Current status of systemic therapy in hepatocellular cancer

Hepatocellular cancer (HCC) is a common cancer and an important cause of cancer-related death globally. Although surgery is the primary curative treatment, most patients at diagnosis are not surgical candidates and are treated with liver-directed therapy and or systemic therapy. Over the past decade, the systemic treatment options for patients with advanced HCC have evolved. This paper reviews recent progress in systemic therapy and the results of major clinical trials involving novel compounds in patients with HCC. A literature search was performed using keywords related to HCC and systemic therapy. The evidence shows that at the present time an effective adjuvant systemic therapy is not available for patients with early-stage HCC following surgery. In patients with advanced HCC, in addition to sorafenib at least four other targeted agents and several immune checkpoint inhibitors, alone or in combination have been shown to be associated with improved progression-free and overall survival. The optimal sequence of agents, is currently not known, and is determined by patient characteristics, toxicities profile, patients and physicians preference. The future identification of novel active agents and predictive biomarkers are vital to personalize systemic therapy in HCC.     

Implications of biomarkers in human hepatocellular carcinoma pathogenesis and therapy

Hepatocellular carcinoma(HCC)is one of the most frequent tumors worldwide and accounts for approximately one-third of all malignancies.In the past decade,advances have been made to improve the prognosis of HCC,including improvement in the clinical diagnosis of early-stage HCC using molecular biomarkers and molecular-targeted therapy to treat advanced HCC.However,the diagnosis,pathogenesis and targeted therapy of HCC are not completely independent,and should be comprehensively studied.For example,a number of tumor markers provide useful clinical information not only for prognosis,but also in pathogenesis and treatment efficacy.Therefore,this review will focus on the role of several specific biomarkers implicated in the pathogenesis of HCC and several promising molecular-targeted drugs that target the biomarkers of HCC.     

Hepatocellular carcinoma： Therapy and prevention

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major etiologies and risk factors for the development of HCC are well defined and some of the multiple steps involved in hepatocarcinogenesis have been elucidated in recent years. Despite these scientific advances and the implementation of measures for the early detection of HCC in patients at risk, patient survival has not improved during the last three decades. This is due to the advanced stage of the disease at the time of clinical presentation and limited therapeutic options. The therapeutic options fall into five main categories: surgical interventions including tumor resection and liver transplantation, percutaneous interventions including ethanol injection and radiofrequency thermal ablation, transarterial interventions including embolization and chemoembolization, radiation therapy and drugs as well as gene and immune therapies. These therapeutic strategies have been evaluated in part in randomized controlled clinical trials that are the basis for therapeutic recommendations. Though surgery, percutaneous and transarterial interventions are effective in patients with limited disease (1-3 lesions, <5 cm in diameter) and compensated underlying liver disease (cirrhosis Child A), at the time of diagnosis more than 80% patients present with multicentric HCC and advanced liver disease or comorbidities that restrict the therapeutic measures to best supportive care. In order to reduce the morbidity and mortality of HCC, early diagnosis and the development of novel systemic therapies for advanced disease, including drugs, gene and immune therapies as well as primary HCC prevention are of paramount importance. Furthermore, secondary HCC prevention after successful therapeutic interventions needs to be improved in order to make an impact on the survival of patients with HCC. New technologies, including gene expression profiling and proteomic analyses, should allow to further elucidate the molecular events underlying HCC development and to identify novel diagnostic markers as well as therapeutic and preventive targets.     

Management of advanced hepatocellular carcinoma in the era of targeted therapy

Systemic chemotherapy has had a disappointing track record in the management of advanced hepatocellular carcinoma (HCC). Single‐agent doxorubicin produces a response rate of 10–15%, but without any survival benefit, and combination chemotherapy has also yielded unimpressive results. With recent advances in the knowledge of hepato‐carcinogenesis, there has been encouraging development in the systemic therapy of advanced HCC patients, and particularly in the targeted therapy of advanced HCC. Among the newly identified targets, exciting results have been shown in targeting the anti‐angiogenic pathway and the Raf/mitogen‐activated protein kinase pathways. Bevacizumab, both as a single agent and in combination with other agents, has shown initial encouraging activity in treating advanced HCC. More recently, single‐agent sorafenib, a putative multitargeted kinase inhibitor, has shown to prolong the overall survival of patients with advanced HCC in the pivotal phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) and Oriental study. Currently, sorafenib is the only approved targeted therapy for patients with advanced HCC. In addition, however, promising early results have been reported for other molecular‐targeted drugs including erlotinib and sunitinib. Future progress seems likely to depend on using controlled clinical trials to optimize synergistic combination treatments.     

程序性细胞死亡受体1及其配体抑制剂在肝细胞癌治疗中的应用进展

肝细胞癌(HCC)是我国最常见的恶性肿瘤之一,由于缺乏特异性表现,超过一半的患者在初诊时已处于进展期。靶向治疗和系统化疗是进展期HCC的主要治疗方法,疗效有限。近年来,免疫治疗迅速发展。介绍了免疫检查点抑制剂——程序性细胞死亡受体1及其配体(PD-1/PD-L1)抑制剂在HCC治疗中的现状,归纳了多项临床试验的数据结果,分析了单药治疗及联合治疗的安全性及有效性。通过分析表明,免疫治疗已成为全身系统治疗的重要方法之一,尤其是联合治疗可显著提高HCC的疗效,其安全性亦在可控范围内,是未来发展的重要方向。     

Molecular targeted therapy for hepatocellular carcinoma:Current and future

Hepatocellular carcinoma(HCC)is one of the most frequent tumors worldwide.The majority of HCC cases occur in patients with chronic liver disease.Despite regular surveillance to detect small HCC in these patients,HCC is often diagnosed at an advanced stage.Because HCC is highly resistant to conventional systemic therapies,the prognosis for advanced HCC patients remains poor.The introduction of sorafenib as the standard systemic therapy has unveiled a new direction for future research regarding HCC treatment.However,given the limited efficacy of the drug,a need exists to look beyond sorafenib.Many molecular targeted agents that inhibit different pathways involved in hepatocarcinogenesis are under various phases of clinical development,and novel targets are being assessed in HCC.This review aims to summarize the efforts to target molecular components of the signaling pathways that are responsible for the development and progression of HCC and to discuss perspectives on the future direction of research.     

Evolution of systemic therapy of advanced hepatocellular carcinoma

Hepatocellular carcinoma （HCC） commonly occurs in hepatitis B endemic areas, especially in Asian countries. HCC is highly refractory to cytotoxic chemotherapy. This resistance is partly related to its tumor biology, pharmacokinetic properties, and both intrinsic and acquired drug resistance. There is no convincing evidence thus far that systemic chemotherapy improves overall survival in advanced HCC patients. Other systemic approaches, such as hormonal therapy and immunotherapy, have also disappointing results. Recently, encouraging results have been shown in using sorafenib in the treatment of advanced HCC patients. In this review, we concisely summarize the evolution of developments in the systemic therapy of advanced HCC.     

Multimodal and systemic therapy with cabozantinib for treatment of recurrent hepatocellular carcinoma after liver transplantation: A case report with long term follow-up outcomes

Rationale:Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major therapeutic challenge. In recent years, new molecular-targeted therapies, such as cabozantinib, have been approved for the treatment of advanced HCC. However, clinical experience with these new drugs in the treatment of HCC in the LT setting is very limited.Patient concerns:In 2003, a 36-year-old woman was referred to the hospital with right upper abdominal pain.Diagnosis:An initial ultrasound of the liver demonstrated a large unclear lesion of the left lobe of the liver. The magnet resonance imaging findings confirmed a multifocal inoperable HCC in a non-cirrhotic liver. Seven years after receiving a living donor LT, pulmonary and intra-hepatic recurrence of the HCC was radiologically diagnosed and histologically confirmed.Interventions:Following an interdisciplinary therapy concept consisting of surgical, interventional-radiological (with radiofrequency ablation [RFA]) as well as systemic treatment, the patient achieved a survival of more than 10 years after tumor recurrence. As systemic first line therapy with sorafenib was accompanied by grade 3 to 4 toxicities, such as mucositis, hand-foot skin reaction, diarrhea, liver dysfunction, and hyperthyroidism, it had to be discontinued. After switching to cabozantinib from June 2018 to April 2020, partial remission of all tumor manifestations was achieved. The treatment of the remaining liver metastasis could be completed by RFA. The therapy with cabozantinib was well tolerated, only mild arterial hypertension and grade 1 to 2 mucositis were observed. Liver transplant function was stable during the therapy, no drug interaction with immunosuppressive drugs was observed.Outcomes:More than 10 years survival after recurrence of HCC after living-donor LT due to intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy with cabozantinib in the second line therapy.Lessons:In conclusion, this report highlights the tolerability and effectiveness of cabozantinib for the treatment of HCC recurrence after LT. We show that our patient with a late recurrence of HCC after LT benefitted from intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy.     

Advances in non-surgical management of primary liver cancer

Hepatocellular carcinoma(HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. There have been great improvements in the diagnosis and treatment of HCC in recent years, but the problems, including difficult diagnosis at early stage, quick progression, and poor prognosis remain unsolved. Surgical resection is the mainstay of the treatment for HCC. However, 70%-80% of HCC patients are diagnosed at an advanced stage when most are ineligible for potentially curative therapies such as surgical resection and liver transplantation. In recent years, non-surgical management for unrespectable HCC, such as percutaneous ethanol injection, percutaneous microwave coagulation therapy, percutaneous radiofrequency ablation, transcatheter arterial chemoembolization, radiotherapy, chemotherapy, biotherapy, and hormonal therapy have been developed. These therapeutic options, either alone or in combination, have been shown to control tumor growth, prolong survival time, and improve quality of life to some extent. This review covers the current status and progress of non-surgical management for HCC.     

Immunotherapy for recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is presented frequently in late stages that are not amenable for curative treatment. Even for patients who can undergo resection for curative treatment of HCC, up to 50% recur. For patients who were not exposed to systemic therapy prior to recurrence, recurrence frequently cannot be subjected to curative therapy or local treatments. Such patients have several options of immunotherapy(IO). This includes programmed cell death protein 1(PD-1) and cytotoxic T-lymphocyte...     

Diagnostics and treatment of hepatocellular carcinoma. Recommendations of the Portal Hypertension Working Group of the Czech Hepatology Society and the J.E. Purkinje Czech Medical Society

Hepatocellular carcionma (HCC) is almost exclusively associated with liver cirrhosis as a significant HCC risk marker in advanced countries. Applicable therapy depends on early diagnosis, and risk patients should be screened for the presence of HCC on a regular basis. Liver ultrasound and determination of alpha-fetoprotein serum levels (AFP) are the screening methods used. Spiral CT is the most often used method for HCC staging. Non-invasive methods may under certain circumstances replace aimed biopsy. There are 3 basic curative therapies for the early stage of HCC: liver transplantation, surgical resection and different methods of local destruction of tumour (i.e., ethanolisation, thermoablation, etc.). Patients at medium stage of HCC may profit from chemoembolisation. Current available systemic chemotherapy is ineffective. Patients with advanced HCC are treated symptomatically. Patient survival prognosis after the application of one of the above treatment methods may be similar with that for HCC free cirrhosis patients, however, prognosis for advanced HCC patients is bad, with survival period from one to nine months.     

中晚期肝癌临床治疗进展

肝癌的发病隐匿,早期诊断困难,进展较快,临床上仅有不足30%的患者就诊时可获得手术治疗的机会,因此非手术疗法是中晚期肝癌的主要治疗方式。总结了几种主要的非手术治疗方式———血管介入治疗、分子靶向和化疗药物治疗、放疗以及局部消融治疗在肝癌治疗中的地位。认为尽管综合治疗已成为肝癌治疗的共识,但是他们在综合治疗中的地位及次序等仍未形成共识,还需要进行更多的临床研究,从而为中晚期肝癌患者的治疗提供更好的选择。     

Non-alcoholic fatty liver disease-related hepatocellular carcinoma: Is there a role for immunotherapy?

Hepatocellular carcinoma (HCC) is among the most common cancers and it is a major cause of cancer-related deaths. Non-alcoholic fatty liver disease (NAFLD) affects approximately one fourth of individuals worldwide and it is becoming one of the most important causes of HCC. The pathogenic mechanisms leading to NAFLD-related HCC are complex and not completely understood. However, metabolic, fibrogenic, oncogenic, inflammatory and immunological pathways seem to be involved. First-line therapy of advanced HCC has recently undergone major changes, since the combination of atezolizumab and bevacizumab was proven to increase survival when compared to sorafenib. Other immune-oncology drugs are also demonstrating promising results in patients with advanced HCC when compared to traditional systemic therapy. However, initial studies raised concerns that the advantages of immunotherapy might depend on the underlying liver disease, which seems to be particularly important in NAFLD-related HCC, as these tumors might not benefit from it. This article will review the mechanisms of NAFLD-related hepatocarcinogenesis, with an emphasis on its immune aspects, the efficacy of traditional systemic therapy for advanced NAFLD-related HCC, and the most recent data on the role of immunotherapy for this specific group of patients, showing that the management of this condition should be individualized and that a general recommendation cannot be made at this time.     

Chemotherapy for hepatocellular carcinoma: The present and the future

Hepatocellular carcinoma(HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it's still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatinand gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.     

肝细胞癌非手术治疗的现状和进展

在过去的20多年中,肝细胞癌（hepatocellular carcinoma,HCC）的诊断和治疗有了显著提高,但仍具有早期诊断难、发展快、恶性程度高、预后差的临床特点。手术切除一直被认为是可能治愈HCC的惟一方法。但70％～80％的患者确诊HCC时已为中晚期,无手术切除时机。对不能手术切除的HCC患者,近年发展的非手术治疗技术可延缓甚至控制肿瘤生长,延长生存期,提高生活质量。本文对HCC非手术治疗现状和进展进行综述。     

MET inhibitors for treatment of advanced hepatocellular carcinoma: A review

The current standard treatment option for advanced hepatocellular carcinoma(HCC) is sorafenib, but its clinical benefit is modest. In spite of many attempts, few drugs can provide any significant improvement of survival as the first- or second-line therapy of choice in phase Ⅲ randomized controlled trials. Recently, the subgroup analysis of a phase Ⅱ randomized controlled trial has shown that tivantinib, a selective MET inhibitor, can significantly improve the overall survival in patients with MET-positive advanced HCC after the failure or intolerance of a prior systemic therapy. These findings enlighten the role of MET inhibitors in the treatment of advanced HCC. In this paper, we review all ongoing and completed clinical trials regarding this topic. As for the first-line therapy of advanced HCC, INC280 and foretinib are being evaluated in 2 phase Ⅱ single-arm trials; and MSC2156119 J and golvatinib plus sorafenib are being compared with sorafenib alone in 2 phase Ⅱ randomized controlled trials. As for the second-line therapy of advanced HCC, tivantinib and cabozantinib are being compared with placebo in 2 phase Ⅲrandomized controlled trials.     

Management of patients with hepatocellular carcinoma and extrahepatic metastasis

Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) has recently been paradoxically increasing due to increased survival with effective locoregional therapies. The intrahepatic stage of the tumor is important for determining the risk of an extrahepatic lesion. Almost all patients with intrahepatic stage T(3-4), with or without EHM, die of progressive intrahepatic HCC but not due to EHM; thus, the majority of patients with HCC and EHM need to undergo concurrent treatment for intrahepatic HCC. There is no convincing evidence, to date, that systemic chemotherapy improves overall survival. Sorafenib is the first systemic agent that has demonstrated a significant survival benefit in patients with advanced HCC; however, the modest improvement of 3 months is far from satisfactory. Therefore, most hepatologists still rely on the conventional multidisciplinary approach to treat patients with EHM. The concept of the multidisciplinary treatment is the combination of locoregional therapies for both the intrahepatic HCC and symptomatic EHM when confined to a single organ. Targeted therapy may be considered for patients with advanced intrahepatic HCC and multiple EHM, however the potential efficacy of this approach requires confirmation. The outcome of ongoing clinical trials of the multidisciplinary approach, combining conventional locoregional therapy and targeted systemic therapy, is pending.     

Suppression of hepatocellular carcinoma development in hepatitis C patients given interferon‐based antiviral therapy

The advance of antiviral treatment for chronic hepatitis C has brought a high sustained virological response (SVR) rate. In this review article, the suppressive effect of interferon (IFN)‐based therapy on the development of hepatocellular carcinoma (HCC), risk factors for developing HCC and the characteristics of HCC development after SVR among chronic hepatitis C patients given IFN‐based therapy were studied. The HCC incidence has been revealed to decrease with IFN‐based antiviral therapy, especially in SVR, and the risk factors for developing HCC were older age, advanced liver fibrosis and male sex. α‐Fetoprotein levels at 24 weeks after the end of IFN‐based treatment was associated strongly with HCC incidence irrespective of virological response. In patients with SVR, other risk factors were glucose metabolism disorders, lipid metabolism disorders and alcohol intake. Extra attention to the possibility of HCC incidence should be required for these SVR patients. Antiviral therapy with a combination of HCV‐specific direct‐acting antivirals (DAA) is expected to be utilized in the future. However, it is not known whether DAA‐based treatment can suppress HCC to the level of IFN‐based treatment. Further research is required to clarify this.