat cases [36].

Fig. 10.7

Representative case treated with radiofrequency ablation using the fusion imaging and artificial pleural effusion. (a) A small HCC nodule was detected in segment 2 under the right hepatic dome. (b) The left panel shows a virtual image reconstructed based (more...)

Combination with Other Treatment Modalities

Combination with Transarterial Embolization

The ablation zone by RFA or MWA can be expanded by occluding blood flow by a balloon catheter or transarterial embolization to reduce the surrounding blood flow and the heat-sink effect [45]. There are several studies, including randomized controlled trials, that compared survival of patients with medium to large HCC treated by RFA with or without transarterial chemoembolization (TACE) [46, 47]. Although the results are somewhat inconsistent, single-electrode RFA with TACE for HCC lager than 3 cm in diameter suggestively lowers local progression rate (Fig. 10.8).

Fig. 10.8

A case with 5 cm HCC treated with TACE + RFA. (a) An arterial phase of dynamic CT shows hypervascular tumor in segment 7. (b) The tumor was treated with TACE + RFA. A dense lipiodol deposit was surrounded by un-enhanced area indicating ablative margin (more...)

Combination with Immunotherapy

Immunomodulatory effect of percutaneous ablation, either with the use of extreme heat or cold, has been investigated for decades in multiple cancer types. One of the earlier observations is spontaneous regression of untreated tumor accompanied with ablation of other tumors [48, 49]. In thermal ablation by RFA and MWA, the electrode directly heats the tissue with emitted energy in the central zone. Outside the central zone, there is transitional zone heated to 41–50 °C by thermal conduction from the central zone [50]. Inflammatory cells, including neutrophils, macrophages, dendritic cells, natural killer cells, B cells, and T cells, were found to infiltrate in the transitional zone, some of which may elicit tumor-specific immune response [51, 52]. These immune cells were also observed in distant unablated tumors and peripheral blood, suggesting a systemic immune response induced by thermal ablation. Similar immune activation was observed in the presence of necrosis and apoptosis induced by cryoablation [53]. More prominent release of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6 was observed in cryoablation compared to heat ablation, although this may be related to cryoshock, the critical complication unique to cryoablation. Antigen accumulation in dendritic cells was also greater in cryoablation compared to RFA [54].

Although such immune reaction induced by percutaneous ablation is often observed, its clinically recognizable antitumor effect is rarely seen in daily clinical practice. This may indicate that the infiltrating immune cells need additional step(s) to be activated to elicit cancer cell killing. Recently developed immunotherapy agents, especially immune checkpoint inhibitors, may serve as drivers that activate such antitumor immununity [55]. In a pilot study combining RFA or cryoablation with tremelimumab, a monoclonal antibody to cytotoxic T-lymphocyte-associated protein 4 (CTLA4), an increase of intra-tumor CD8+ T cells was observed after 6 weeks of treatment in patients who showed response [56]. A phase III randomized controlled trial is ongoing to test nivolumab, monoclonal antibody to programmed cell death 1 (PD-1), as adjuvant therapy in patients who are at high risk of recurrence after curative HCC resection or ablation (NCT03383458).

Complications

Complications of percutaneous ablation have been well described in RFA, MWA, and ethanol injection [57]. Low-grade pain and transient fever and increased liver enzymes are commonly observed minor side effects. This section summarizes major (incidences that need specific therapy and potentially result in permanent disability or death) or minor (incidences that need no or minimal therapy including overnight admission for observation only) complications according to the grade of complications defined by the Society of Interventional Radiology [58].

Bleeding

Bleeding is a common complication across percutaneous ablation techniques that use needle-type devices especially because HCC patients often have coagulopathy due to underlying cirrhosis (Fig. 10.9). Bleeding complications are categorized as hemoperitoneum, hemothorax, and hemobilia [59]. Hemoperitoneum or intrahepatic hemorrhage is a consequence of intrahepatic vascular injury by needle devices. The risk factors of hemoperitoneum include long needle tract to the index tumor and low platelet counts [59]. The risk likely increases according to the needle thickness and number of needle insertion sessions to achieve destruction of target tumor. Bleeding is more frequent in cryoablation than RFA and MWA that have hemostatic effect per se. In fact, RFA and MWA can be used to stop bleeding by coagulating the bleeding point. Recently developed length-adjustable electrode enables the use of RFA for this purpose, with 1 cm electrode exposure.

Fig. 10.9

Bleeding complications of percutaneous ablation. (a) Hemoperitoneum is intraperitoneal bleeding from intrahepatic vasculature. (b) Hemothorax is bleeding to the pleural cavity from intercostal arteries. Hemothorax is always complicated with pleural effusion (more...)

Hemothorax is a rarer complication than hemoperitoneum and is caused by injury of intercostal arteries. However, once hemothorax occurs, the morality rate is higher than hemoperitoneum because spontaneous hemostasis less likely happens in arterial bleeding. Furthermore, bleeding to the pleural cavity causes reactive pleural effusion and sometimes systematic inflammatory response, which could lead to respiratory failure. Involvement of interventional radiologist is needed to control hemothrax. When the intervention is ineffective, surgical procedures should be considered.

Hemobilia is a bleeding caused by injuring intrahepatic portal vein or artery and bile duct simultaneously with the needle devices. Unlike other two bleeding complications, hemobilia is rarely accompanied with hypovolemic shock. On the other hand, hemobilia is often first recognized as obstructive jaundice. Hemobilia can be identified by hemobilia sign, a clot formation in the gallbladder [60]. Hemobilia is generally self-limiting, and endoscopic intervention should be withheld unless patients are complicated with infection, since the intervention sometimes promotes rebleeding and infection [61].

Infection

Major infectious complications include liver abscess and cholangitis. Liver abscess is likely related to trans-biliary bacterial translocation. Previous history of biliary intervention that causes enterobiliary reflux is a strong risk factor for developing liver abscess after percutaneous ablation. Specifically, a history of enterobiliary anastomosis is a contraindication for RFA and MWA given the extremely high risk (>50%) of abscess after these procedures [62]. Cholangitis is rarer complication compared to abscess [57]. However, the incidence of cholangitis may be underestimated because the diagnosis of cholangitis is often indeterminate unless accompanied with hemobilia and obstructive jaundice.

Biliary Injury

Intrahepatic biliary injury often emerges as intrahepatic bile duct dilatation more frequently after RFA or MWA than cryoablation. Heat produced by the thermal procedures can injure the intrahepatic bile duct, where blood flow-related local cooling effect is not expected. Peripheral biliary injury is usually asymptomatic with elevated alkaline phosphatase and gamma-glutamyl transferase levels in the blood. However, injury of major intrahepatic bile duct can cause segmental atrophy of the liver parenchyma, which may lead to long-term deterioration of liver function [63]. IRE is expected to preserve biliary structure and therefore can be an alternative to RFA and MWA when the index tumor is located close to hepatic hilum [28].

Neoplastic Seeding

Neoplastic seeding is another well-documented complication in percutaneous ablation of HCC (Fig. 10.10). Intrahepatic neoplastic seeding can be surgically resected or re-ablated, but it is difficult to treat intraperitoneal dissemination of cancer cells, which could significantly deteriorate patient prognosis. The risk factors of neoplastic seeding include tumor located on the surface of the liver, poorly differentiated histology, and multiple treatment sessions [64, 65]. Preceding tumor biopsy can also cause neoplastic seeding [66]. In order to avoid direct puncture of the target tumor and consequential neoplastic seeding, “no-touch” ablation using multiple electrodes inserted around the index tumor has been developed [14].

Fig. 10.10

Neoplastic seeding. (a) Hypervascular HCC tumor in segment 4. (b) The tumor was completely ablated by RFA. (c) Intraperitoneal tumor seeding (arrow) along the needle tract was detected 1.5 years later

Radiotherapy

The emergence of CT-based 3D conformal radiotherapy in the 1980s enabled more precise tumor targeting with reduced radiation-induced liver injury compared to whole-liver irradiation and opened the path toward further development of radiotherapy in HCC [67]. Newly established techniques, including intensity-modulated radiotherapy (IMRT), stereotactic ablative radiotherapy (SABR) also known as stereotactic body radiation therapy (SBRT), and charged particle therapy such as proton beam therapy and carbon ion radiotherapy, have been utilized to achieve either local tumor control or enhanced efficacy of other treatment modalities.

There is certain diversity in their indication and application (e.g., does, schedule) across geographic regions, representing a range of dominant disease stages and infrastructure for radiotherapy, and high-level clinical evidence such as randomized controlled trial (RCT) is relatively limited.

Major Radiotherapeutic Approaches

Because of relative scarcity of high-level clinical evidence as well as geographic diversity in tumor characteristics and access to the technologies and facilities, there is no globally accepted indication and treatment protocols, but in general, SABR and proton beam therapy are more widely used compared to other new modalities to achieve local tumor control or to enhance efficacy of other treatment modalities such as transarterial chemoembolization, whereas 3D conformal radiotherapy is utilized when such new techniques are not available.

Stereotactic Ablative Radiotherapy (SABR)

Recent technological development has enabled development of SABR, which delivers highly conformal radiation dose within tumor, while sparing large portions of the liver from radiation-induced liver disease (RILD), and is typically indicated for treatment of inoperable tumors [68]. Although evidence supporting its survival benefit is still limited, local tumor control rates that are comparable to resection and RFA and exceeding transarterial chemoembolization have been reported (Table 10.1). SABR can be applied to treat tumors in technically less accessible and/or challenging regions such as hepatic hilum and dome. Tumors close to or invading into the vasculature can also be treated without being affected by blood flow. SABR has been applied to diverse and somewhat biased tumor stages across geographic regions, and therefore there is no commonly used protocol. For example, small HCC tumors in livers with preserved function tend to be treated with higher radiation dose in Japan, whereas more advanced tumors in functionally impaired livers are more likely treated with lower dose in Western countries and China. Predictive score or biomarker of response to SABR will enable more personalized application. Combination with medical therapies, especially immune checkpoint inhibitors, has also been explored [69].

Table 10.1

Stereotactic ablative radiotherapy

Charged Particle Therapy

Charged particle therapy such as proton beam therapy and carbon ion therapy is characterized by its higher radiation dose concentration in tumor compared to X-ray and a high local tumor control rate comparable to SABR (Table 10.2) [70]. Application to various forms of advanced tumor such as portal venous tumor thrombus (PVTT) and large tumors (>10 cm in diameter) has been reported [71–73]. Concern about adverse event is noted when targeted lesions are located close to hepatic hilum and gastrointestinal tract, although relatively rarely observed [74–80]. Indocyanine green retention test (ICG-r15) was reported to predict posttreatment prognosis in Child-Pugh class A patients [81].

Table 10.2

Charged particle radiotherapy

3D Conformal Radiotherapy

Compared to the new modalities such as SABR and charged particle therapy, it is less likely to achieve comparable irradiation dose and local tumor control with 3D conformal radiotherapy. However, given the limited availability of the new techniques, 3D conformal radiotherapy still has roles as palliative and/or supplementary therapy in daily clinical practice. Multiple prospective and retrospective studies have reported survival benefit of combining 3D conformal radiotherapy to TACE, although such clinical trials were mostly conducted in China [82, 83]. In combination with surgical resection, survival benefit was observed in patients with small (<5 cm in diameter) tumors [84]. Combination with RFA, PEI, or high-intensity focused ultrasound (HIFU) did not yield survival benefit. In patients with unresectable HCC with PVTT, TACE combined with radiotherapy yielded better survival compared to sorafenib after propensity score matching [85, 86].

Conclusions

Locoregional therapies have significantly expanded available options in the HCC treatment algorithms by providing good local tumor control with less invasive procedures compared to surgical therapies. Recent advancements in technologies and supporting techniques have contributed to substantial expansion of our capability to treat HCC at various stages. With the better characterization of the new modalities and identification of prognostic factors for each specific clinical scenario, it is expected that personalized application of the methods is facilitated to maximize prognosis of HCC patients.

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