Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out

As the leading cause of disease-related deaths, cancer is a major public health threat worldwide. Surgical resection is still the first-line therapy for patients with early-stage cancers. However, postoperative relapse and metastasis remain the cause of 90% of deaths of patients with solid organ malignancies, including hepatocellular carcinoma (HCC). With the rapid development of molecular biology techniques in recent years, molecularly targeted therapies using monoclonal antibodies, small molecules, and vaccines have become a milestone in cancer therapeutic by significantly improving the survival of cancer patients, and have opened a window of hope for patients with advanced cancer. Hypervascularization is a major characteristic of HCC. It has been reported that anti-angiogenic treatments, which inhibit blood vessel formation, are highly effective for treating HCC. However, the efficacy and safety of anti-angiogenesis therapies remain controversial. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC. While sorafenib has shown promising therapeutic effects, substantial evidence of primary and acquired resistance to sorafenib has been reported. Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC, but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib. Therefore, understanding the mechanism(s) underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC. This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies.     

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.     

Targeted therapy of hepatocellular carcinoma: present and future

Following the encouraging results of sorafenib in advanced hepatocellular carcinoma (HCC), targeted therapy has become a new direction of research in the treatment of HCC. Emerging data provide evidence that the pathogenesis and progression of HCC are mediated by a number of molecular defects and dysregulated pathways. Novel targeted therapies are designed to inhibit the aberrant pathways at a molecular level with an aim to improve the clinical outcome. For the past few years, an increasing number of targeted agents have been tested in HCC in the clinical setting. This review aims to summarize the current status of clinical development of targeted therapy in HCC, with focus on novel agents targeting angiogenesis, signal transduction and epigenetic dysregulation of tumors. The review also discusses the lessons learned from outcomes of completed clinical trials and provides perspectives on future clinical trials in HCC.     

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc . Based on the investigated mechanisms,some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC.     

Future treatment option for hepatocellular carcinoma: a focus on brivanib

Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, is particularly prevalent in the Asia-Pacific region. Guidelines on the treatment of HCC in Japan come from both consensus-based and evidence-based treatment algorithms. However, patients with extensive liver damage and/or more advanced disease (major vascular invasion and/or extrahepatic spread) are currently ineligible for any treatment. Recent knowledge of hepatocarcinogenesis has led to the targeting of new pathways, particularly the angiogenic pathway, with a specific focus on the vascular endothelial growth factor receptor (VEGFR). Apparently the most studied systemic antiangiogenic agent for HCC is sorafenib. An updated version of the aforementioned treatment algorithms recommends sorafenib therapy for advanced HCC patients with Child-Pugh A liver function and extrahepatic spread or major vascular invasion. Moreover, sorafenib is recommended for use in HCC patients who are refractory or intolerant to transarterial chemoembolization (TACE) with well-preserved liver function (Child-Pugh A). However, one of the unresolved issues is anti-VEGF resistance. It is speculated that novel antiangiogenic agents that combine inhibition of other pathways such as fibroblast growth factor receptor signaling in addition to VEGFR signaling might provide a potential mechanism to overcome anti-VEGF resistance in HCC. Brivanib inhibits both VEGF and fibroblast growth factor receptor signaling. To further investigate the benefits of brivanib for advanced HCC, a broad-spectrum, global, phase III development plan, the Brivanib studies in HCC patients at RISK (BRISK) clinical program, has been initiated. Clinical benefits seen with brivanib in the first-line setting, and following the failure of sorafenib therapy, highlight the potential to improve the clinical course of patients with advanced HCC, and this agent may provide a novel therapeutic option for the growing population of patients for whom no other treatment choice exists.     

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.     

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.     

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.     

Current status and future prospects of chemotherapy for advanced hepatocellular carcinoma

Sorafenib is the only drug that demonstrates a survival benefit for advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is limited, so development of a more effective treatment method and second-line treatments is needed. Since the advent of sorafenib, clinical studies have been conducted with a variety of drugs and treatment methods, mainly with molecular targeted therapy, but almost all trials have ended in failure. The reasons for the difficulty in the development of a novel drug or treatment method include the diversity of mechanisms in the carcinogenesis and development of HCC, as well as the presence of background liver diseases such as chronic hepatitis and cirrhosis. Trials with immune-checkpoint inhibitors, which have an entirely different anti-tumor mechanism from that of molecular targeted drugs or cytotoxic drugs, have recently begun. Based on the results to date, clinical trials are now being conducted with enriched target subjects. In the future, providing more individualized treatment approaches for patients with advanced HCC will be essential.     

Systemic therapy of hepatocellular carcinoma:Current status and future perspectives

The management of hepatocellular carcinoma(HCC)has substantially changed in the past few decades,the introduction of novel therapies(such as sorafenib)have improved patient survival.Nevertheless,HCC remains the third most common cause of cancer-related deaths worldwide.Decision-making largely relies on evidencebased criteria,as showed in the US and European clinical practice guidelines,which endorse five therapeutic recommendations:resection;transplantation;radiofrequency ablation;chemoembolization;and sorafenib.Many molecularly targeted agents that inhibit angiogenesis,epidermal growth factor receptor,and mammalian target of rapamycin are at different stages of clinical development in advanced HCC.Future research should continue to unravel the mechanism of hepatocarcinogenesis and to identify key relevant molecular targets for therapeutic intervention.Identification and validation of potential surrogate and predictive biomarkers hold promise to individualize patient’s treatment to maximize clinical benefit and minimize the toxicity and cost of targeted agents.     

Current chemotherapies for advanced hepatocellular carcinoma

The incidence of hepatocellular carcinoma (HCC) increases with the advancement of chronic liver diseases such as hepatitis C or B. The recurrence rate is very high and causes disease progression to an advanced stage. Recent development of molecularly targeted agents for the treatment of advanced HCC has dramatically changed the chemotherapies used for this disease. We summarize the current findings on several drugs that are commonly used for the treatment of advanced HCC including sorafenib and hepatic arterial infusion chemotherapies.     

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.     

Metastatic Bladder Cancer: Role of Chemotherapy and New Agents

The M-VAC chemotherapy regimen has been widely used in locally advanced as well as in metastatic disease. Since only a proportion of patients with advanced disease will survive, there is a dire need to identify patients who will respond to chemotherapy and to identify new agents, targets and strategies to improve treatment outcome. Approaches to the management of advanced urothelial cancer include: intensifying the dose intensity, doublet and triplet combination chemotherapy, sequential regimens, reducing toxicity in unfit or elderly patients, and the use of biologic targeted therapies and promising new chemotherapeutic agents. These include MTA, the epothilones, topoisomerase inhibitors and vinflunine which act upon folate metabolism or upon different phases of the cell cycle. New agents that are coming into clinical trials include farnesyl transferase inhibitors, several growth factors receptor inhibitors, anti-sense therapy and COX-2 inhibitors. Significant progress has been made in understanding the molecular biology of cancer. Numerous novel agents, many of which are in clinical trials, have been developed to target various processes of tumor progression. The rationale behind application of these molecularly targeted therapies is to overcome resistance to cytotoxic therapies. Bladder cancer represents a unique model for targeted therapy. As our understanding increases, integration of newer biologic agents will condition future trials, and our ability to target bladder and urothelial cancers will be enhanced.     

Treatment strategies for advanced hepatocellular carcinoma: Sorafenib vs hepatic arterial infusion chemotherapy

Sorafenib is used worldwide as a first-line standardsystemic agent for advanced hepatocellular carcinoma(HCC) on the basis of the results of two large-scale Phase Ⅲ trials. Conversely,hepatic arterial infusion chemotherapy(HAIC) is one of the most recommended treatments in Japan. Although there have been no randomized controlled trials comparing sorafenib with HAIC,several retrospective analyses have shown no significant differences in survival between the two therapies. Outcomes are favorable for HCC patients exhibiting macroscopic vascular invasion when treated with HAIC rather than sorafenib,whereas in HCC patients exhibiting extrahepatic spread or resistance to transcatheter arterial chemoembolization,good outcomes are achieved by treatment with sorafenib rather than HAIC. Additionally,sorafenib is generally used to treat patients with Child-Pugh A,while HAIC is indicated for those with either Child-Pugh A or B. Based on these findings,we reviewed treatment strategies for advanced HCC. We propose that sorafenib might be used as a first-line treatment for advanced HCC patients without macroscopic vascular invasion or Child-Pugh A,while HAIC is recommended for those with macroscopic vascular invasion or Child-Pugh A or B. Additional research is required to determine the best second-line treatment for HAIC non-responders with Child-Pugh B through future clinical trials.     

Targeting receptor tyrosine kinases in gastric cancer

Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials.One group of representative targeted oncogenic kinases,the receptor tyrosine kinases(RTKs),has been associated with gastric cancer development.Trastuzumab,an inhibitor of ERBB2,has been approved for the treatment of gastric cancer,although other receptor tyrosine kinases,such as epidermal growth factor receptor,vascular endothelial growth factor,platelet-derived growth factor receptor,c-Met,IGF-1R and fibroblast growth factor receptor 2,are also activated in gastric cancer.The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients.On the other hand,the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients;however,a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial.Other clinical trials,especially phaseⅢtrials that have tested drugs targeting RTKs,such as cetuximab,panitumumab,gefitinib,erlotinib,figitumumab,sorafenib,sunitinib and lapatinib,have shown that these drugs have modest effects against gastric cancer.This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies.     

非编码RNA在索拉非尼治疗肝细胞癌耐药中的作用机制

索拉非尼作为晚期肝细胞癌的一线治疗药物,能够有效改善肝癌患者预后。但索拉非尼耐药已经成为影响肝细胞癌治疗效果的主要障碍。近年来研究发现,非编码RNA在肝细胞癌索拉非尼耐药中起着关键作用。总结了非编码RNA通过诱导肝癌细胞自噬、促进肝癌干细胞增殖、促进肝癌细胞上皮-间质转化过程、抑制肝癌细胞凋亡以及调节肝癌组织微环境来调节肝癌细胞对索拉非尼的敏感性。指出了非编码RNA调控肝细胞癌索拉非尼耐药的分子机制在克服耐药方面的潜在临床意义。     

Hepatocellular carcinoma review:Current treatment,and evidence-based medicine

Hepatocellular carcinoma(HCC)is the fifth most common tumor worldwide.Multiple treatment options are available for HCC including curative resection,liver transplantation,radiofrequency ablation,trans-arterial chemoembolization,radioembolization and systemic targeted agent like sorafenib.The treatment of HCC depends on the tumor stage,patient performance status and liver function reserve and requires a multidisciplinary approach.In the past few years with significant advances in surgical treatments and locoregional therapies,the short-term survival of HCC has improved but the recurrent disease remains a big problem.The pathogenesis of HCC is a multistep and complex process,wherein angiogenesis plays an important role.For patients with advanced disease,sorafenib is the only approved therapy,but novel systemic molecular targeted agents and their combinations are emerging.This article provides an overview of treatment of early and advanced stage HCC based on our extensive review of relevant literature.     

Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update

Sorafenib is the first and only p.o. administrated drug currently approved to treat advanced hepatocellular carcinoma (HCC). However, concerns have been raised about sorafenib therapy, including acquired drug resistance. This review provides an overview of sorafenib in the treatment of HCC on the basis of data obtained in the laboratory and in clinical studies. Three underlying mechanisms have been found to support sorafenib therapy. First, sorafenib blocks HCC cell proliferation by inhibiting BRaf and Raf1/c‐Raf serine/threonine kinase phosphorylation in the mitogen‐activated protein kinase pathway. Second, sorafenib induces apoptosis by reducing elF4E phosphorylation and downregulating Mcl‐1 levels in tumor cells. Third, sorafenib prevents tumor‐associated angiogenesis by inactivating vascular endothelial growth factor receptors (VEGFR‐2 and ‐3) and the platelet‐derived growth factor receptor‐β. Clinical trials have demonstrated the effectiveness and relative safety of sorafenib, and thus the drug is used in unresectable HCC. However, many patients may develop acquired resistance to sorafenib, so their response to sorafenib is eventually lost. Sorafenib may induce autophagy, which leads to apoptosis. However, autophagy can also cause drug resistance. Many studies have combined sorafenib with other treatments in an effort to increase its effects, reduce the necessary dose or overcome resistance. It is urgent to study the mechanisms underlying how sorafenib interacts with cellular molecules and other drugs to increase its efficacy and reduce resistance in HCC patients.     

Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other smallmolecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c- MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.