Current Therapeutic Strategies for Hepatocellular Carcinoma in Japan

Introduction

The treatment outcomes of patients with hepatocellular carcinoma (HCC) in Japan have improved dramatically over the past 40 years and are probably the best in the world. According to the Nationwide Follow-up Survey by the Japan Liver Cancer Association (JLCA) (formerly Liver Cancer Study Group of Japan), the 5-year survival rate for the 2,323 cases registered between 1978 and 1980 is 5%, with a median overall survival (OS) of 4 months [1]. By contrast, among the 58,418 patients with all stages of HCC enrolled between 2010 and 2013, the 5-year survival rate is 58% and the median OS is 80 months (Fig. 1) [2–6]. The number of patients with HCC has increased steadily since the 1980s, and the improved survival of these patients is due to several factors, including the establishment of a nationwide surveillance system for HCC in the 1980s, the use of safe techniques for resection and transarterial chemoembolization (TACE), the development of ethanol injection therapy in the 1990s, the increased use of helical computed tomography and magnetic resonance imaging for diagnosis, the reimbursement approval of protein induced by vitamin K absence or antagonist-II (PIVKA-II) measurement (1989), the expanded use of hepatic arterial infusion chemotherapy (HAIC) in the 1995s, the development of AFP-L3 in 1996, the widespread use of radiofrequency ablation (RFA) in 2004, and the increased application of multidetector computed tomography in routine clinical practice (Fig. 1) [6]. In addition, the approval of several therapeutic agents such as the molecular-targeted agent sorafenib [7] in 2009, regorafenib in 2017 [8], lenvatinib [9] in 2018, ramucirumab in 2019 [10], and cabozantinib in 2020 [11] likely contributed to the improved survival. The combination of atezolizumab and bevacizumab (Atezo/Bev) [12] was approved in 2020 and the combination of durvalumab plus tremelimumab and durvalumab monotherapy [13] were approved in 2023 in Japan (Fig. 1). These systemic therapies may be related to the improved prognosis of patients enrolled between 2010 and 2013 (Fig. 1).

Fig. 1.

Improvement of median OS and 5 years survival rate in patients with all stages of HCC in Japan (modified from Kudo [6]).

The latest Nationwide Follow-up Survey by JLCA [5] shows that 48% of cases registered in 2016–2017 underwent resection, 19% had local ablation therapy, and 27% underwent TACE; approximately 67% of cases received curative treatments such as resection or RFA as the initial treatment. The proportion of patients undergoing resection has increased gradually since the year 2000, when resection was the initial treatment in 28–29% of patients [6]. This increase may be due to the increasing proportion of HCCs of non-viral etiology, especially nonalcoholic steatohepatitis-related HCCs, which show a lower degree of fibrosis and preserved liver function [6, 14]. Unlike viral HCCs, nonalcoholic steatohepatitis-related HCCs are large at the time of detection because patients at high risk of HCC are not identified effectively. However, many patients maintain good liver function and show a low degree of fibrosis, which makes them eligible for resection. Non-viral HCCs account for 60–70% of surgical resections. This editorial describes the current treatments for HCC in Japan.

Treatment of Early-Stage HCC (BCLC-0 and BCLC-A)

Resection or Local Ablation for Small HCC: Results of the SURF Trial

The SURF trial was a phase 3 prospective randomized controlled trial (RCT) conducted in Japan that compared the efficacy of resection versus RFA [15]. Between 2009 and 2015, 308 patients with up to three HCC nodules (≤3 cm) who were eligible for both resection and RFA were enrolled from 49 centers in Japan. Although several RCTs of similar comparative studies were published previously [16–18], the studies analyzed included a small number of patients, ranging from 100 to 230. The SURF trial was initially designed to compare recurrence-free survival (RFS) and OS between patients undergoing resection and RFA. The study was initiated with 600 cases (300 resections and 300 RFAs) to verify the superiority of resection over RFA regarding RFS and OS. The rationale for setting this number of cases was based on a study by Hasegawa et al. [19], assuming that resection outperforms RFA by 10% in 3- and 5-year survival rates, the number of cases required to statistically verify the superiority of resection with a power of 0.8 and an alpha value of 0.05 was calculated to be 600. However, case enrollment did not proceed as planned. In February 2016, the Independent Data Monitoring Committee recommended that further patient enrollment be halted because it was impractical, and the 308 enrolled patients were analyzed. The results showed no difference in RFS or OS between the two groups; RFS was 3.5 years in the resection group and 3.0 years in the ablation group (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.67–1.25; p = 0.58), and the superiority of resection over RFA was thus not demonstrated. The results were presented at the 2019 American Society of Clinical Oncology (ASCO) [20] meeting. The OS results were subsequently reported at the 2021 ASCO meeting but failed to show a significant difference, with a HR of 0.96 (95% CI, 0.64–1.43, p = 0.838) [21]. The results of the SURF non-randomized cohort study (propensity score matching of a cohort of patients who underwent RFA or resection under real-world clinical conditions) were presented at ASCO in 2022 [22]. Inverse probability of treatment weighting analysis showed that the 5-year RFS rate was 46.6% for 382 resected patients and 39.3% for 371 RFA patients (HR, 0.86; 95% CI, 0.71–1.06; p = 0.155); there was no significant difference in OS: the 5-year survival rate was 79.7% for resection and 79.3% for RFA (HR, 0.98; 95% CI, 0.75–1.30; p = 0.906) [22].

The results of the SURF trial suggest that the prognosis of patients does not differ between resection and RFA in cases in which both are feasible, namely, for nodules ≤3 cm in diameter and three or fewer nodules. Based on these results, the 2021 edition of the Japan Society of Hepatology (JSH) Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma was revised to recommend resection and ablation equally for early-stage HCC (Fig. 2) [23, 24].

Fig. 2.

Treatment algorithm for HCC established by Japan Society of Hepatology in 2021 (cited from Hasegawa et al. [23]).

Clinical Trials of Adjuvant Therapy after Curative Treatment

Four clinical trials of adjuvant therapy are ongoing (Fig. 3). Among them, positive results from the IMbrave050 trial were reported [25, 26]. We also conducted an exploratory multicenter single-arm phase 2 study (NIVOLVE trial, UMIN 000026648) of single-agent nivolumab that included 55 patients with HCC treated with liver resection or RFA. The results were presented at the 2021 ASCO meeting [27] and at the ASCO Gastrointestinal Cancers Symposium (ASCO-GI) [28, 29] in 2022. The study included patients at intermediate and high risk for recurrence and excluded those with a single tumor <2 cm in diameter (low-risk recurrence group). These criteria are the same as those of the STORM trial [30]. The results showed that the RFS was 26.3 months. In addition, analysis of genetic mutations by next-generation sequencing, immunohistochemical staining for protein related to WNT/β-catenin signaling, and analysis of tumor-infiltrating immune cells in patients who relapsed after resection indicated that the risk of recurrence was higher in: (1) patients with WNT/β-catenin mutations, (2) patients with regulatory T-cells (Tregs) infiltration, and (3) patients with low CD8-positive cell infiltration. These results suggest that immune checkpoint inhibitors alone have limited efficacy in suppressing recurrence, and improving the immune microenvironment by eliminating Tregs with anti-vascular endothelial growth factor (VEGF) antibodies or other drugs targeting VEGF is necessary to suppress recurrence. This anti-VEGF activity may explain the success of the IMbrave050 study, which combined atezolizumab with bevacizumab. If atezolizumab + bevacizumab is approved in the adjuvant setting in Japan, it will undoubtedly be used aggressively as adjuvant therapy after curative treatments (Fig. 4).

Fig. 3.

Ongoing phase 3 clinical trials for HCC.

Fig. 4.

New paradigm of treatment strategy in HCC.

Treatment of Intermediate-Stage HCC (BCLC-B Stage)

Concept of TACE Refractoriness

A drastic paradigm shift in the treatment strategy for intermediate-stage HCC, defined in the AASLD and EASL guidelines [31, 32] as multiple HCCs, is currently taking place. The treatment recommended by the AASLD and EASL guidelines was TACE alone until recently. However, the 2021 edition of the JSH Clinical Practice Guidelines for Hepatocellular Carcinoma recommends resection, systemic therapy, and HAIC in addition to TACE for multifocal HCCs with four or more tumors and large HCCs >3 cm in size (Fig. 2) [23]. The consensus-based JSH clinical practice guidelines, which were the first of its kind in the world regarding the concept of “TACE refractoriness,” were established in 2011 [33] and updated in 2014 [34]. After this, the concept of “TACE refractoriness” spread rapidly around the world [35, 36]. In Taiwan, sorafenib was initially indicated only for advanced HCC. However, after the concept of TACE refractoriness was clearly stated in the “Consensus-based Clinical Practice Guidelines for the Treatment of Liver Cancer” in Japan [33, 34], the insurance system was changed accordingly [37, 38]. Two retrospective clinical studies that applied the TACE refractoriness criteria of the JSH showed that “patients who switched to molecular-targeted therapy as soon as TACE became refractory” had better survival than “patients who continued TACE after it had become refractory” [39, 40]. The OPTIMIS study, a global non-interventional prospective trial designed to validate the results of these retrospective clinical studies, also clearly demonstrated that switching to a molecular-targeted agent at the point of TACE failure was associated with a greater survival benefit [41]. Therefore, the concept of TACE failure/refractoriness and early transition to systemic therapy at that point has become almost a global consensus.

The Concept of TACE Unsuitability

Recently, the JSH and Asia-Pacific Primary Liver Cancer Expert Association (APPLE) proposed the concept of “TACE unsuitability” [24, 42]. “TACE unsuitability” refers to the following (1): conditions that are likely to become TACE-refractory (2), conditions that are likely to deteriorate to Child-Pugh B liver function due to TACE, and (3) conditions that are inherently resistant to TACE [42]. APPLE and the JSH published a “Consensus Statement and Recommendations” on this topic [24, 42]. Among these conditions, HCCs beyond the up-to-seven criteria are prone to TACE refractoriness or transition to Child-Pugh B. In such cases, prior administration of lenvatinib can (1) induce tumor necrosis and achieve downstaging (2), suppress the release of hypoxia-inducible cytokines (e.g., VEGF) induced by TACE and inhibit invasion and metastasis, and (3) exert an anti-VEGF effect, which normalizes tumor blood vessels and enhances the effect of TACE. LEN-TACE sequential therapy improves the prognosis of patients beyond the up-to-seven criteria compared with TACE alone [43] and is gradually becoming common practice for TACE-unsuitable HCCs in Japan [44]. In China, LEN-TACE was shown to improve PFS and OS compared with TACE alone or lenvatinib alone in patients with intermediate- and advanced-stage HCC [45, 46].

SORA-TACE Sequential Therapy

The administration of molecular-targeted agents with anti-VEGF activity prior to TACE can increase the efficacy of TACE by normalizing tumor vasculature and increasing microvessel density, interstitial pressure, and vascular permeability, thereby improving drug delivery [47]. Therefore, combining TACE with systemic therapy is recommended. Six trials have assessed the combination of TACE and molecular-targeted agents, and all of them showed negative results except the TACTICS trial [48–53], in which the primary endpoint was PFS. In the TACTICS trial, the HR for PFS was 0.59 (95% CI, 0.41–0.78) [51]. The HR for PFS in the BRISK-TA and ORIENTAL trials was also significantly better (0.61 [95% CI, 0.74–0.99] than TACE alone for BRISK-TA and 0.86 [0.74–0.99] for ORIENTAL) [52, 53]. However, the primary endpoint of the ORIENTAL and BRISK-TA trials was OS, and the trials failed [52, 53]. The HRs of the BRISK-TA and ORIENTAL trials, in which OS was the primary endpoint, and those of the SPACE, TACE-2, and post-TACE trials, in which PFS was the primary endpoint, did not show a significant prognostic benefit in TACE plus sorafenib compared with TACE alone.

The TACTICS trial showed that combination treatment significantly improved PFS, which was the primary endpoint, and there were high expectations regarding OS benefit, which was the co-primary endpoint. However, the final data showed that the OS in the TACE plus sorafenib group was 36.2 months (95% CI, 30.5–44.1), whereas that for TACE alone was 30.8 months (95% CI, 23.5–40.8) (HR = 0.86; 95% CI, 0.61–1.22; p = 0.40) [54]. The negative OS results of the TACTICS trial were attributed to the following factors: (1) there were 156 patients in the phase 2 trial, which was thus underpowered to meet the OS requirement and (2) post-progression survival was highly extended (17.3 months) because 76.3% of the patients in the TACE alone group received post-trial treatment (including 50% treated with sorafenib). However, the longest OS (36.2 months) in the six clinical trials and the prolongation of OS by 5.4 months in the TACE plus sorafenib arm compared with the TACE alone arm suggest that TACE plus molecular-targeted agents is an effective strategy [55]. In addition, the results of the TACTICS trial suggest that OS cannot be used as the primary endpoint in combination trials of TACE and systemic therapy in an era in which effective post-trial therapies are available [54, 55]. Actually, primary endpoint of all of currently ongoing TACE combination trial is PFS (Fig. 4).

The correlation coefficient (r) between OS HR and PFS HR in the six TACE combination trials is 0.56 [54], indicating that although there is some correlation between PFS HR and OS HR, it is weaker than that in advanced HCC [56, 57]. In other words, this result is not consistent with the strong correlation coefficient of r = 0.84 in the PFS HR versus OS HR plot for first-line and second-line therapy for advanced HCC reported by Llovet et al. [56, 57]. This weak correlation may be attributed to the fact that PFS has a weaker impact on OS since post-progression survival has stronger impact on OS in case of intermediate-stage HCC [58]. According to the AASLD guidelines, the primary endpoints in clinical trials of TACE combined with systemic therapy can be PFS [56] or objective response rate (ORR) [59]. Subanalysis in the REFLECT trial showed that OR is a predictive marker of OS in individual patients [60].

The TACTICS trial also showed that (1) PFS and OS prolongation is superior in patients with HCC beyond the up-to-seven criteria than in patients within the up-to-seven criteria; (2) clinically meaningful PFS and OS prolongation occurs even in patients with HCC within the up-to-seven criteria; and (3) time to vascular invasion/extrahepatic spread is prolonged by combining TACE with sorafenib [51, 54, 55]. Therefore, the combination of systemic therapy and TACE is recommended in patients who are not suitable for TACE [61, 62].

LEN-TACE Sequential Therapy

Upfront administration of lenvatinib followed by TACE may be more effective than TACE alone in patients who are initially unsuitable for TACE, such as patients with bilobar multifocal disease [63]. In 2019, a proof-of-concept study showed that patients with HCC beyond the up-to-seven criteria respond better when treated with upfront lenvatinib followed by selective TACE [43]. The OS of the LEN-TACE group was 37.9 months versus 21.3 months in the TACE alone group (HR, 0.48; 95% CI, 0.16–0.79; p < 0.01), suggesting the good efficacy of LEN-TACE. Lenvatinib, which has a high response rate, should be administered as the first-line treatment for intermediate-stage HCC patients with HCC exceeding the up-to-seven criteria. The response rate of lenvatinib was 40.6% in the REFLECT trial and 61.3% in the Japanese subpopulation with intermediate-stage HCC [64]. The reason for the high response rate of 73.3% in a proof-of-concept study could be that many TACE naïve patients have ALBI grade 1 liver function and therefore have fewer adverse events and a lower rate of dose reduction, interruption, and discontinuation, which allows the administration of high doses of lenvatinib [65]. The high response rate in the proof-of-concept study results from many patients receiving a full dose of lenvatinib. The high response rate may be attributed to the following factors: (1) lenvatinib induces tumor shrinkage and necrosis; (2) selective TACE can be curative when additional TACE is performed after lenvatinib, thus preserving liver function; (3) upfront lenvatinib therapy suppresses hypoxia-inducible cytokines such as VEGF, thereby inhibiting recurrent metastasis, and (4) normalization of tumor vasculature with lenvatinib reduces vascular permeability and intra-tumoral interstitial pressure; this facilitates the spread of lipiodol containing anticancer drugs throughout the tumor, thereby enhancing the embolic effect, which may lead to pathological complete response. Therefore, LEN-TACE sequential therapy is a theoretically effective treatment for intermediate-stage HCC exceeding the up-to-seven criteria and is currently the standard of care for intermediate-stage HCC with a high tumor burden in Japan [66]. The treatment strategies for HCC are changing dramatically, and the administration of lenvatinib prior to TACE has little disadvantages, at least in patients with a high tumor burden.

TACTICS-L, a prospective, multicenter, single-arm phase 2 trial showed similar results [67]. The TACTICS-L and TACTICS trials gradually led to the worldwide acceptance of the concept that “high tumor burden should be treated with systemic therapy first, followed by TACE” rather than TACE alone [51, 61]. This concept is reflected in various global guidelines such as AASLD [56, 68], ESMO [69], and BCLC [70].

ABC Conversion Therapy

Atezo/Bev is a new regimen approved in 2020 based on the success of the IMbrave150 trial [12]. A high ORR of 44% in intermediate-stage HCC patients according to RECIST 1.1 was recently published [71, 72].

Of 110 patients with Child-Pugh grade A liver function included in a multicenter study of the Atezo/Bev combination in the first-line setting, 38 (35%) achieved clinical CR. These patients all achieved cancer-free status, which is defined as CR per mRECIST and the normalization of three tumor markers including AFP, PIVKA-II, and AFP-L3. In addition, 25 (23%) patients achieved drug-free status [73]. Seven cases achieved CR with resection, 13 with ablation, and 15 with curative TACE [73]. Three cases achieved cancer-free status with Atezo/Bev alone. As a result, the curative conversion rate was extremely high at 35% [73]. Unlike molecular-targeted drugs, Atezo/Bev has a strong tumor-shrinkage effect even in PET-positive HCCs with extremely high malignancy features, including poorly differentiated types. The results of this study indicate that pathological CR can be achieved and patients can achieve drug-free status (ABC conversion therapy) [74, 75].

In general, if a positive response to systemic therapy is obtained, it is common practice in oncology to continue the drug. Although this applies to advanced HCC, in intermediate-stage HCC or locally advanced HCC without vascular invasion or extrahepatic spread, once tumor shrinkage is achieved, ablation, or curative TACE, as well as resection, are highly effective measures to achieve pathological CR. Therefore, continuing systemic therapy without performing curative conversion is not recommended. If tumor shrinkage is achieved with Atezo/Bev combination therapy, curative conversion should be considered while systemic therapy is effective to ensure the optimal timing for achieving clinical CR. Therefore, it is crucial to consider whether curative conversion is possible [62, 73–75]. Because OS is prolonged in patients who achieve curative conversion, the treatment strategy for intermediate-stage HCC should be different from the conventional sequential systemic therapy for advanced HCC [76].

The 44% response rate to Atezo/Bev treatment in intermediate-stage HCC [71, 72] indicates that one out of every 2 patients may undergo curative conversion. Therefore, the use of Atezo/Bev in intermediate-stage HCC results in high response rates. If a deep response is achieved, curative treatment should be initiated immediately instead of continuing the drug until progressive disease because, as with lenvatinib, achieving pathological CR with Atezo/Bev alone is not possible. Even when CR according to mRECIST is achieved, viable cancer cells (drug therapy resistant clone) may remain in the resected specimen, and, therefore, curative conversion should be performed whenever possible [62]. Even in cases of SD, slow progressive disease, or at the time of discontinuation due to adverse events, TACE may be effective during Atezo/Bev therapy to decrease tumor volume and release tumor antigens, which enhances cancer immunity cycle, resulting in clinical CR (ABC-TACE sandwich therapy) (Fig. 5) [73–75, 77].

Fig. 5.

Atezolizumab-bevacizumab followed by curative (ABC) conversion: Relationship between response to Atezo/Bev and achievement of clinical complete response (CR) (modified from Kudo [73]).

Ongoing Clinical Trials

Several clinical trials of TACE combined with immunotherapy are ongoing and the results are eagerly awaited. If positive results are obtained in at least one of these trials, the treatment strategies described above may become the standard of care (Fig. 3) [61].

Treatment of Advanced-Stage HCC (BCLC-C Stage)

First-Line Therapy for Advanced HCC

Atezo/Bev combination treatment was tested in a phase 3 trial with sorafenib as the control [12]. The results of the first interim analysis demonstrated the overwhelming statistical superiority of the Atezo/Bev combination over sorafenib regarding PFS and OS. These results marked a significant turning point in the history of sorafenib, which had been the standard first-line treatment for 11 years since 2009 in Japan. OS in the Atezo/Bev arm was not reached, whereas OS in the sorafenib group was 13.2 months (95% CI, 10.4–NE) (HR, 0.58; 95% CI, 0.42–0.79; p < 0.001). PFS was 6.8 months (95% CI, 5.7–8.3) in the Atezo/Bev group compared with 4.3 months (95% CI, 4.0–5.6) in the sorafenib group (HR, 0.59; 95% CI, 0.47–0.76; p < 0.001). Adverse events were generally lower in the Atezo/Bev group than in the sorafenib group, and the time to deterioration of quality of life according to patient-reported outcomes was 11.2 months in the Atezo/Bev group versus 3.6 months in the sorafenib group (HR, 0.63; 95% CI, 0.46–0.85). The Atezo/Bev combination treatment did not affect liver function and the ALBI score was maintained [78]. This result confirms the efficacy of the Atezo/Bev combination as the first-line treatment unless there is a contraindication to immunotherapy, such as in autoimmune diseases [24, 56, 69, 70, 79].

Updated OS data of 19.2 months were published for an extended follow-up period from 8.6 months at the interim analysis to 15.6 months (HR, 0.66; 95% CI, 0.52–0.85; p = 0.0009). The updated PFS in the Atezo/Bev group was 6.9 months (95% CI, 5.7–8.6) (HR, 0.65; 95% CI, 0.53–0.81; p = 0.0001) compared with 4.3 months (95% CI, 4.0–5.6) in the sorafenib group [71]. The updated ORR in the Atezo/Bev arm was 30% (95% CI, 25–35) in the updated analysis. The ORR in the sorafenib group was 11% (95% CI, 7–17), which was almost unchanged from the ORR in the interim analysis. The duration of response in the Atezo/Bev group was 18.1 months compared with 14.9 months in the sorafenib group [71].

These results indicate that Atezo/Bev is the first-line regimen for advanced HCC as indicated by the JSH clinical practice guidelines for the treatment of HCC, the AASLD, and the ESMO and ASCO guidelines. Regarding second-line agents, there is insufficient evidence to support the use of the previous five drugs (lenvatinib, sorafenib, regorafenib, ramucirumab, and cabozantinib) as post-treatment for Atezo/Bev, although all are candidates.

The phase 3 HIMALAYA trial showed the superiority of tremelimumab plus durvalumab (STRIDE regimen) [80, 81] over sorafenib, and this regimen and durvalumab monotherapy were approved as first-line treatment in Japan in 2023. The STRIDE regimen is inferior to atezolizumab plus bevacizumab in terms of efficacy and safety according to phase 3 data and the recently published 3 network meta-analysis [82–84]. Therefore, STRIDE regimen is indicated for patients who are unsuitable for bevacizumab [85–88] (Fig. 6), and actually in the clinical practice in Japan, 70% of 1st-line agents currently used is Atezo/Bev followed by lenvatinib (15%), STRIDE (10%), and durvalumab monotherapy (5%) (Fig. 6) although the JSH systemic therapy algorithm suggests that the two regimens are equally recommended because there is no direct comparison between the 2 regimens (Fig. 7) [23]. Durvalumab monotherapy may be indicated for patients with Child-Pugh score 7 or 8 liver function since ICI monotherapy showed good efficacy and safety in patients with Child-Pugh score 7 and 8 liver function similar to those with Child-Pugh A liver function in the CheckMate 040 [89] study and in the meta-analysis [90].

Fig. 6.

1st-line systemic treatment algorithm currently conducted in practice in Japan for advanced-stage HCC.

Fig. 7.

Systemic treatment algorithm for unresectable HCC established by Japan Society of Hepatology (cited from Hasegawa et al. [23]).

Combination Treatment with TACE and Systemic Therapy in Advanced HCC

The results of the LAUNCH trial of LEN-TACE versus LEN for advanced HCC showed that LEN-TACE is superior to LEN regarding OS and PFS [46] (OS HR, 0.45; PFS HR, 0.43). This result is reasonable because intrahepatic lesions often determine the prognosis of patients with advanced HCC. The control of intrahepatic lesions by LEN-TACE significantly prolongs survival compared with LEN alone. The IMPACT trial (iRCTs051230037), a phase 3 trial of Atezo/Bev plus TACE versus Atezo/Bev alone, is currently ongoing in Japan (Fig. 3).

Hepatic Arterial Infusion Chemotherapy

HAIC was developed in Japan and is now actively used predominantly in Asian countries and rarely outside Asia. In Japan, several regimens are used including low-dose 5-fluorouracil (5-FU) plus cisplatin (CDDP) (FP) [91], New FP, or one-shot infusion of CDDP [92]. The role of HAIC in the treatment of HCC was evaluated in a subanalysis of the SILIUS trial [93, 94]. The efficacy of HAIC compared with sorafenib was demonstrated using propensity score matching by Ueshima, Ogasawara et al. [91], and in prospective RCT by He et al. [95]. Systemic therapy and HAIC have different indications in the following settings: (1) HAIC is mainly indicated for HCC with major vascular invasion, including Vp3 or Vp4; (2) systemic therapies such as Atezo/Bev, Durva/Treme, or LEN are recommended only for Child-Pugh A patients with multiple nodules in both lobes; and (3) durvalumab monotherapy or HAIC are both options for HCCs with Child-Pugh B liver function in Japan (Fig. 2, 6) [89, 91].

Radiation, Proton Beam, and Heavy Particle Beam Therapy

Stereotactic body radiation therapy is used for the treatment of HCC, especially in cases of portal vein tumor invasion. In April 2022, proton beam and heavy particle beam therapies were approved by insurance coverage for the treatment of HCCs with a diameter of ≥4 cm and are expected to be actively used for curative purposes in the future.

Current Status of Treatment for Terminal Stage HCC (BCLC-D)

Child-Pugh C HCC is considered a terminal stage, and the JSH clinical practice guidelines (Fig. 2) recommend transplantation if the tumor burden is small or best supportive care if the tumor burden is large. For liver transplantation, the 5-5-500 criteria, which is defined as tumor status up to 5 nodules with a maximum diameter of 5 cm and AFP value of 500 ng/mL or less were approved by insurance coverage in April 2020 [96, 97] in addition to the Milan criteria [98] and included in the 2021 edition of the JSH Clinical Practice Guidelines for HCC (Fig. 2) [23]. This revision was made because both living and brain-death donor liver transplants are currently covered by insurance in cases of tumor burden within the Milan and the 5-5-500 criteria.

Conclusion

This editorial summarizes the most updated clinical practice being conducted in Japan in the treatment of HCC with emphasis on the latest advances. Many clinical trials evaluating the treatment of HCC at different stages are ongoing (Fig. 3); the results of these trials will undoubtedly change the treatment paradigm for HCC and contribute to improving the prognosis in all stages of HCC patients.

Conflict of Interest Statement

Lecture: Eli Lilly, Bayer, Eisai, Chugai, Takeda, AstraZeneca; Grants: Taiho, Otsuka, EA Pharma, AbbVie, Eisai, Chugai, GE Healthcare; Advisory consulting: Chugai, Roche, AstraZeneca, Eisai. Masatoshi Kudo is the Editor-in-Chief of Liver Cancer.

Funding Sources

There is no funding for this Editorial.

Author Contributions

Masatoshi Kudo conceived, wrote, and approved the final manuscript.

Funding Statement

There is no funding for this Editorial.