Treatment for hepatocellular carcinoma in Japan over the last three decades: Our experience and published work review

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer‐related mortality worldwide. In the last few decades, there has been a marked increase in therapeutic options for HCC and epidemiological characteristics at HCC diagnosis have also significantly changed. With these changes and advances in medical technology and surveillance program for detecting earlier stage HCC, survival in patients with HCC has significantly improved. Especially, patients with liver cirrhosis are at high risk of HCC development, and regular surveillance could enable early detection of HCC and curative therapy, with potentially improved clinical outcome. However, unfortunately, only 20% of HCC patients are amenable to curative therapy (liver transplantation, surgical resection or ablative therapies). Locoregional therapies such as radiofrequency ablation, percutaneous ethanol injection, microwave coagulation therapy and transcatheter arterial chemoembolization play a key role in the management of unresectable HCC. Currently, molecular‐targeted agents such as sorafenib have emerged as a promising therapy for advanced HCC. The choice of the treatment modality depends on the size of the tumor, tumor location, anatomical considerations, number of tumors present and liver function. Furthermore, new promising therapies such as gene therapy and immunotherapy for HCC have emerged. Approaches to the HCC diagnosis and adequate management for patients with HCC are improving survival. Herein, we review changes of epidemiological characteristics, prognosis and therapies for HCC and refer to current knowledge for this malignancy based on our experience of approximately 4000 HCC cases over the last three decades.     

Re‐evaluating transarterial chemoembolization for the treatment of Hepatocellular Carcinoma: Consensus recommendations and review by an International Expert Panel

Patients with unresectable hepatocellular carcinoma (HCC) usually receive transarterial chemoembolization (TACE) or systemic therapies with intermediate and advanced‐stage disease. However, intermediate‐stage HCC patients often have unsatisfactory clinical outcomes with repeated TACE and there is considerable uncertainty surrounding the criteria for repeating or stopping TACE treatment. In July 2012, an Expert Panel Opinion on Interventions in Hepatocellular Carcinoma (EPOIHCC) was re‐convened in Shanghai in an attempt to provide a consensus on the practice of TACE, particularly in regard to evaluating TACE ‘failure’. To that end, current clinical practice throughout Asia was reviewed in detail including safety and efficacy data on TACE alone as well as in combination with targeted systemic therapies for intermediate HCC. This review summarizes the evidence discussed at the meeting and provides expert recommendations regarding the use of TACE for unresectable intermediate‐stage HCC. A key consensus of the Expert Panel was that the current definitions of TACE failure are not useful in differentiating between situations where TACE is no longer effective in controlling disease locally vs. systemically. By redefining these concepts, it may be possible to provide a clearer indication of when TACE should be repeated and more importantly, when TACE should be discontinued.     

Targeted and immune therapies for hepatocellular carcinoma:Predictions for 2019 and beyond

Systemic therapy for hepatocellular carcinoma(HCC) has markedly advanced since the survival benefit of a molecular targeted agent, sorafenib, were demonstrated in the SHARP and Asia Pacific trials in 2007. Treatment options for patients with advanced HCC increased by sorafenib, and long-term survival for patients with advanced stage HCC has become possible to some extent. However,development of a more potent first-line novel molecular targeted agent replacing sorafenib and a potent second-line agent after disease progression on or intolerant to sorafenib has been warranted because sorafenib lacks tumor shrinking/necrotizing effects and induces relatively severe adverse events such as hand foot skin reaction. Many agents in the 1 st line and 2 nd line setting were attempted to develop between 2007 and 2016, but all of these clinical trials failed.On the other hand, clinical trials of 4 agents(regorafenib, lenvatinib,cabozantinib, and ramucirumab) succeeded in succession in 2017 and 2018, and their use in clinical practice is possible(regorafenib and lenvatinib) or underway(cabozantinib and ramucirumab). Furthermore, all of 5 clinical trials of combination therapy with transcatheter chemoembolization(TACE) plus a molecular targeted agent failed to date, however, the combination of TACE and sorafenib(TACTICS trials) was reported to be successful and presented at ASCO in 2018. Phase 3 clinical trials of immune checkpoint inhibitors and a combination therapy of immune checkpoint inhibitors and molecular targeted agents are also ongoing, which suggests treatment paradigm of HCC in all stages from early,intermediate and advanced stage, is expected to be changed drastically in the very near future.     

Recent advances in multidisciplinary management of hepatocellular carcinoma

The incidence of hepatocellular carcinoma(HCC) is increasing, and it is currently the second leading cause of cancer-related death worldwide. Potentially curative treatment options for HCC include resection, transplantation, and percutaneous ablation, whereas palliative treatments include trans-arterial chemoembolization(TACE), radioembolization, and systemic treatments. Due to the diversity of available treatment options and patients’ presentations, a multidisciplinaryteam should decide clinical management of HCC, according to tumor characteristics and stage of liver disease. Potentially curative treatments are suitable for very-early- and early-stage HCC. However, the vast majority of HCC patients are diagnosed in later stages, where the tumor characteristics or progress of liver disease prevent curative interventions. For patients with intermediate-stage HCC, TACE and radioembolization improve survival and are being evaluated in addition to potentially curative therapies or with systemic targeted therapy. There is currently no effective systemic chemotherapy, immunologic, or hormonal therapy for HCC, and sorafenib is the only approved moleculartargeted treatment for advanced HCC. Other targeted agents are under investigation; trials comparing new agents in combination with sorafenib are ongoing. Combinations of systemic targeted therapies with local treatments are being evaluated for further improvements in HCC patient outcomes. This article provides an updated and comprehensive overview of the current standards and trends in the treatment of HCC.     

Consensus recommendations and review by an International Expert Panel on Interventions in Hepatocellular Carcinoma (EPOIHCC)

Hepatocellular carcinoma (HCC) presents with a high burden of disease in East Asian countries. Intermediate‐stage HCC as defined by the Barcelona Clinic Liver Cancer (BCLC) staging system poses a clinical challenge as it includes a heterogeneous population of patients that can vary widely in terms of tumour burden, liver function and disease aetiology. Intermediate HCC patients often have unsatisfactory clinical outcomes with repeated transarterial chemoembolization (TACE, due to non‐response of the target tumour or the development of further metastasis indicating progressive disease. In September 2011, an Expert Panel Opinion on Interventions in Hepatocellular Carcinoma (EPOIHCC) was convened in HK in an attempt to provide a consensus on the practice of TACE. To that end, current clinical practice throughout Asia was reviewed in detail including safety and efficacy data on TACE alone as well as in combination with targeted systemic therapies. This review summarises the evidence discussed at the meeting and provides expert recommendation regarding the available therapeutic options for unresectable intermediate stage HCC. A key consensus of the Expert Panel was that in order to improve patient outcomes and long‐term survival, the possibility of using TACE in combination with targeted agents given systemically should be explored. While the currently available clinical data is promising, the expected completion of several pivotal phase II and III RCTs will provide further evidence in support of the rationale for combination therapy regimens.     

Transarterial chemoembolization in hepatocellular carcinoma treatment: Barcelona clinic liver cancer staging system

Hepatocellular carcinoma(HCC),the fifth most common cancer that predominantly occurs in liver cirrhosis patients,requires staging systems to design treatments. The barcelona clinic liver cancer staging system(BCLC) is the most commonly used HCC management guideline. For BCLC stage B(intermediate HCC),transarterial chemoembolization(TACE) is the standard treatment. Many studies support the use of TACE in early and advanced HCC patients. For BCLC stage 0(very early HCC),TACE could be an alternative for patients unsuitable for radiofrequency ablation(RFA) or hepatic resection. In patients with BCLC stage A,TACE plus RFA provides better local tumor control than RFA alone. TACE can serve as bridge therapy for patients awaiting liver transplantation. For patients with BCLC B,TACE provides survival benefits compared with supportive care options. However,because of the substantial heterogeneity in the patient population with this stage,a better patient stratification system is needed to select the best candidates for TACE. Sorafenib represents the first line treatment in patients with BCLC C stage HCC. Sorafenib plus TACE has shown a demonstrable effect in delaying tumor progression. Additionally,TACE plus radiotherapy has yielded better survival in patients with HCC and portal venous thrombosis. Considering these observations together,TACE clearly has a critical role in the treatment of HCC as a stand-alone or combination therapy in each stage of HCC. Diverse treatment modalities should be used for patients with HCC and a better patient stratification system should be developed to select the best candidates for TACE.     

Interventional treatment for unresectable hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the sixth most common cancer and third leading cause of cancer-related death in the world. The Barcelona clinic liver cancer classification is the current standard classification system for the clinical management of patients with HCC and suggests that patients with intermediate-stage HCC benefit from transcatheter arterial chemoembolization(TACE). Interventional treatments such as TACE, balloon-occluded TACE, drug-eluting bead embolization, radioembolization, and combined therapies including TACE and radiofrequency ablation, continue to evolve, resulting in improved patient prognosis. However, patients with advanced-stage HCC typically receive only chemotherapy with sorafenib, a multi-kinase inhibitor, or palliative and conservative therapy. Most patients receive palliative or conservative therapy only, and approximately 50% of patients with HCC are candidatesfor systemic therapy. However, these patients require therapy that is more effective than sorafenib or conservative treatment. Several researchers try to perform more effective therapies, such as combined therapies(TACE with radiotherapy and sorafenib with TACE), modified TACE for HCC with arterioportal or arteriohepatic vein shunts, TACE based on hepatic hemodynamics, and isolated hepatic perfusion. This review summarizes the published data and data on important ongoing studies concerning interventional treatments for unresectable HCC and discusses the technical improvements in these interventions, particularly for advanced-stage HCC.     

Management of hepatocellular carcinoma with transarterial chemoembolization in the era of systemic targeted therapy

The clinical management of hepatocellular carcinoma (HCC) is often complicated by poor liver function. Treatment options for intermediate- and advanced-stage disease are limited. Transcatheter arterial chemoembolization (TACE) is an effective first-line therapy for intermediate-stage HCC. By interrupting blood flow to the tumor and administering concentrated chemotherapy locoregionally, TACE induces necrosis at the tumor site, but may create conditions that permit or encourage angiogenesis and recurrence of the tumor. Combination of TACE with new targeted agents may be an effective way to treat intermediate-stage HCC, particularly in higher risk patients. Because of the efficacy and safety of sorafenib-the first systemic therapy to show significant clinical benefit in advanced HCC-there is great interest in its potential use in combination with existing treatment modalities. The synergistic combination of TACE plus sorafenib represents a promising opportunity for tumor control.     

Efficacy of platinum analogue for advanced hepatocellular carcinoma unresponsive to transcatheter arterial chemoembolization with epirubicin

Aim:  Hepatocellular carcinoma (HCC) often shows resistance to transcatheter arterial chemoembolization (TACE). Such patients often have a poor prognosis and are unresponsive to other forms of therapy. The aim of this retrospective study was to determine the response to TACE using platinum analogues in patients deemed resistant to TACE using epirubicin.
Methods:  We studied 152 consecutive patients with advanced HCC resistant to TACE using epirubicin. All cases were treated with platinum analogue using transcatheter arterial chemotherapy with or without embolization.
Results:  Computed tomography at 3 months after therapy showed complete response (CR) in 6 patients (4.0%), partial response (PR) in 28 (18%), stable disease (SD) in 35 (23%), and progressive disease (PD) in 83 (55%). The cumulative survival rates for PR/CR patients who received platinum analogue-transcatheter arterial chemotherapy with or without embolization (81.8% at first year, 53.9% at second year, and 33.1% at third year) were significantly higher than those of SD/PD patients (36.6%, 17.5% and 7.4%, respectively) ( P  < 0.001). The 50% survival period was extended almost 1.4 year in PR/CR patients who received platinum analogue-transcatheter arterial chemotherapy with or without embolization.
Conclusion:  Our retrospective study is the first to report the efficacy of platinum analogues for advanced HCC unresponsive to TACE using epirubicin.     

Treatment strategies for hepatocellular carcinoma in Japan

The main methods of treatment for hepatocellular carcinoma (HCC) in Japan are hepatic resection, radiofrequency ablation (RFA) and transcatheter arterial chemoembolization (TACE). Meticulous follow up is then undertaken to check for recurrence, which is treated using repeated RFA or TACE. Hepatic arterial infusion chemotherapy has been introduced as treatment for advanced HCC, and the molecular‐targeted drug sorafenib is also now available. Rigorous medical care using these treatment methods and early diagnosis mean that the prognosis for HCC in Japan is the best in the world. This paper reviews the treatment strategies for HCC in Japan.     

Subsequent Treatment after Transarterial Chemoembolization Failure/Refractoriness: A Review Based on Published Evidence

Transarterial chemoembolization (TACE) is widely applied for the treatment of hepatocellular carcinoma. Repeat TACE is often required in clinical practice because a satisfactory tumor response may not be achieved with a single session. However, repeated TACE procedures can impair liver function and increase treatment-related adverse events, all of which prompted the introduction of the concept of “TACE failure/refractoriness”. Mainly based on evidence from two retrospective studies conducted in Japan, sorafenib is recommended as the first choice for subsequent treatment after TACE failure/refractoriness. Several studies have investigated the outcomes of other subsequent treatments, including locoregional, other molecular targeted, anti-programmed death-1/anti-programed death ligand-1 therapies, and combination therapies after TACE failure/refractoriness. In this review, we summarize the up-to-date information about the outcomes of several subsequent treatment modalities after TACE failure/refractoriness.     

Balloon-occluded transcatheter arterial chemoembolization for hepatocellular carcinoma

Transcatheter arterial chemoembolization(TACE) is widely accepted as a treatment for patients with hepatocellular carcinoma(HCC) in the intermediate stage according to the Barcelona Clinic Liver Cancer(BCLC) guidelines. Recently, balloon-occluded TACE(B-TACE) was developed in Japan. Despite the lack of a clear definition, B-TACE is generally defined as the infusion of emulsion of chemotherapeutic agents with lipiodol followed by gelatin particles under the occlusion of feeding arteries by a microballoon catheter, which leads to the dense lipiodol emulsion(LE) accumulation in HCC nodules. This phenomenon cannot be explained only by the prevention of proximal migration and leakage of embolization materials; it further involves causing local changes in the hemodynamics of the surrounding occlusion artery and targeted HCC nodules. Balloon-occluded arterial stump pressure plays an important role in the dense LE accumulation in targeted HCC nodules. Although randomized controlled trials comparing the therapeutic effect and the prognosis of B-TACE to those of the other TACE procedures, such as conventional-TACE and drug-eluting beads TACE, are still lacking, B-TACE is thought to be a promising treatment. The purpose of this review is to summarize the mechanism, therapeutic effect, indication, prognosis and complications of BTACE.     

Hemobilia immediately after transcatheter arterial chemoembolization using drug‐eluting beads for hepatocellular carcinoma with intrahepatic bile duct invasion

Transcatheter arterial chemoembolization (TACE) is used as a palliative treatment for unresectable hepatocellular carcinoma (HCC) worldwide. Recently, a novel drug delivery–embolic agent, the drug‐eluting bead (DEB), was introduced for TACE. There are a few reports of tumor hemorrhage after TACE using DEB (DEB‐TACE) for HCC. However, there have not been any reports of hemobilia immediately after DEB‐TACE for HCC with intrahepatic bile duct invasion. Here, the first such case is reported. A 71‐year‐old woman was admitted to our hospital to undergo DEB‐TACE for multiple HCCs with worsening left intrahepatic bile duct dilatation. She was diagnosed with HCC that extensively invaded the left hepatic duct. After DEB‐TACE through the left hepatic artery, a hepatic arteriogram showed extra flow of the contrast agent to the left hepatic and common bile ducts. Therefore, transcatheter arterial embolization (TAE) of the responsible vessel was carried out using coils, and no extra flow of the contrast agent was identified. The patient was discharged 14 days after TAE without deterioration of liver function. Although hemobilia immediately after DEB‐TACE is rare, there may be increased potential for hemobilia when DEB‐TACE is carried out for HCC with extensive bile duct invasion. We suggest that DEB‐TACE may be contraindicated for such cases.     

Spontaneous Regression of a Large Hepatocellular Carcinoma with Multiple Lung Metastases

A 75-year-old Japanese man with chronic hepatitis C was found to have a large liver tumor and multiple nodules in the bilateral lungs. We diagnosed the tumor as hepatocellular carcinoma (HCC) with multiple lung metastases based on imaging studies and high titers of HCC tumor markers. Remarkably, without any anticancer treatment or medication, including herbal preparations, the liver tumor decreased in size, and the tumor makers diminished. Moreover, after 1 year, the multiple nodules in the bilateral lungs had disappeared. Fifteen months after the first medical examination, transcatheter arterial chemoembolization (TACE) was performed for the residual HCC. Because local relapse was observed on follow-up computed tomography, a second TACE was performed 13 months after the first one. At 4 years after the second TACE (7 years after the initial medical examination), there was no recurrence of primary or metastatic lesions. Spontaneous regression of HCC is very rare, and its mechanism remains unclear. Understanding the underlying mechanism of this rare phenomenon may offer some hope of finding new therapies, even in advanced metastatic cases.     

肝细胞癌的分子靶向治疗

分子靶向治疗是近10年来肿瘤治疗领域的重大突破,在肺癌、恶性胃肠间质细胞瘤、恶性淋巴瘤、肠癌、乳腺癌等肿瘤的治疗中已获得很大的成功,尤其HCC的分子靶向治疗在小分子靶向治疗上取得了令人瞩目的新进展,特别是多靶点药物索拉非尼在HCC的靶向治疗中取得的成功,使HCC分子靶向全身治疗有了新的标准。     

Novel approaches for molecular targeted therapy against hepatocellular carcinoma

Systemic chemotherapy using a multitargeted tyrosine kinase inhibitor is an established treatment for advanced‐stage tumors in various organs. Comprehensive genomic analyses using next‐generation sequencing technology revealed the intra‐ and intertumor heterogeneity of human hepatocellular carcinomas (HCCs), and provided evidence for the use of therapeutic agents effective against multiple targets in tumor cells. Recently, the efficacy and safety of a multitargeted tyrosine kinase inhibitor, lenvatinib, was confirmed by a randomized global phase III trial; thus, lenvatinib was approved as first‐line therapy for HCC, providing a new therapeutic option for patients at an advanced stage. In this article, we introduce the application of molecular targeted therapy using lenvatinib and discuss future aspects of therapeutic options for advanced HCC.     

High rate of complete histopathological response in hepatocellular carcinoma patients after combined transarterial chemoembolization and stereotactic body radiation therapy

BACKGROUNDLiver transplantation (LT) presents a curative treatment option in patients with early stage hepatocellular carcinoma (HCC) who are not eligible for resection or ablation therapy. Due to a risk of up 30% for waitlist drop-out upon tumor progression, bridging therapies are used to halt tumor growth. Transarterial chemoembolization (TACE) and less commonly stereotactic body radiation therapy (SBRT) or a combination of TACE and SBRT, are used as bridging therapies in LT. However, it remains unclear if one of those treatment options is superior. The analysis of explant livers after transplantation provides the unique opportunity to investigate treatment response by histopathology.AIMTo analyze histopathological response to a combination of TACE and SBRT in HCC in comparison to TACE or SBRT alone. METHODSIn this multicenter retrospective study, 27 patients who received liver transplantation for HCC were analyzed. Patients received either TACE or SBRT alone, or a combination of TACE and SBRT as bridging therapy to liver transplantation. Liver explants of all patients who received at least one TACE and/or SBRT were analyzed for the presence of residual vital tumor tissue by histopathology to assess differences in treatment response to bridging therapies. Statistical analysis was performed using Fisher-Freeman-Halton exact test, Kruskal-Wallis and Mann-Whitney-U tests.RESULTSFourteen patients received TACE only, four patients SBRT only, and nine patients a combination therapy of TACE and SBRT. There were no significant differences between groups regarding age, sex, etiology of underlying liver disease or number and size of tumor lesions. Strikingly, analysis of liver explants revealed that almost all patients in the TACE and SBRT combination group (8/9, 89%) showed no residual vital tumor tissue by histopathology, whereas TACE or SBRT alone resulted in significantly lower rates of complete histopathological response (0/14, 0% and 1/4, 25%, respectively, P value < 0.001). CONCLUSIONOur data suggests that a combination of TACE and SBRT increases the rate of complete histopathological response compared to TACE or SBRT alone in bridging to liver transplantation.     

Transarterial chemoembolization for hepatocellular carcinoma: A review of techniques

Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide. While curative therapies, including resection, liver transplantation, and percutaneous ablation (percutaneous ethanol injection and radiofrequency ablation), are applicable for only a portion of the HCC population, transcatheter arterial chemoembolization (TACE) has been recognized as an effective palliative treatment option for patients with advanced HCC. TACE is also used even for single HCCs in which it is difficult to perform surgical resection or locoregional treatment due to systemic co-morbidities or anatomical problems. TACE has become widely adopted in the treatment of HCC. By using computed tomography-angiography, TACE is capable of performing diagnosis and treatment at the same time. Furthermore, TACE plays an important role in the multidisciplinary treatment for HCC when combined with other treatment. In this review, we first discuss the history of TACE, and then review the previous findings about techniques of achieving a locoregional treatment effect (liver infarction treatment, e.g., ultra-selective TACE, balloon-occluded TACE), and the use of TACE as a drug delivery system for anti-cancer agents (palliative, e.g., platinum complex agents, drug-eluting beads) for multiple lesions.     

Molecular targeting agents associated with transarterial chemoembolization or radiofrequency ablation in hepatocarcinoma treatment

Hepatocellular carcinoma(HCC)is the fifth most common cause of cancer in the world.According to Barcelona Clinic Liver Cancer modified criteria,patients with early stage disease are candidate to radiofrequency ablation(RFA),while patients with intermediate stage HCC are usually treated by transarterial chemoembolization(TACE).TACE and RFA induce a transient devascularisation effect followed by strong neoangiogenic stimulus.In fact,after these procedures,it has been demonstrated an up-regulation of pro-angiogenic and growth factors such as vascular endothelial growth factor-A,which might contribute to accelerated progression in patients with incomplete response.Several studies have demonstrated that MAP-kinase and AKT pathways,in addition to neo-angiogenesis,have an important role in the development of HCC.In advanced HCC,anti-angiogenic therapy and tyrosine kinases inhibitors showed potential clinical benefit.Actually,a number of clinical studies are ongoing testing these agents in combination with TACE or RFA.In this paper,we have reviewed the most recent preclinical and clinical results of such trials.