Asian Conference on Tumor Ablation Guidelines for Hepatocellular Carcinoma

Primary liver cancer is the third leading cause of cancer-related death worldwide and one of the few cancers still increasing in mortality rate because of growing incidence and poor prognosis. A total of 865,269 were diagnosed worldwide in 2022 with a mortality of 757,948 [1]. The most common type of primary liver cancer is hepatocellular carcinoma (HCC). Currently, around 75% of deaths from HCC are found in the Asia-Pacific region [2, 3].

Only 20% of HCC patients are candidates for surgical resection [4]. Furthermore, recurrence is frequent even after apparently curative resection [5]. Liver transplantation, which is the best therapeutic option in some patients as it can be a treatment for both HCC and cirrhosis, plays a limited role due to organ donor shortage. Thus, various nonsurgical therapies have been developed [6, 7].

Among nonsurgical therapies, image-guided percutaneous ablation is considered the best for treating early-stage HCC. The proportion of early stage cancer among all HCC patients has been increasing because of surveillance on high-risk patients for developing HCC. Ablation includes ethanol injection [8‒10], microwave ablation (MWA) [11], radiofrequency ablation (RFA) [12, 13], etc. It can be potentially curative, is minimally invasive, and is easily repeatable in cases of recurrence. As ablation becomes more widely used and various procedures are performed, standardization has been sought for optimal patient care. Additionally, skills and knowledge in ablation are different from country to country and from institution to institution.

The Guideline Committee of Asian Conference on Tumor Ablation (ACTA) has developed these guidelines (hereinafter referred to as the Guidelines) comprising 47 recommendations, with the aim of ensuring the appropriate clinical introduction of image-guided tumor ablation for HCC (Table 1). To achieve optimal outcomes in ablation, it is essential to acquire expertise in the following: indications, pre-ablative diagnosis and planning, techniques, peri-ablative management, evaluation of therapeutic effectiveness, complications, post-ablative follow-up, prevention, and treatment of recurrence. The development of these guidelines is crucial as Asia performs the highest number of ablation procedures for HCC and has the largest number of doctors specializing in ablation in the world.

Members of the ACTA Guideline Committee discussed each guideline, which was developed after a comprehensive review of various studies, including randomized controlled trials, meta-analyses, case-control studies, expert opinions, and case series. Each guideline was ultimately established through a consensus agreement, supported by both literature reviews and our collective experiences. The evidence and recommendations in these guidelines have been graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system (Table 2) [14, 15].

When determining the indication for ablation, it is essential to evaluate both effectiveness and safety. In cases where the risks outweigh the benefits – such as when a patient’s general condition is extremely poor – it is recommended to forgo the treatment. Before proceeding, a thorough evaluation of the patient’s general condition and comorbidities is necessary, and informed consent must be obtained.

Generally, ablation has been indicated for cases with three or fewer tumors, each 3 cm or less in diameter [16]. Recent innovations and advanced instruments may allow for a broader application of this technique. However, satisfactory long-term prognosis is required to justify expanding the indication.

Understanding “ablatability” for image-guided tumor ablation is essential, similar to the concept of resectability in surgical resection, even though resectability lacks a standard definition [17‒21]. “Ablatability” should be determined by tumor-related factors, patient-related factors, and resource-related factors as will be discussed later (Table 3).

In many guidelines for HCC, such as AASLD guidelines [18], EASL guidelines [22], and APASL guidelines [23], treatment is determined only by tumor-related factors and liver-related factors, which is the main consideration among patient-related factors. However, ablation is highly operator-dependent. Thus, it is imperative to consider resource-related factors as well. “Ablatability” differs from operator to operator and from institution to institution because of the resource-related aspect.

It should be determined prior to the procedure whether ablation will be performed for curative or for debulking intent. In cases in which ablation is performed with curative intent, all tumors detected by imaging modalities must be eradicated. While ablation is less invasive than surgical resection and can be more easily repeated in cases of recurrence, it is important to avoid local tumor progression as this is associated with poorer outcomes. If there is a possibility of viable residual tissue, ablation should be repeated until entire necrosis is achieved.

Conversely, ablation can also be used for reducing tumor burden to control tumor progression and improve prognosis. In cases treated with debulking intent, the main tumors should be ablated safely and efficiently. For such patients, ablation can be combined with vascular intervention or pharmacological therapies to optimize outcomes.

Tumor-related factors that determine the indications for ablation should include not only tumor size and number but also tumor location and conspicuity. In many treatment algorithms, tumor number and size are the primary factors considered. However, it is indisputable that tumor location and conspicuity also significantly influence the level of technical difficulty associated with ablation.

The indications for ablation could be expanded, under favorable conditions for tumors larger than 3 cm and/or for cases involving more than three tumors in carefully selected cases. Cases of three or fewer tumors, each 3 cm or less in diameter, have been the most widely accepted indication of ablation. However, this 3-3 rule was introduced almost 40 years ago, in the era of ethanol injection. Since then, ablation techniques have evolved from ethanol injection to RFA and MWA. Additionally, various methods have been introduced to assist with ablation, such as artificial pleural effusion, artificial ascites, CEUS, and multimodality fusion imaging [24‒29]. Although the prognosis for HCC patients gradually worsens with increasing tumor size and number, no clear threshold has been identified for the diameter or number of nodules.

In the real world, ablation for tumors larger than 3 cm and/or for more than three nodules is widely performed. In fact, there are guidelines which recommend ablation as the treatment of choice for tumors exceeding 3 cm in size [30, 31].

Conventional Indications. A tumor size of up to 3 cm is a conventional indication for ablation [16, 22, 23, 32]. The criterion of 3 cm or smaller in diameter and three or fewer nodules was proposed for ethanol injection in HCC patients nearly 40 years ago [8, 10]. In ethanol injection, the local tumor progression rate was higher when the tumor diameter exceeded 3 cm [33], primarily because the spread of injected ethanol is significantly influenced by the capsule or septa of the lesion [34]. Its effectiveness remains unreliable even after several sessions of injection [35, 36]. For tumors of 2 cm or less, ablation has achieved comparably good results to surgical resection. According to EASL Clinical Practice Guidelines, RFA may be considered as first-line option [22], while surgery is reserved for patients with nodules unsuitable for RFA or those who fail treatment. For tumors of 2.1–3.0 cm, thermal ablation procedures, such as RFA and MWA, may prove more reliable than ethanol injection.

Expanded Indications. Tumor size of 3.1–5.0 cm is already an expanded indication for ablation [31, 37]. However, overlapping techniques are essential as a single ablation may not adequately cover tumors of this size. Using multiple applicators – by inserting a few applicators to ensure the merging of ablation zones – can cover the entire tumor with a sufficient safety margin. Tumors larger than 5.0 cm represent an exceptional indication [38]. Ablation of such tumors could be a treatment of choice only in high-volume centers with advanced expertise. In such cases, combination therapy with transarterial chemoembolization (TACE) or pharmacotherapy may be considered. The feasibility should be assessed by a multidisciplinary team [39].

A study showed that the prognosis of patients treated with RFA worsened gradually as tumor size increased. No apparent threshold in the diameter, however, was detected [40]. It concluded that ablation can be applied beyond the conventional indications of 3 cm or smaller in diameter.

A tumor number of three or fewer is the conventional indication for ablation [16, 22, 23, 32]. Many patients with four or more tumors likely have micrometastases that are too small to be detected by ultrasound (US), CT, or MRI. Since ablation is a local treatment, it is not effective for micrometastases outside of the ablated area. Consequently, many patients with multiple tumors develop recurrence shortly after ablation. However, ablation of tumors detected by imaging modalities may significantly reduce tumor burden and prolong survival. A study showed that although the prognosis of patients treated with RFA worsened gradually as tumor number increased, no clear threshold was identified [40]. In favorable circumstances, ablation may be considered for select cases of more than three tumors.

A multicenter randomized controlled trial was conducted across 49 Japanese institutions to evaluate the efficacy of surgery versus RFA for small HCC (SURF trial). The results revealed that neither overall survival nor recurrence-free survival differed significantly between surgery and RFA for small HCC (≤3 cm) and three or fewer tumors [41].

In addition to the size and number of tumors, gross pathological type, including nodular, confluent multinodular, and infiltrative types, should also be considered when determining the indications for ablation (Fig. 1) [42]. In cases of confluent multinodular or infiltrative types, other treatment modalities, such as hepatic resection, may be more appropriate if conditions permit. However, if the patient’s liver function and overall condition do not permit surgery, or if the patient declines surgical treatment, ablation can still serve as an alternative option. In such cases, achieving a larger ablative margin is crucial.

Tumor location may be a crucial factor in determining the indication for ablation. Tumor location is closely related to safety and the risk of complications. Tumors located near major vessels or extrahepatic organs are considered risky to ablate because unexpected extension of the ablation zone may injure these structures [43, 44]. Ablation of Glisson’s sheath can lead to hepatic infarction in the perfusion area, while ablation of a hepatic vein may result in hepatic congestion in the drainage area. Intrahepatic bile ducts are more susceptible to thermal injury than vessels, and injury to these ducts may manifest as focal strictures, diffuse dilation of peripheral bile ducts, bilomas, or liver parenchymal atrophy [45]. In terms of adjacent organs, the intestines are more vulnerable to thermal injury compared to the stomach, gallbladder, or other structures, which may result in perforation or penetration. Tumor location also influences whether a safe applicator path exists [44]. Puncture of Glisson’s sheath can lead to hemobilia or aneurysm, while puncture of vital organs may result in complications such as bleeding, pneumothorax, and perforation.

Tumor location significantly influences therapeutic efficacy. Tumors adjacent to large vessels or extrahepatic organs are considered difficult to ablate [43, 44]. Insufficient ablation can result in residual viable tumor tissue, while excessive ablation may damage adjacent structures. The heat sink effect – caused by cooling from blood flow in large vessels – reduces the thermal effect and may lead to incomplete ablation [46]. Additionally, tumors in certain locations may not be detectable by US due to liver atrophy resulting from advanced cirrhosis or deformities caused by previous surgical or nonsurgical treatments. Risks and difficulties associated with tumor location may be mitigated by employing techniques such as artificial pleural effusion [26], artificial ascites [24], and multimodality fusion imaging [25].

Tumor conspicuity may also influence the decision to ablate a tumor, considering both the efficacy and safety of the procedure. Obscure tumors are difficult to puncture and ablate, which can result in ineffective and risky treatment. Various factors can affect tumor conspicuity, including the echogenicity and presence or absence of a tumor capsule, the homogeneity or heterogeneity of the surrounding liver tissue, the depth of the tumor, liver deformities due to advanced cirrhosis or prior surgical and nonsurgical treatments, and the patient’s body shape.

Tumor conspicuity can be enhanced using techniques such as CEUS [27], artificial ascites [24], artificial pleural effusion [26], and others. Even ultrasonographically invisible tumors can be accurately ablated if their location is definitively identified using multimodality fusion imaging [25].

Extrahepatic spread or vascular invasion cases are not traditionally considered indications for ablation [18, 22, 23] as these conditions generally preclude curative treatment. However, ablation might still be considered in select scenarios where it could achieve substantial tumor debulking, which may offer survival benefits [47, 48]. Compared to surgical resection, ablation is significantly less invasive, allowing its use even when curative outcomes are unattainable. Reducing tumor burden in cases of extrahepatic spread or vascular invasion might contribute to better outcomes by mitigating tumor progression and its associated complications. In patients with extrahepatic spread, the majority succumb to uncontrolled liver lesions due to either tumor progression or hepatic decompensation [49]. Therefore, achieving control of intrahepatic lesions is critical. Furthermore, extrahepatic lesions may also be addressed using ablation in select cases [50]. In the context of vascular invasion, studies have reported that ablation, in combination with TACE or systemic therapies, has shown improved outcomes in well-selected patient groups [51]. However, due to the lack of robust evidence, the application of ablation in such cases should be approached with caution and confined to experienced centers as part of a comprehensive multimodal treatment strategy.

Patient-related factors may include not only liver function but also ECOG performance status, the American Society of Anesthesiologists (ASA) Physical Status Classification, and others. These factors impact the safety of ablation. Special attention should be given to patients’ histories of upper abdominal surgeries as adhesions may increase the risk of injury to adjacent organs.

The most widely used method for assessing liver function is the Child-Pugh classification. In general, ablation is indicated for patients classified as Child-Pugh A or B [18, 22, 23]. The survival benefit of ablation may decrease in proportion to the deterioration of liver function, while the risk of procedure-related adverse events (AEs) may increase as liver function declines. In patients classified as Child-Pugh C, there is considerable variability in clinical status, ranging from those who are almost asymptomatic to those who are near the end of life. Thus, the decision to perform ablation in Child-Pugh C patients should be made after carefully weighing the benefits and risks of treatment. For those in whom ablation is expected to significantly prolong survival, the procedure should be performed. However, in those for whom ablation is unlikely to improve prognosis – such as patients who are more likely to die from liver failure rather than HCC, ablation is not indicated. In patients with Child-Pugh C, the median survival time is approximately 16 months [52]. For candidates awaiting liver transplantation for more than 3 months, including selected Child-Pugh C patients, ablation may be considered as bridging therapy [53]. Ablation is used to prevent tumor progression beyond the transplant eligibility criteria that would disqualify the patient from the transplant list. These criteria, including tumor size, tumor number, and other factors, may vary between institutions [54, 55]. The risk of complications and periprocedural mortality may be higher in patients with Child-Pugh C cirrhosis, so careful consideration of the indications, as well as the risks and benefits of ablation, is essential for this patient group.

ECOG performance status is an independent prognostic predictor, with long-term survival tending to be worse in patients with progressively poor performance status in HCC as well as other malignancies [56]. Performance status should be considered in determining the indication for ablation, although there have been few studies in which indication for ablation is analyzed from the viewpoint of performance status.

Estimating periprocedural risks is essential as most patients with HCC have underlying cirrhosis. There are many periprocedural risk predictors for surgical treatments, including the Child-Pugh classification (Child-Turcotte-Pugh score) [57], the Model for End-Stage Liver Disease (MELD) score [57], ASA Physical Status Classification [58], Charlson Comorbidity Index (CCI) [59], and cardiopulmonary exercise tests (CPET) [60]. However, none of these predictors have been well evaluated in the context of ablation. This may be due to the significantly lower mortality and morbidity rates associated with ablation compared to surgical resection or even TACE [61].

Many patients with a history of upper abdominal surgery face challenges in undergoing ablation. First, past upper abdominal surgeries may cause adhesion formation between the abdominal wall or gastrointestinal tract and the liver, making it difficult to produce artificial ascites, also known as hydrodissection. Such surgeries include hepatectomy, gastrectomy, cholecystectomy, and others. The artificial ascites or hydrodissection technique is useful for displacing adjacent organs away from the target tumor, thereby making percutaneous ablation safer. This technique also helps reduce pain during or after ablation by preventing heat transmission to the parietal peritoneum or diaphragm. Second, previous upper abdominal surgeries often result in liver deformity, which complicates tumor detection and the safe insertion of an applicator.

Resource-related factors may include institutional volume, the operator’s skills and experience, paramedical staff training, ablation equipment, equipment to assist ablation, and others. These factors affect both the efficacy and safety of ablation. While tumor-related and patient-related factors are unchangeable, resource-related factors can be improved.

Institutional volume may affect efficacy and safety in ablation, namely, the indication. High-volume institutions are often able to perform ablation more effectively and safely, leading to broader indications. The association between institutional volume and outcomes may be attributed to learning curve effects and standardization of practices. Although there are few reports analyzing institutional volume and outcomes in minimally invasive procedures [62], this scarcity may be due to their low morbidity and mortality rates [63, 64]. In surgical treatments, numerous studies have evaluated the association between institutional volume and treatment outcomes [65, 66]. Notably, in-hospital mortality rates are significantly better in high-volume hospitals compared to low-volume ones [64, 67].

Ablation is highly operator-dependent. Skills and outcomes may be notably different from operator to operator and from institution to institution. A notable learning curve has been reported in RFA for liver tumors [68]. The risk of HCC recurrence can be substantially reduced by experienced RFA operators [69].

The skills and experience of paramedical staff are crucial for ensuring the smooth execution of ablation procedures. Training for ultrasonographers, medical engineers, and nurses involved in ablation is essential.

The ablation equipment used significantly impacts both efficacy and safety. Chemical ablation and energy-based ablation are different. Within energy-based ablation, RFA and MWA are also distinct from one another. These topics will be discussed in detail later under the section on Techniques.

US, CT, and MRI equipment are crucial for image-guided procedures. For instance, tumor conspicuity can vary significantly depending on the quality of US machines. Moreover, image-guided ablation is facilitated by US transducers designed specifically for interventional procedures and dedicated procedure tables. Image fusion and navigation systems that integrate multiple modalities, such as US, CT, and MRI, are widely utilized for tumor targeting [70]. Additionally, CEUS can enhance tumor conspicuity in certain cases [27].

The high-risk group for developing HCC includes patients with chronic hepatitis B, chronic hepatitis C, or cirrhosis. US is the most widely used modality for HCC screening and surveillance. However, US alone is insufficient to confirm a diagnosis of HCC due to the overlapping imaging features of benign and malignant cirrhotic nodules.

In cases where nodules are detected by US, dynamic CT or MRI should be considered as diagnostic tools for confirmation [71, 72]. In high-risk groups, nodules can be diagnosed as HCC based on typical imaging findings, specifically the presence of arterial enhancement followed by washout of the tumor in the portal venous or delayed phases on dynamic CT or MRI [73]. Gd-EOB-DTPA-enhanced MRI can improve the detection of HCC; a definitive diagnosis can be made for a hypervascular nodule that exhibits venous washout or hypointensity in the hepatobiliary phase [74, 75]. Additionally, CEUS using microbubble contrast agents and low mechanical index contrast-specific imaging techniques has proven useful for characterizing liver tumors (Fig. 2) [76, 77]. CEUS can be employed to characterize US-detected liver nodules and diagnose HCC in patients for whom contrast-enhanced CT or MRI are contraindicated due to renal dysfunction or allergy to contrast agents.

Liver tumor biopsy is unnecessary in the high-risk group for developing HCC when imaging techniques reveal the hallmark features of HCC. Biopsy carries potential risks, including bleeding and seeding [78, 79]. Therefore, it should be performed only in cases where imaging techniques do not show the typical findings of HCC.

Tumor marker measurement is necessary before ablation. Changes in tumor marker levels from the baseline value serve as effective indicators of treatment outcomes in elevated cases [80‒82]. Chest CT, bone scintigraphy, and FDG-PET are unnecessary in most situations where ablation is considered [83]. Although the presence or absence of extrahepatic metastasis is a critical factor in determining the indication for ablation, extrahepatic spread is relatively rare at the time of initial diagnosis of HCC [84]. Surveillance for extrahepatic metastasis is necessary only in cases with extremely high tumor marker levels [85] or findings suggestive of extrahepatic lesions [86].

Pre-ablative planning is crucial for the smooth execution of ablation. Understanding the patient’s clinical history related to HCC, including details about any previously resected or ablated liver segments, is essential. All imaging studies should be evaluated [87]. A careful US examination should be performed to identify target tumors and determine access routes [88]. During the US examination, CT and/or MRI images should be displayed for reference at any time. It is vital to understand the relationship between the tumor and surrounding structures, such as vessels and adjacent organs, to prevent complications. Identifying adjacent Glisson’s sheaths is particularly important as puncturing them may lead to hemobilia or pseudoaneurysm. Additionally, ablation can cause hepatic infarction or biliary complications, such as stricture and biloma. Intrahepatic bile ducts are more susceptible to thermal injury than blood vessels. Thus, it is important to identify on which side of a Glisson’s sheath a bile duct runs. Ablation can be performed relatively safely on the side opposite to a bile duct compared to the side closer to it. The intestines are also more vulnerable to thermal injury than the stomach, gallbladder, or kidneys. Fusion imaging can provide a 3-dimensional relationship between a tumor and adjacent intrahepatic and extrahepatic structures.

It is essential to determine the optimal patient position for each target tumor prior to the procedure: supine, right hemilateral (low, moderate, high), left hemilateral (low, moderate, high), upright, or 180° bed rotation with a left intercostal approach. Additionally, it is important to assess whether artificial ascites or artificial pleural effusion will be necessary. In cases with multiple target tumors, the order of ablation – deciding which tumor to treat first, second, and so on – should be determined during the pre-ablative planning phase. As a general rule, tumors located in risky sites or those that are difficult to access should take priority for treatment.

Several thermal and nonthermal ablation modalities are available for the treatment of HCC, including RFA, MWA, cryoablation, high-intensity focused ultrasound, laser ablation, irreversible electroporation, and chemical ablation (ethanol and acetic acid). Among these, thermal ablations, such as RFA and MWA, are the most widely used procedures.

RFA remains the most commonly used treatment for small liver malignancies due to its extensive study and widespread clinical application. Two types of monopolar equipment, designed as a straight cooled-tip electrode and multi-tined electrodes, have been available for over 2 decades [89]. Hepatic neoplasms less than 3 cm can be completely ablated in more than 90% of patients [13]. Using multiple electrodes (2–3) based on impedance and a power pulsing algorithm to expand the ablation zone may yield better outcomes for tumors ranging from 3 to 5 cm [90]. Additionally, some reports suggest that combining TACE with RFA may have a synergistic effect, potentially improving survival outcomes for tumors larger than 5 cm [91].

MWA ablates cancer tissue through dielectric heat generated by microwave energy emitted from an inserted bipolar-type applicator. The first-generation MWA system was introduced into clinical practice in the 1990s [11]. However, it has been replaced by RFA due to its smaller ablation volume and higher complication rates associated with the heated shaft of the applicator [92]. Recently, new-generation MWA systems of high-power generation and incorporating antenna cooling have been developed and received attention [93]. These systems may produce a more predictable ablation zone, create a larger ablation volume in a shorter procedure time, and have a lower heat-sink effect [94]. It is not easy to compare RFA and MWA because there are variations in both treatments. Generally, MWA is more expensive. Unlike RFA, MWA does not require grounding pads. The MWA antenna has a larger diameter than the RFA electrode, so extra caution is needed to prevent bleeding. MWA is more powerful and suitable for treating larger tumors. However, MWA still lacks sufficient clinical data, particularly long-term data, compared to RFA.

Cryoablation can effectively treat tumors near vulnerable structures, such as central bile ducts, as it creates well-defined ablation zone [95]. However, a rare but potentially fatal complication known as cryoshock may occur, and HCC patients with liver cirrhosis face an increased risk of bleeding [96]. There have been insufficient data on cryoablation for HCC. Clinical data on high-intensity focused ultrasound are still limited, preventing meaningful conclusions. Chemical ablation is now more commonly used as an adjunct in treating tumors that are difficult to address with thermal therapies alone. Examples include tumors that abut major bile ducts or are adherent to the bowel [97].

In image-guided tumor ablation of HCC, most procedures are performed under US guidance [88, 98, 99]. US offers advantages in real-time monitoring, flexibility, and cost-effectiveness compared to CT and MRI. However, US guidance has some limitations. A primary limitation is the isoechogenicity of tumors. Isoechogenicity can sometimes be mitigated by using higher-resolution US machines or CEUS. Moreover, even isoechoic tumors that are not detectable by US may still be ablated using a fusion imaging system. Fusion imaging may be able to identify the location of the tumors accurately. Thus, even when US does not visualize the tumor, it may still be possible to ablate it precisely as shown in Figure 3. Another limitation arises from tumor invisibility due to the effects of air in the lungs, bones, omentum, or other tissues covering the liver’s surface. Blind areas on US include the lateral end of the left lobe and the posterior-inferior segment of the right lobe. This invisibility can often be addressed by optimal patient positioning or by utilizing artificial ascites or pleural effusion (Fig. 4). CEUS and fusion imaging may further help resolve this issue. Additionally, gas bubbles produced by heat during ablation can obscure US images, complicating the following insertion of the applicator. Waiting for 5–15 min can often reduce the impact of these gas bubbles and improve US imaging in many cases. These limitations may be addressed by using CT or MRI guidance, or by combining CT/MRI with US in certain situations [100].

CT guidance is not the primary method for liver tumor ablation. However, in CT-guided tumor ablation, the position of the applicator and its relation to adjacent organs are clearly visualized due to CT’s high resolution. This imaging technique allows for almost all organs to be seen without interference from bones or gas. Some investigators suggest that CT guidance may have advantages for tumors located beneath the diaphragm, near bones, or at the edges of the left lateral segment and posterior segment. Nevertheless, with the use of artificial ascites or pleural effusion, most of these tumors can be effectively identified and ablated under US guidance by experienced operators. In certain cases, ablation is performed following TACE to enhance local control of the tumors. In such scenarios, CT guidance may be beneficial since the tumor can be clearly visualized through the Lipiodol deposit. Traditional CT guidance requires a slow, slice-by-slice process to confirm the updated position of the applicator. In contrast, fluoroscopic CT enables the operator to continuously monitor the trajectory of the applicator during insertion, simplifying the CT-guided interventional procedure [101]. However, it is important to note that CT-guided interventions expose patients to radiation.

MRI is the least commonly used imaging modality for percutaneous ablation, [102, 103], although it has been considered as a versatile and suitable option for guidance [104]. Compared to both US and CT guidance, MR guidance is more expensive and time-consuming. However, MRI offers excellent soft tissue resolution and the ability to image in arbitrary planes. It provides near real-time imaging, which facilitates the characterization and tracking of anatomical motion while eliminating radiation exposure. Additionally, MRI can monitor temperature changes in the ablation zone, helping to assess the extent of tumor destruction.

Fusion imaging is a system that merges real-time US with previously acquired CT or MRI images [105, 106]. In this technique, a virtual image constructed from CT or MRI data is displayed alongside the real-time US image on a single monitor. The virtual image aligns with the same plane and moves synchronously with the real-time US image. This capability enhances the accurate targeting of inconspicuous tumors on US without using CT or MRI equipment. Fusion image is also useful for demonstrating the 3-dimensional relationship between the tumor and surrounding structures.

Fusion imaging may serve as an alternative to CT or MRI guidance for patients with tumors that are poorly visualized on US. Additionally, three-dimensional US can be fused with real-time US for the percutaneous ablation of liver tumors that require overlapping ablation.

CEUS is an US examination that utilizes gas-filled microbubbles to provide sensitive information about blood flow and tissue perfusion [27, 107]. CEUS is beneficial for guiding the insertion of an applicator into inconspicuous tumors on US. Additionally, it is effective for evaluating ablation areas to determine whether any viable tumor portions remain [108]. Unlike CT and MRI, which provide only static images, CEUS offers real-time, continuous dynamic imaging of tumors. The unique intravascular properties of microbubbles enable CEUS to characterize malignant tumors with increased vascular permeability. Furthermore, CEUS is not affected by motion artifacts, making it a safe and easily performed technique that does not involve ionizing radiation or pose a risk of nephrotoxicity. It is suitable for patients with renal dysfunction, allowing for multiple microbubble injections and repeated observations of tumor enhancement patterns during a single examination. However, CEUS does have specific limitations, including blind spots, particularly in areas located more than 10 cm from the body surface, in addition to the inherent blind areas of US. In some situations where percutaneous ablation is not feasible due to anatomical constraints or poor tumor visibility, laparoscopic or open approaches may serve as alternatives [109, 110].

It is important to recognize that a sufficiently ablated area does not merely refer to a large volume of ablation. To eliminate potential occult metastases adjacent to a targeted tumor, it is essential to ablate not only the tumor itself but also some surrounding liver tissue [34]. To ensure an adequate ablation zone, overlapping ablation is necessary in many cases.

Single-needle type electrodes generate an ablated area that typically resembles a prolate spheroid or rugby ball shape. The size and shape of this ablation zone can be unpredictable. The dimensions of the minor axis often vary unpredictably, likely due to the cooling effect of adjacent vessels, which restricts the spread of the ablated area. In contrast, the size of the major axis remains relatively stable. Expandable type electrodes can create an oblate spheroid-shaped ablation zone, characterized by a wider horizontal axis compared to the vertical axis.

Regarding the output mode, the stepwise increment of output is widely used in Asian countries [36, 111]. This gradual increase is implemented to prevent or delay “popping,” a form of explosive tissue disruption resulting from a rapid rise in intra-tissue pressure. Such popping can lead to tumor cell dispersion or bleeding [112].

We should avoid popping, especially in cases where the target tumor is located on the liver surface, as this may lead to malignant dissemination into the peritoneal cavity [113]. Additionally, popping should be avoided when the target tumor is adjacent to a hepatic vein or the inferior vena cava as it could increase the risk of pulmonary metastasis [86, 114]. However, if popping does occur, the procedure should be continued until complete ablation is achieved. In RFA, popping is typically followed immediately by an impedance out or “break,” which interrupts the ablation process in most cases. In contrast, in MWA, the procedure continues for the scheduled duration required to achieve the planned ablation size. Notably, once popping occurs, intra-tissue pressure does not increase further due to the tissue disruption. Overall, popping should be avoided whenever possible as it may lead to complications such as bleeding or tumor cell dispersion.

Most microwave antennas produce a pear-shaped ablated area, which elongates along the antenna shaft. However, a more spherical and less elongated ablated zone can enhance ablation precision and reduce complications. Several advanced technologies have been developed to create a more spherical ablation zone, including dual-slot antennas [115], paired antennas [116], an antenna with thermal control, field control, and wavelength control [117]. The stepwise increment of output is also used in MWA to prevent popping, which carries the risk of hemoperitoneum or malignant seeding.

Peri-ablative management is fundamental for conducting ablation procedures smoothly and safely. Preparation is essential to minimize AEs, such as bleeding and infection. In many hospitals, ablation is performed on an inpatient basis as severe AEs can occur even more than 8 h post-procedure. Continuous observation is crucial for the timely detection of any complication.

Control of bleeding disorder is important in ablation because image-guided percutaneous ablation precludes the operator from direct visualization and management of bleeding at the procedure site. Ablation carries the risk of bleeding. On the other hand, some patients who undergo ablation have thrombotic risks and thus are under antithrombotic medication. These agents are increasingly utilized by clinicians to reduce thromboembolic events in conditions like cardiac arrhythmia, coronary artery disease, valvular heart disease, deep vein thrombosis, various other vascular occlusions, and hypercoagulable states. Antithrombotic medications can be classified into two main categories: antiplatelet agents and anticoagulants. Commonly used antiplatelet agents include aspirin (acetylsalicylic acid) and thienopyridines (clopidogrel, prasugrel, ticlopidine, ticagrelor), while anticoagulants include warfarin and direct oral anticoagulants (DOACs).

Risk stratification for ablative procedure has been defined by the American Society of Gastrointestinal Endoscopy and the Society of Interventional Radiology guidelines [118, 119]. These guidelines are designed to assist clinicians in their decision-making processes rather than serve as rules to follow. The final decision for antithrombotic management should also be patient tailored.

Low platelet count is relevant to the risk of bleeding events during and after invasive procedures [120]. In patients with severe thrombocytopenia (platelet count below 50,000/μL), many institutions administer platelet transfusions before ablation. However, platelet transfusions might be associated with febrile nonhemolytic and allergic reactions, risk of infection, and platelet refractoriness. Alternatives are splenectomy or partial splenic arterial embolization, which carry considerable complications. Thrombopoietin receptor agonists such as lusutrombopag [119, 121] and avatrombopag [122] may be a treatment of choice in ablation for severe thrombocytopenic patients. They can increase the platelet count effectively in most cases.

Many patients with HCC have coagulopathy due to comorbid liver cirrhosis. In most institutions, ablation is performed in patients with prothrombin activity of 50% or higher [88, 98]. In general, ablation should not be performed on patients with advanced cirrhosis whose prothrombin activity is below 50% as liver failure, rather than HCC, is likely to be the primary factor that would shorten life expectancy. Additionally, replacement therapy tends to have only short-term efficacy.

Antiplatelet agents are widely used for the primary and secondary prevention of thrombotic cerebrovascular and cardiovascular diseases. Because of lack of robust evidence, such as randomized controlled trials, the management of antithrombotic agents has resulted in considerable variety in clinical practice. Regarding antithrombotic medication, it is essential to weigh the risk of clot formation from stopping the medication against the risk of bleeding from continuing it during or after ablation in each case [123]. For some patients who are at high risk of thrombosis, we may consider switching to an antiplatelet drug with a shorter half-life. The decision should be aligned with each institutional standard or consensus. We generally stop aspirin (acetylsalicylic acid) and other antiplatelet agents such as thienopyridines (clopidogrel, prasugrel, ticlopidine, ticagrelor) a week before ablation.

Anticoagulants, such as warfarin and DOACs, are used in patients with atrial fibrillation, mechanical heart valves, and deep vein thrombosis, among other conditions. Anticoagulant therapy can prevent the formation or growth of dangerous clots. Temporarily interrupting anticoagulation increases the risk of thromboembolic events, while continuation raises the risk of bleeding associated with ablation. The decision regarding anticoagulant interruption must be evaluated as a balance between the benefits and risks in each case. Bridging therapy may be required for patients with a high risk of thromboembolic events [118]. Patients with atrial fibrillation should be evaluated using the CHA2DS2-VASc score, and the type of mechanical valve should be assessed for those with valvular heart disease. The risk of thromboembolic events when warfarin is interrupted for 4–7 days is approximately 1% [124, 125]. DOACs are increasingly used in various clinical indications to replace warfarin. Generally, discontinuation of DOACs 1–2 days prior to ablation is recommended; however, a longer duration of drug interruption may be necessary in cases of renal impairment [118, 126].

Any invasive procedure carries the risk of infection. According to the literature, 0.3–2.4% of patients develop infections, such as liver abscess and cholangitis, after ablation [127‒130]. Most operators use prophylactic antibiotics for ablation not based on robust evidence but rather on personal or anecdotal experience, or on ablative or surgical literature [131‒135]. Currently, there is no consensus on the first-choice antibiotic agent. The lack of randomized controlled trials has led to the routine use of antibiotic prophylaxis as a perceived standard of care. However, it is essential to use prophylactic antibiotics judiciously, considering the costs of antibiotic therapy, the increasing incidence of antibiotic resistance, and the potential complications from nosocomial infections. Further investigations are necessary to clarify the role of prophylactic antibiotics in ablation [136].

In patients with papillary sphincter dysfunction due to enterobiliary anastomosis, sphincterectomy, biliary drainage, or stent placement, the incidence of liver abscess following ablation can be as high as 22–100% [127, 137, 138]. Papillary sphincter dysfunction is considered a significant risk factor for the development of liver abscess and is generally regarded as a contraindication for liver tumor ablation [130, 138‒140]. In addition to papillary sphincter dysfunction, other risk factors for developing liver abscess include larger ablation volumes, porta hepatis tumors, diabetes mellitus, and advanced liver cirrhosis.

Patients undergoing ablation under sedation or general anesthesia require regular monitoring of vital signs – including blood pressure, heart rate and rhythm, pulse oximetry, and airway status – throughout the procedure. Assistant operators, anesthesiologists, and nursing staff must be sufficiently skilled to manage any emergent situations that may arise during sedation or anesthesia. Emergency cart, oxygen tank, and other resuscitative equipment should be readily available. Vital signs recorded prior to the procedure can help screen for potential underlying conditions that may be exacerbated during sedation or general anesthesia. Post-procedure monitoring is also important for the prompt management of potential AEs resulting from sedatives or the ablation itself. Sedatives and analgesics are necessary because ablation can be painful, and patients often experience anxiety and discomfort. Anesthetic agents not only relieve pain but also reduce the risk of patient injury caused by movement during the procedure.

In cases where the operator encounters difficulty before or during the ablation and is not able to finish the procedure, he/she should request a substitute or cancel the procedure. In some patients with multiple tumors, the procedure may be divided between two operators. Tumors that are easier to ablate may be treated by a less experienced operator, while those that are more difficult to ablate should be handled by a more experienced operator. For large tumors, the portions that are easier or less risky to ablate can be addressed by the less experienced operator, while the more challenging or risky areas should be managed by the more experienced operator.

During post-procedural recovery, attention should be given to the recovery of consciousness, spontaneous respiration, hemodynamics, and urinary retention. Reversal agents such as naloxone for opioids and flumazenil for benzodiazepines may be administered in cases of prolonged sedation. Urinary retention should be monitored, particularly in elderly patients. An indwelling Foley catheter may be used when necessary. In the event of cardiorespiratory depression, advanced airway management and resuscitative medications should be administered by medical professionals with Advanced Cardiovascular Life Support qualifications.

Despite the low rate of major complications, operators must be vigilant about potential procedure-related problems for prompt detection and management [111, 129, 141]. Immediate post-procedural care should focus on hemorrhages, ground-pad thermal injury, pneumothorax, visceral damage, reactive pleural effusion, and ascites. Hemorrhagic complications are the most frequently encountered and most devastating if neglected. A study identified several risk factors for bleeding [120]. Recognizing high-risk procedures prevent delayed diagnosis. Post-procedural observation is mandatory as some complications may take hours to days to manifest obvious symptoms.

Evaluation of therapeutic effectiveness is critical for understanding the efficacy of ablation and assessing technical success. This assessment is commonly performed using contrast-enhanced imaging studies (CT or MRI) with a slice thickness of 5 mm within 6 weeks post-ablation [142, 143]. If feasible, early imaging a day after the procedure may be beneficial for assessing technical success and detecting any complications promptly. Multiphasic contrast-enhanced CT may be preferred due to its cost-effectiveness and convenience [144]. Technical success is defined by a target tumor completely covered by the ablation zone [145]. Appropriate post-treatment evaluation is associated with a reduction in local tumor progression and an improvement in overall recurrence rates [146]. If an unsatisfactory safety margin is identified, salvage ablation should be arranged timely. A study using enhanced CT or MRI for safety margin assessment showed comparable ability to predict local tumor progression [147]. The safety margin is conventionally assessed through visual examination of contrast-enhanced images taken before and after the ablation. However, some studies indicated that using software for safety margin assessment was superior to visual evaluation, effectively identifying patients at risk for local tumor progression [148, 149]. CEUS may be beneficial for patients with allergies to contrast agents or renal dysfunction, serving as a complementary tool to assess therapeutic response and safety margin [150], although safety margin could not be determined in 34.8% of the cases.

The concept of safety margin arose from a histopathologic study of resected specimen treated by ethanol injection [34], which revealed residual viable cancer tissue remains in the peripheral area of the nodule or in the extracapsular growth. The 5 mm safety margin was derived from the formula relating the volume of ethanol injected to the tumor size [32]. The safety margin must be adjusted for each case or each tumor. The safety margin needs to be modified based on gross pathological type of HCC as shown in Figure 1 [42]; a larger ablative margin is necessary in the simple nodular type with extranodular growth and the confluent multinodular type compared to small nodular type with indistinct margins and the simple nodular type. The safety margin should also be modified based on the tumor’s relationship with nearby structures. The hepatic artery, portal vein, and hepatic vein are less vulnerable to thermal injury compared to the intrahepatic bile duct. Particular attention should be paid to the intrahepatic bile duct running parallel to the portal vein; the anatomy of their relationship must be recognized, like whether the intrahepatic bile duct runs along a shallower or deeper portion of the portal vein. The hepatobiliary phase of an EOB-MRI can show the relationship between the portal vein and the parallel-running intrahepatic bile duct in certain cases. There was a report indicating that ablation covering the entire tumor blood drainage area improved survival in patients with HCC [151].

An adequate safety margin around the tumor is necessary to minimize the risk of local tumor progression, while also considering that excessive ablation of surrounding liver parenchyma may deteriorate liver function and negatively affect long-term survival. In some cases, a challenging decision must be made regarding the sacrifice of the Glisson’s sheath. Sacrificing it can lead to hepatic infarction or intrahepatic bile duct dilatation, resulting in subsequent atrophy of the peripheral liver parenchyma. Alternatively, preserving the Glisson’s sheath may increase the likelihood of residual viable cancer tissue remaining. The safety margin should be tailored in terms of liver function.

Ablation procedures can pose potential risks; however, when performed correctly and with appropriate safety systems, complications can be minimized. Two types of safety systems are employed: active and passive. Active safety systems aim to prevent complications by evaluating factors associated with risk and implementing preventive measures. Conversely, passive safety systems are designed to mitigate the consequences of complications if they occur. Early detection and management of complications are essential to prevent fatal outcomes. While there are various complications associated with ablation, the frequency of each is relatively low. Therefore, sharing knowledge and experiences related to these complications is crucial.

The Society of Interventional Radiology (SIR) proposed a classification system for AEs, categorizing them into five levels: mild AE, moderate AE, severe AE, life-threatening or disabling event, and patient death or unexpected pregnancy termination [152]. The SIR AE Severity Scale is designed to align with the surgical Clavien-Dindo scale [153] and the National Cancer Institute Common Terminology Criteria for Adverse Events scale [154]. All AEs occurring within 30 days of a procedure should be included in the AE description and analysis, regardless of their causality, to ensure objectivity.

Bleeding is a common complication associated with all types of locoregional ablation that use needle-type devices. These bleeding complications can be further classified into hemoperitoneum, hemothorax, and hemobilia [120]. Hemoperitoneum or intraperitoneal hemorrhage typically results from injuries to intrahepatic or abdominal wall vessels caused by needle devices. Patients with HCC are at a higher risk of bleeding complications since most are in the state of coagulopathy because of underlying chronic liver disease. Risk factors for hemoperitoneum include a longer needle tract to the target tumor and lower platelet counts, among others. A longer needle tract increases the likelihood of injuring vessels along the puncture route, thereby heightening the risk of bleeding. Theoretically, the risk of bleeding increases with greater needle thickness and the number of insertions required to achieve tumor destruction. Additionally, bleeding is more frequent in cryoablation compared to RFA and MWA, which inherently possess hemostatic effects. Notably, these procedures can also be employed to control bleeding by coagulating the bleeding site.

Hemothorax, a rarer complication than hemoperitoneum, occurs due to injury to the intercostal vessels. However, the mortality rate associated with hemothorax is higher than that of hemoperitoneum as spontaneous hemostasis is rarely achieved in cases of arterial bleeding. Additionally, bleeding into the pleural cavity can lead to reactive pleural effusion and, in some cases, a systemic inflammatory response syndrome, resulting in respiratory failure. An interventional radiological procedure is typically required to manage hemothorax. If the intervention is ineffective, surgical options should be considered.

Hemobilia occurs when a needle device simultaneously penetrates an intrahepatic portal vein or artery and a bile duct. Unlike other bleeding complications, hemobilia is rarely associated with hypovolemic shock. Instead, it typically presents as obstructive jaundice. Hemobilia can be identified by the presence of a clot in the gallbladder, known as the hemobilia sign [155]. Since hemobilia is generally self-limiting, endoscopic intervention should be deferred unless patients develop an infection as a subsequent complication. This is because intervention can sometimes promote rebleeding and infection [156].

Liver abscess is typically associated with transbiliary bacterial translocation. Consequently, a history of biliary intervention that leads to enterobiliary reflux is a significant risk factor for developing a liver abscess following locoregional ablation. Specifically, a history of enterobiliary anastomosis should be considered a contraindication for RFA or MWA due to the extremely high risk (exceeding 50%) of abscess formation after these procedures [138].

Intrahepatic biliary injury, characterized by intrahepatic bile duct dilatation, is more prevalent in RFA and MWA compared to cryoablation. The heat produced by RFA or MWA can more easily injure the intrahepatic bile ducts compared to blood vessels as the cooling effect of bile flow is less than that of blood flow. In most cases, biliary injury is asymptomatic, typically indicated by elevated alkaline phosphatase and gamma-glutamyl transferase levels. However, injury to a major intrahepatic bile duct can lead to segmental atrophy of the liver parenchyma, resulting in long-term deterioration of liver function [45]. There have been some reports that intraductal chilled saline perfusion during ablation may be useful to reduce biliary complications [157]. Irreversible electroporation may be a preferable option when the target tumor is located in the liver hilum as it is less likely to damage the biliary structures [158].

Hepatic infarction is an ischemic complication, resulting from the simultaneous occlusion of both intrahepatic arterial and portal blood flow [159]. Hepatic venous congestion is caused by the occlusion of the hepatic vein. Both complications are characterized by massive parenchymal loss with highly elevated liver enzyme levels and subsequent inflammatory response syndrome, which can result in high fever and potentially fatal outcomes. To mitigate the risk of these complications, careful electrode placement along with minimized ablation power and duration are recommended.

Neoplastic seeding is classified as a late-onset complication that can occur up to 5 years after ablation [160]. While some instances of neoplastic seeding may be amenable to surgical resection, the prognosis is generally poor in cases involving intraperitoneal dissemination. Factors associated with an increased risk of neoplastic seeding include tumor location on the surface of the liver, poorly differentiated tumor characteristics, and multiple treatment sessions [160, 161]. Additionally, a preceding tumor biopsy has been linked to neoplastic seeding [162]. No-touch ablation using multiple electrodes placed around the target tumor is a method to avoid puncturing the target tumor directly [163].

Approximately 70%–80% of patients with HCC develop recurrence within 5 years, even after curative resection or ablation, due to occult metastasis or metachronous multicentric (de novo) carcinogenesis [164, 165]. Early detection of recurrence is crucial as most recurrences can be treated curatively with another ablation, unlike many other solid tumors [88]. Comprehensive post-treatment surveillance is essential for improving prognosis after ablation. A combination of dynamic CT or MRI and tumor marker tests is recommended for follow-up, similar to the surveillance protocol for patients at extremely high risk for developing HCC. Screening should be conducted every 3–4 months. The interval should be tailored based on tumor marker level trend and others [166].

Extrahepatic recurrence following ablation is uncommon. Therefore, imaging modalities such as CT, MRI, FDG-PET, or bone scintigraphy should be considered only when patients have symptoms of extrahepatic metastasis or when intrahepatic recurrence is not detected despite a gradual increase in tumor marker levels.

Incidentally, ablation is theoretically associated with a higher recurrence rate compared to surgical resection. Local tumor progression can occur following incomplete ablation. Additionally, ablation may result in more frequent distant recurrences from the initial target tumor than resection due to the smaller volume of surrounding tissue that is ablated.

Preventing the recurrence of HCC is crucial for long-term survival. One primary reason for recurrence is the presence of microscopic residual tumors. Notably, even small tumors measuring 2 cm or less were found to have portal vein invasion in 27% of cases and intrahepatic metastasis in approximately 10% [167]. Theoretically, adjuvant chemotherapy may reduce or delay such recurrences, but few cytotoxic anticancer drugs have been effective against HCC while many of them may be hepatotoxic. This may result in poor prognosis because of worsening liver function.

Adjuvant sorafenib after surgical resection and ablation for HCC did not provide additional benefit in terms of recurrence-free survival in the STORM trial [168]. The Phase 3 IMbrave 050 trial initially demonstrated that adjuvant atezolizumab with bevacizumab improved recurrence-free survival compared to placebo, but it failed to show a sustained benefit in overall survival or recurrence-free survival [169, 170]. Several ongoing trials are investigating the role of adjuvant targeted therapies for HCC. These include the EMERALD-2 trial on durvalumab alone or in combination with bevacizumab versus placebo, the KEYNOTE-937 trial on pembrolizumab versus placebo, and the trial on nivolumab versus placebo as adjuvant therapies after curative resection or ablation [171‒173]. To date, there has been no conclusive evidence that pharmacotherapy can reliably prevent recurrence or improve survival after curative resection or ablation of HCC. While certain treatments, such as targeted therapies or immunotherapy, have been explored, their effectiveness in reducing recurrence and improving long-term survival remains unproven in large-scale clinical trials.

Furthermore, antiviral treatment may help prevent recurrence, maintain and enhance liver function, and ultimately improve survival in patients with HCC associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) [174, 175]. Interferon has been shown to improve survival, although it does not significantly increase the recurrence-free survival rate in HBV-related HCC [176]. Nucleos(t)ide analogs are effective in reducing the risk of recurrent HBV-related HCC. Recurrence is particularly frequent in HCV-related HCC, with a substantial proportion of these recurrences – especially in the later stages – thought to represent metachronous, multicentric hepatocarcinogenesis. Both direct-acting antiviral therapies and interferon-based treatments may reduce the risk of recurrence and improve survival in patients with HCV-related HCC [175].

Alcohol abuse is another main cause of HCC. Therefore, for these patients, alcohol abstinence is a critical issue following curative liver resection or ablation. Alcohol abstinence may reduce recurrence of HCC and improve overall survival [177, 178].

HCC frequently recurs even after curative locoregional treatment. Unlike other tumors, however, most recurrent HCC can be treated curatively similar to primary HCC. With rigorous post-treatment surveillance, up to 89% of initial recurrences were treated by iterative RFA [88]. Ablation is easily repeatable for recurrences due to its minimal invasiveness. In contrast, only 11–30% of recurrent HCC cases following hepatectomy can be treated with repeat hepatectomy.

In general, local tumor progression is more difficult to treat than the primary tumor. The most important thing is to ensure that the primary HCC is treated in a definitively curative manner to prevent local tumor progression. The second priority is rigorous surveillance to detect any local tumor progression at an earlier stage. When ablation is used for local tumor progression, it should be performed carefully to eradicate the entire viable portion. To facilitate detection of the viable portion, CEUS and/or fusion imaging should be used. Surgical resection may be the preferred treatment for cases with extensive local tumor progression and/or more than three satellite lesions [179]. While some reports suggest that the efficacy of hepatectomy and ablation for local tumor progression is not significantly different [37, 180], we should not hesitate to pursue salvage surgery if necessary.

Most recurrences that are distant from the primary tumor can be treated with ablation, similar to the primary treatment approach. Surgical options, vascular interventions, radiation therapy, and pharmacological therapies should be chosen based on the individual case. Generally, the same strategies used for primary HCC should be applied to recurrent HCC.

According to a nationwide follow-up survey of primary liver cancer in Japan, the cumulative survival rate for patients treated with surgical resection improved significantly in the 1990s compared to the 1980s. On the other hand, the recurrence-free survival did not improve significantly. This indicates that advancements in the treatment of recurrent HCC play a crucial role in improving long-term prognosis [181].

These guidelines have potential limitations. Despite an exhaustive review of available literature, only a small number of relevant randomized controlled trials and meta-analyses met the criteria and could be included in the guidelines. Consequently, some of the recommendations in these guidelines are based on expert opinion and limited data. Future randomized controlled trials and meta-analyses are essential to validate these recommendations and provide stronger evidence for clinical practice.

The authors thank Dr. Yasuyuki Komiyama, Dr. Hsin-Yi Chen, and Dr. Javkhlan Maikhuu for their invaluable time and effort to the guidelines.

The authors have no conflict of interest to declare.

The authors have no funding source.

Conceptualization and design: S.S., R.T., J.I.H., Z.M., L.S., J.-I.C., S.-N.L., S.Y.K., and P.W.; data curation and drafting of the manuscript: Y.A., S.-M.L., K.-W.H., H.R., P.L., U.P., M.T., T.B., and Q.D.; and review and editing of the manuscript: M.T., H.M., and L.M.C. The final version of this manuscript was approved by all the authors.