INTRODUCTION

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality globally, and seventh in terms of cancer incidence in South Korea. Although the overall clinical course and prognosis of HCC remain unsatisfactory, treatment is effective in select patients with early-stage HCC, potentially resulting in excellent recurrence-free and overall survival (OS) outcomes. Therefore, diagnosis of early-stage HCC and timely treatment are of utmost importance.

The criteria for early-stage HCC vary according to the staging system. The Barcelona Clinic Liver Cancer (BCLC) system, one of the most widely used HCC staging systems, was updated in 2022.¹ It defines early HCC into two groups: very early-stage HCC, which includes single HCC ≤2 cm with preserved liver function and a performance status of 0, and early-stage HCC, which includes single HCC or ≤3 nodules, each ≤3 cm in diameter, with preserved liver function and a performance status of 0. The modified Union for International Cancer Control (mUICC) staging system considers the number of tumors, diameter of the largest tumor ≤2 cm, and the absence of vascular or bile duct invasion. Although early-stage HCC is not precisely defined in the mUICC staging system, depending on the number of fulfilled criteria, HCC diagnosed as stage I (all three criteria fulfilled) or stage II (two of three criteria fulfilled, especially in a specific setting without vascular or bile duct invasion) may be regarded as early HCC in the mUICC staging system with respect to the BCLC system and Milan criteria.^2,3

Treatment methods for early-stage HCC may be categorized into three modalities: liver transplantation (LT), surgical resection (SR), and local ablation.^1,4 These three efficient modalities have been explored in various clinical studies and have yielded favorable outcomes in early-stage HCC. However, owing to diverse clinical variables, such as tumor biology, liver functional reserve, patient comorbidities, and the anatomical location of the tumor, routine application of these conventional treatment methods for HCC is not always feasible, resulting in unexpected insufficient anti-tumor responses (Fig. 1).

In this review, we summarize the challenges in the treatment of early-stage HCC and discuss potential strategies to overcome these hurdles.

PITFALLS FOR INSUFFICIENT TREATMENT OUTCOMES

1. LT

1) Criteria for transplantation

LT is often recommended for patients who are ineligible for SR when tumor stage falls within the Milan criteria. Theoretically, LT is the most efficient treatment strategy, because it enables removal of not only the tumor tissue but also the cirrhotic liver, thereby preventing de novo carcinogenesis. However, due to shortage of organ availability for patients with early HCC, only living-donor LT (LDLT) is selectively performed in a few centers in South Korea. The Milan criteria, introduced by Mazzaferro et al.,³ include a single tumor ≤5 cm or up to three tumor nodules, each with a maximum diameter of 3 cm, without macrovascular invasion or extrahepatic location. Although the Milan criteria have been associated with a 92% recurrence-free survival (RFS) rate at 4 years, several patients, who may otherwise have favorable prognosis, may be excluded from LT, due to their stringency. Therefore, extended criteria for LT have been proposed with reported favorable outcomes (Table 1). Often, these expanded criteria adapt morphometric variables, such as tumor number and size, to identify specific patients beyond the Milan criteria without increasing the risk of post-transplantation recurrence.^5,6 Both the University of California, San Francisco criteria and the Asan criteria have shown positive results in expanding the conventional Milan criteria, although a few conflicting results have been reported, indicating that additional validation is required.

2) Tumor markers

In addition to morphometric variables, the biology of the tumor is a critical parameter to consider for recurrence after LT, because large or multiple HCCs do not always correlate with poor prognosis. Since pre-transplantation tumor biopsy is not generally applicable due to the risk of tumor cell seeding, and a biopsy may not represent the entire tumor biology due to tumor heterogeneity, predicting post-LT outcomes with noninvasive biomarkers would be valuable.

Serum alpha-fetoprotein (AFP) and prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II) have been associated with the aggressiveness of tumors.^7,8 In particular, AFP has become the most widely used prognostic marker for predicting the aggressiveness of tumors, and some studies have proposed prediction models combined with AFP. Kwon et al.⁹ and Suh et al.¹⁰ emphasized the importance of AFP in assessing the risk and prognosis of HCC using specific thresholds related to survival and recurrence rates. Choi et al.¹¹ also demonstrated that the 5-year disease-free survival (DFS) was 88.6% in patients with serum AFP <100 ng/mL and tumor size <5 cm. Additionally, PIVKA-II, also known as des-γ-carboxy prothrombin, has been suggested as a predictive marker for outcomes after LT, as shown in studies reporting on recurrence and survival rates in different patient groups.^12,13 Taketomi investigated the impact of PIVKA-II on HCC recurrence after LDLT and found that the 5-year OS and RFS rates were 82.7% and 87.0%, respectively, in patients with tumors <5 cm in diameter and PIVKA-II <300 mAU/mL.¹⁴ Another study from 49 centers including 653 patients found that the 5-year RFS rate was 84.3% in transplant recipients beyond the Milan criteria, serum AFP levels ≤200 ng/mL, and PIVKA-II levels ≤100 mAU/mL.¹⁴ Furthermore, Lee et al.⁷ proposed a model to predict tumor recurrence after LT for HCC beyond Milan criteria (MoRAL score) with serum AFP and PIVKA-II, and demonstrated 5-year recurrence-free and OS rates with MoRAL scores as high as 66.3% and 82.6%, respectively.

3) Inflammation markers

The neutrophil-to-lymphocyte ratio (NLR) is a wellknown marker of active systemic inflammation, and several studies have correlated NLR with recurrence after LT. For instance, Halazun et al.¹⁵ found that patients within the Milan criteria and with elevated NLR had significantly poorer DFS relative to those with normal NLR within the Milan criteria (30% vs. 81%; P<0.0001). Similarly, Harimoto et al.¹⁶ revealed distinct survival rates based on NLR levels in patients who had undergone LT for HCC.

Serum C-reactive protein (CRP), a commonly used marker for systemic inflammation, has also been demonstrated as a predictive marker for HCC recurrence after LT. Studies by An et al.¹⁷ and Na et al.¹⁸ have further highlighted the importance of CRP levels in predicting outcomes, including recurrence and survival, with specific thresholds indicating significantly worse results. The integration of these markers into a newly designed model consisting of NLR and CRP levels has underscored the potential of noninvasive inflammatory markers to predict prognosis in the context of LT for HCC.

4) Positron emission tomography

¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) is commonly performed to assess potential extrahepatic metastasis before LT. Research has shown that ¹⁸F-FDG PET scanning can help to characterize tumor biology and prognosis after HCC treatment.^19,20 Lee et al.²¹ proposed new criteria using ¹⁸F-FDG PET scans and tumor size to select optimal patients and expand the LDLT pool (with negative findings on PET and total tumor size <10 cm). Additional studies have reported that increased ¹⁸F-FDG uptake on PET may predict microvascular invasion (MVI) or unfavorable tumor histology, resulting in poor outcomes after LT.^22-24

2. SR

1) Criteria for SR including clinical variables

Among the curative-intent therapies against HCC, SR has the broadest range of indications relative to other modalities, such as LT and local ablation therapies. SR has shown favorable outcomes for large HCCs, even those >10 cm, when compared to those associated with non-surgical treatments, such as transarterial chemoembolization (TACE), with a fair safety profile.^25,26 For example, Hwang et al.²⁵ reported that the 5-year survival rate was 35.5% in 471 patients who had undergone SR for HCC >10 cm, noting that tumor volume did not affect recurrence or survival.

In cases of multiple HCCs, SR has also shown superior results compared to those associated with alternative treatments such as radiofrequency ablation (RFA) and TACE. Comparative studies have reported better long-term survival with SR for multifocal HCCs than that associated with RFA (hazard ratio [HR], 0.69; P<0.001).²⁷ Moreover, a nationwide survey in Japan including 2,178 patients with multiple HCCs (1,089 patients allocated to each SR and TACE group) demonstrated better 5-year survival rates in the SR group for patients with tumors ≥30 mm in diameter (53.0% vs. 32.7%; P<0.001).²⁸

2) Liver functional reserve and portal hypertension

SR of HCC is the preferred treatment for patients with a single tumor and preserved liver function, who can survive post-hepatectomy. Therefore, a thorough preoperative assessment of the liver function reserve is crucial to avoid postoperative liver dysfunction (Table 2). The indocyanine green retention rate at 15 minutes (ICG-R15) is commonly used for this purpose, with values under 10% generally recommended, although this may vary depending on the extent of SR.²⁹ Fan et al.³⁰ suggested an ICG-R15 <14% for patients undergoing SR more extensive than right hemi-hepatectomy. Moreover, Schwarz et al.³¹ analyzed 698 patients who had undergone liver resection for HCC (minor, 44.8%; major, 55.2%) and concluded that indocyanine green <19.5% is the optimal cut-off value for predicting postoperative liver dysfunction. Choi and colleagues demonstrated postoperative hepatic decompensation and poor prognosis in patients with significant portal hypertension (defined by the BCLC criteria as presence of esophageal or gastric varices or splenomegaly [diameter ≥12 cm] with platelet count <100,000/mm3) before SR of HCC.^32,33 However, Cucchetti et al.³⁴ demonstrated that the model for end-stage liver disease score and the extent of hepatectomy may server as predictors for postoperative liver failure, regardless of the presence or absence of portal hypertension. The albumin-bilirubin (ALBI) grade has emerged as a reproducible and objective measurement of liver functional reserve in patients with HCC. The ALBI grade defines liver function impairment across three grades and correlates with survival, tumor relapse, and post-hepatectomy liver failure, thus aiding the precise selection of patients suited for SR.³⁵ Lastly, liver stiffness measurement (LSM) by transient elastography is emerging as the most promising noninvasive test to measure liver functional reserve and grade of portal hypertension. Many studies have demonstrated the relationship between LSM and post-hepatectomy liver failure^36-38 and Serenari et al.³⁹ recently proposed a nomogram based on LSM to predict postoperative complications in patients with HCC, thus providing a helpful reference for clinicians in decision-making regarding SR.

3) Factors associated with recurrence after SR

Despite promising postsurgical outcomes, the risk of recurrence remains high in specific patient groups. Factors associated with an increased likelihood of recurrence include advanced age, male sex, a high degree of liver dysfunction, and various tumor characteristics such as size, number, grade/differentiation, invasion, presence of satellite lesions, and AFP levels.^40,41 To mitigate the risk of suboptimal outcomes following SR, these variables should be considered alongside tumor size and number in determining the suitable HCC treatment modality.

Recent research has also determined predictive variables for early HCC recurrence after SR, such as sex, albumin-bilirubin grade, and serum AFP.⁴⁰ Additionally, underlying cirrhosis, more than one nodule and AFP >100 ng/mL have been proposed as preoperative predictors for non-transplantable recurrence after SR.⁴²

The optimal surgical margins for preventing HCC recurrence after SR were also investigated. Findings suggest that a margin >7 mm is vital for preventing early recurrence, especially in subgroups with specific characteristics such as high AFP levels, non-capsule formation, or MVI.⁴³ Further evidence indicates that wide-margin resection results in better clinical outcomes in patients with solitary HCC ≤5 cm.⁴⁴

3. RFA

RFA for the treatment of HCC has been studied in various clinical contexts with a focus on tumor size, number, and outcomes.

1) Criteria for RFA

Long-term survival rates after RFA against HCC vary depending on tumor size and number (Table 3). Specifically, patients with Child-Pugh class A and HCC ≤2 cm exhibit 65-70% 5-year survival rates, while those with HCC tumor size between 2-5 cm have a 5-year survival rate of 50%.^45-47 Comparative studies between RFA and SR have mostly found no significant differences in survival rates.^48-50 Even a meta-analysis of eight randomized controlled trials found similar 5-year survival and DFS rates between RFA and liver resection for patients within the Milan criteria.⁵¹ However, one recent Korean study found superior DFS with SR, although the OS was similar to that associated with RFA.⁵² Similarly, other non-randomized studies have found no significant differences in survival rates between liver resection and RFA for the treatment of HCC <3 cm in diameter.^53-55

2) Technical feasibility of RFA

Efficacy of RFA against HCC may depend on the anatomical location of the tumor. Ideal outcomes occur when the tumor is located distally from the liver capsule, intrahepatic vasculature, or central bile duct, which minimizes complications owing to the heat-sink effect.^56,57 Tumors in the subphrenic region may have an increased risk of local recurrence and peritoneal metastasis (up to 9.5%) post-RFA.^58,59 When the tumor is close to the large portal or hepatic veins (diameter >3 mm), RFA efficacy may be reduced due to suboptimal heat delivery, with risks of vascular or biliary injury.^58,60,61

3) MVI

MVI is recognized as a predictive factor for poor prognosis following various HCC treatment modalities, including RFA.^62,63 Analysis of MVI before treatment is vital for planning and prognostication. Although MVI is typically evaluated based on the microscopic findings of resected tumor specimens, several studies have determined predictive factors for MVI, including non-smooth tumor margins on computed tomography, arterial peritumoral enhancement, hepatobiliary peritumoral hypointensity on magnetic resonance imaging (MRI), increased levels of specific tumor markers (such as AFP and PIVKA-II), and larger tumor size.^64-67

STRATEGIES TO ADDRESS SUBOPTIMAL OUTCOMES

1. LT

LT is vital for treating HCC; however, it may be challenging to predict and prevent recurrence. Strategies developed to address these challenges are discussed in this section.

1) Incorporation of criteria with tumor biologic markers

The primary challenge of LT in HCC is the prediction and prevention of post-transplantation HCC recurrence, while ensuring that patients have adequate access to LT. Numerous studies have proposed LT criteria that incorporate not only morphometric variables but also markers reflecting tumor biology (Table 4). By considering an array of variables associated with recurrence and expanding the criteria for LT, accessibility to this procedure may be improved for patients with HCC while maintaining or possibly mitigating recurrence and survival rates.

2) Treatment migration and downstaging

For patients unable to undergo LT due to not fulfilling the Milan criteria or characterized by the expected aggressive tumor biology, alternative treatment modalities, such as locoregional therapies, may be advisable. If patients are successfully treated and downstaged within the criteria for LT, they may proceed with the procedure. Additionally, downstaging with locoregional therapy may provide an opportunity to observe the response to therapy and assess tumor biology. A randomized controlled trial investigated 45 patients who were successfully downstaged within the Milan criteria through treatment migration and subsequently underwent LT. The study revealed a 77.5% 5-year OS rate in contrast to a 31.2% rate among patients who did not undergo LT (P=0.035).⁶⁸

3) Downstaging of HCC: TACE

The objective of HCC downstaging is to meet the acceptable criteria for LT, with the chosen downstaging therapy often dependent on factors such as tumor burden, location, liver function, and center expertise.^69,70 TACE is commonly used for downstaging HCC beyond the Milan criteria due to multiple tumor burden and its field effect.⁷¹ Both conventional TACE and drug-eluting bead TACE may be employed, although multiple therapy sessions may be necessary for a successful anti-tumor response without residual or recurrent HCC. Yao et al.⁷² compared the outcomes after tumor downstaging, primarily through TACE followed by LT, in 61 patients who did not meet the Milan criteria. They found successful downstaging in 70.5% of the patients and a 4-year post-transplantation survival rate of 92.1%. A subsequent investigation in 118 patients with HCC who had undergone downstaging within the Milan criteria prior to LT revealed that the 5-year post-transplantation survival rate and the RFS rate were 77.8% and 81.0%, respectively, indicating promising outcomes for patients with HCC who underwent LT after successful downstaging.⁷³

4) Downstaging of HCC: transarterial radioembolization

Transarterial radioembolization (TARE) has been proposed as an effective locoregional therapy for HCC that enables delivery of high-dose radiation to the tumor while minimizing complications such as acute tumor ischemia and liver function deterioration, which are common with TACE. Although data regarding TARE are limited, a study of pooled analysis focusing on the role of TARE in downstaging HCC has shown that both the tumor control rate and response are high, with favorable long-term oncological outcomes after LT.⁷⁴ TARE for HCC has been endorsed and recommended by various investigators, with Kim et al. reporting higher disease control rates and better survival outcomes in patients without lymph node metastases or distant metastases, specifically with BCLC stage B or C and tumor size ≥5 cm, compared to the same parameters associated with TACE.⁷⁵ However, the role of TARE in the context of LT and downstaging is still debated due to the absence of clear and unified guidelines.

5) Downstaging of HCC: radiotherapy

Radiotherapy (RT) is a potential treatment modality for downstaging HCC when LT is not an option. Numerous studies have shown that RT is a safe and effective alternative, particularly when other locoregional therapies are unsuitable. A prospective study that compared stereotactic body RT (SBRT) with TACE and high-intensity focused ultrasound as bridge therapies to LT for HCC, revealed that SBRT was not only safe but also had a notably higher tumor control rate and low risk of waitlist dropout.^76-78 The role of RT in bridge therapy to LT for HCC with portal vein tumor thrombosis (PVTT) has also been explored. It has been suggested that LT following RT could be the treatment of choice for HCC compounded with PVTT in certain patients.^79,80 Moreover, the efficacy of neoadjuvant RT prior to LT for HCC that is not amenable to locoregional treatment has been examined. Although a complete pathological response was noted in 47.8% of patients undergoing RT, the 5-year survival rate was not significantly different from that of patients who did not undergo RT (68.7% vs. 61.7%; P=0.829).⁸¹

2. SR

1) Minimally invasive surgical approach

Eligibility for SR depends on various factors such as tumor burden, liver dysfunction, portal hypertension, and planned resection scope, while considering future liver remnants.⁸² SR has traditionally been limited to patients with underlying cirrhosis, significant portal hypertension, or inadequate future liver remnants. However, the recent emergence of minimally invasive surgical (MIS) approaches, along with advances in intraoperative and perioperative management, has increased the number of patients eligible for SR. MIS approaches, including laparoscopic and robot-assisted liver resection, are typically used for limited minor resections in anatomically favorable locations, with major liver resection generally restricted to high-volume centers. Meta-analyses of comparative studies have shown that MIS approaches resulted in reduced surgical blood loss, shorter hospital stay, and decreased 30-day morbidity, compared to the same parameters associated with open resection, while RFS and OS rates appear comparable.^83,84

2) Treatment migration: transarterial therapy

Transarterial therapy is often recommended for intermediate-stage HCC; however, favorable responses have been reported for early-stage HCC. Retrospective studies with patients within the Milan criteria who underwent SR, RFA, or TACE have found that the TACE group experienced a shorter time to tumor progression, with no significant difference in the 5-year survival rate between groups.^53,85 Thus, TACE may serve as an alternative curative option for early-stage HCC when surgical approaches or RFA are not feasible. Additionally, TARE may be an alternative with an efficacy comparable to that of TACE in a neoadjuvant setting, particularly for patients with lobar portal vein thrombosis. TARE provides benefits over TACE, such as reduced toxicity and contralateral remnant liver hypertrophy, without the need for portal vein embolization.^86-88 Thus, TARE is becoming an increasingly preferred method for downstaging patients before surgical intervention.

3) Treatment migration: RT

RT has been proposed as a downstaging tool for HCC when SR is not possible, especially in locally advanced HCC such as PVTT.^89,90 Chong et al.⁹¹ compared the disease-specific survival rate in patients receiving SR after localized concurrent chemoradiotherapy with those receiving SR only and found improved survival in the concurrent chemoradiotherapy group (62 vs. 15 months; P=0.006). Multivariate analysis further determined that the radiological response may influence survival. In addition, a randomized controlled study by Wei et al.⁹² assessed neoadjuvant RT in patients with resectable HCC and PVTT and revealed a significantly higher 2-year survival rate in the neoadjuvant RT group than in the surgery-alone group (27.4% vs. 9.4%; P<0.001), indicating enhanced postoperative outcomes with neoadjuvant RT.

4) Neoadjuvant and adjuvant therapy

Although SR increases the possibility of long-term survival in patients with HCC, the risk of postoperative recurrence remains significant, emphasizing the need for neoadjuvant or adjuvant therapies. In the treatment of various malignant tumors, the use of neoadjuvant or adjuvant therapies with the goal of downstaging the disease to enable resection or improve postoperative outcomes is common. However, the contribution of neoadjuvant and adjuvant therapies in the treatment of HCC is yet to be determined. Preoperative TACE as neoadjuvant therapy has generated conflicting results. A meta-analysis including 32 studies concluded that there was no notable difference in DFS or OS between patients who received preoperative TACE and those who did not. Nevertheless, patients who demonstrated complete response to TACE exhibited significantly improved DFS and OS. Furthermore, a prospective study including 67 patients with early-stage HCC, who were not candidates for LT or SR but underwent TACE, showed a complete anti-tumor response rate of 67.2% after a month and a 3-year survival rate of 80.5%.⁹³

The STORM study, which investigated the efficacy of sorafenib (a tyrosine kinase inhibitor) as adjuvant therapy after SR for HCC in 900 patients across 28 countries, found no difference in RFS between patients treated with postoperative sorafenib and those who did not. Sorafenib was associated with a poor safety profile (including four drug-related deaths). Although currently no randomized trials have evaluated the efficacy of lenvatinib (another first-line systemic tyrosine kinase inhibitor agent for HCC) as an adjuvant therapy in the postoperative setting, small retrospective studies have indicated improved survival outcomes in selected high-risk patient cohorts presenting with MVI.^94,95

Finally, the IMBrave050 trial was the first study where adjuvant therapy showed a tangible benefit in terms of patient outcomes. In this open-label randomized clinical trial, administration of adjuvant atezolizumab and bevacizumab for 12 months significantly improved RFS in high-risk patients.⁹⁶ Furthermore, phase I and II studies employing a combination of immune checkpoint inhibitors (including nivolumab + cabozantinib, and nivolumab ± ipilimumab), yielded major pathologic responses in 30-40% of patients. Despite these encouraging results, further exploration through phase III studies and large-scale real-world data is essential to comprehensively understand the roles of neoadjuvant and adjuvant therapies with immune checkpoint inhibitors in the management of HCC.

3. RFA

1) MVI

RFA generally yields favorable outcomes for the treatment of single tumors ≤2 cm in diameter, but for tumors within the Milan criteria, RFA has been associated with a higher recurrence rate than that associated with SR, despite significantly lower complication rates. If patients are suspected to have high-risk MVI, SR of HCC has shown superior 5-year recurrence and OS rate compared to that associated with RFA for early-stage HCC.⁹⁷ Consequently, RFA should be considered for patients more likely to have a positive treatment outcome or those who cannot undergo invasive treatments such as SR. In such cases, combination treatment with TACE may be considered.^98,99 Chen et al.¹⁰⁰ compared the post-recurrence survival and OS rates in patients with resectable HCC who underwent RFA or TACE, and found no significant difference in MVI association between the groups.

2) Overcoming technical feasibility issues

Technical feasibility of RFA can be enhanced with additional methods. When the tumor is adjacent to other organs, RFA can be performed safely and effectively using artificial ascites to create a barrier between the tumor and neighboring structures.¹⁰¹ When a tumor is not adequately visualized through conventional B-mode ultrasonography, contrastenhanced ultrasonography or navigation fusion imaging may enhance detection and response rates.^102,103 In a Korean prospective study involving 216 patients with HCCs <5 cm in diameter, 30/76 HCCs (39.5%) that were not visible on B-mode ultrasonography were successfully located using fusion imaging. Furthermore, all 60 HCCs that were unsuitable for RFA on B-mode ultrasonography were rendered feasible for RFA when fusion imaging was applied.¹⁰² Contrast-enhanced ultrasonography has also been shown to improve the detection rate of small HCCs that are difficult to be detected on Bmode ultrasonography, with higher detection rates associated with contrast-enhanced ultrasonography under fusion imaging compared to those associated with contrast-enhanced ultrasonography alone.¹⁰³ Regarding perivascular HCC, Lee et al.¹⁰⁴ demonstrated better DFS associated with microwave ablation relative to RFA, although the 2-year survival rate was not significantly different between the two. Moreover, recent advancements in RFA technology have led to the development of no-touch RFA, which involves the placement of multiple electrodes around the periphery of the tumor. This technique has been shown to result in lower local recurrence rate than that associated with conventional RFA, which directly punctures the tumor.^105,106 However, further research is required to ensure that this approach also confers a survival advantage.¹⁰⁷

3) SBRT

SBRT may be an effective alternative when RFA is not feasible. A retrospective study by Kim et al.¹⁰⁸ that compared the treatment efficacy between RFA and SBRT found that SBRT was associated with a significantly lower risk of local recurrence than that associated with RFA (HR, 0.36; P<0.001) and provided superior local control for small tumors (≤3 cm), regardless of location, and in large tumors in the subphrenic region. Another retrospective study by Shin et al.¹⁰⁹ found no significant difference between SBRT and RFA in terms of OS and local tumor control rate. Although more prospective randomized trials are required, SBRT may be the preferred treatment option when RFA is not an option. A randomized phase III trial investigating the treatment efficacy of RFA and proton beam radiotherapy (PBT) against recurrent/residual HCC demonstrated that the 2-year local progression-free survival rate was 92.8% in the PBT group and 83.2% in the RFA group, proving the non-inferiority of PBT to RFA. Furthermore, another network meta-analysis comparing the efficacy of treatment modalities such as PBT and RFA in early-stage HCC showed no significant difference between modalities, suggesting that PBT may be an alternative treatment option when RFA is not feasible.

4) Microwave ablation and cryoablation

As alternatives to RFA, application of microwave ablation (MWA) and cryoablation against early-stage HCC has been increasing. Since microwaves can readily penetrate biologic materials continuously applying high temperatures (>150℃), MWA can improve ablation efficacy by increasing thermal conduction into the surrounding tissue.¹¹⁰ Two randomized controlled studies comparing the RFS, and OS between MWA and RFA in patients with HCC (tumor number ≤3 and tumor size ≤ 4-5 cm) demonstrated no significant difference,^111,112 and meta-analyses also showed no difference between the two groups regarding OS and major complication rates.^113,114 However, microwave energy is inherently more difficult to distribute than radiofrequency energy is, limiting its application in clinical practice.¹¹⁵

Cryoablation has the merit of feasibility for treatment monitoring, because ice balls can be easily identified with ultrasound, non-enhanced CT, or MRI. A multicenter randomized controlled trial comparing cryoablation and RFA in HCC by Wang et al.¹¹⁶ exhibited no significant difference in 1-, 3-, and 5-year OS, RFS, and major complication rates. Although some studies have reported lower complication rate in cryoablation relative to RFA in HCC located near the bile duct or vascular structure, the size of the cryoablated zone is known to correlate with probe diameter.^117,118 Hence, in circumstances when a large ablation zone is required, multiple or large-diameter probes with prolonged treatment time are required.¹¹⁵

SUMMARY AND PERSPECTIVES

Although HCC generally has a poor prognosis, favorable outcomes are possible in patients with early-stage HCC via highly effective treatment modalities, such as LT, SR, and local ablation. However, achieving optimal results with these treatments presents numerous challenges. Management of HCC requires a holistic approach, considering not only the number and size of tumors, but also the underlying tumor biology, residual liver function, and various risk factors that may influence recurrence and survival outcomes. These approaches are only feasible with multidisciplinary approaches with experts in diverse fields of HCC gathering novel opinions on the most optimal treatment strategy. By developing precise criteria for each treatment modality and personalizing approaches based on liver function and tumor-related variables, therapeutic outcomes for patients with early-stage HCC may be enhanced.

Article information

Conflict of Interest

The authors have no conflicts of interest to disclose.

Ethics Statement

This review article is fully based on articles which have already been published and did not involve additional patient participants. Therefore, IRB approval is not necessary.

Funding Statement

None.

Data Availability

Not applicable.

Author Contribution

Conceptualization: JHY

Supervision: SKC

Writing–original draft: JHY

Writing–review & editing: SKC

Acknowledgments

Figure 1.

Pitfalls leading to insufficient treatment outcomes in early-stage hepatocellular carcinoma. ICG-R15, indocyanine green retention rate at 15 minutes; ALBI, albumin-bilirubin; LSM, liver stiffness measurement; AFP, alpha-fetoprotien; PIKVA-II, prothrombin induced by vitamin K absence or antagonist-II; NLR, neutrophil-to-lymphocyte ratio; CRP, C-reactive protein; MVI, microvascular invasion; PET, positron emission tomography.

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