Potentiality of immunotherapy against hepatocellular carcinoma

Hepatocellular carcinoma(HCC),the predominant form of primary liver cancer,is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence,treatment options remain limited for advanced HCC,and as a result prognosis continues to be poor. Current therapeutic options,surgery,chemotherapy and radiotherapy,have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising,novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here,we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies,such as tumor-associated antigen therapy,immune checkpoint inhibitors and cell transfer immunotherapy,have demonstrated safety and feasibility in HCC patients. Unfortunately,immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this chal lenge will place immunotherapy at the forefront of HCC treatment,possibly in the near future.     

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.     

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.     

Systemic treatment of pancreatic cancer

Patients with pancreatic cancer have a poor prognosis although systemic treatment has slightly improved the outcome for those with advanced pancreatic cancer, The approach to a patient with pancreatic cancer remains a great challenge. Patients often present with advanced disease and many are already in poor general condition at the time of diagnosis. Today, surgery remains the only curative therapeutic option. A small number of pancreatic adenocarcinomas, however, are resectable and relapses after surgery are very frequent. The reference treatment in patients with metastatic pancreatic cancer is gemcitabine. The median survival of patients with advanced pancreatic cancer who are treated with gemcitabine is approximately 6 months and only approximately 20% of patients will be alive at 1 year. Combinations of gemcitabine with new cytotoxic agents and with novel targeted agents hold the promise for improving the outcome. Randomized phase III studies are, however, still ongoing. Since most patients will relapse after complete surgical resection of pancreatic cancer, a search for a better adjuvant or neoadjuvant treatment is important. Although several randomized studies have suggested an improved outcome for a postoperative chemoradiotherapy or chemotherapy, the role of an adjuvant treatment remains today controversial. Randomized phase III studies are ongoing. A neoadjuvant strategy might therefore also play a role, but phase III studies are lacking. The systematic evaluation of new drugs in well designed clinical trials and the search for new molecular targets for treatment are crucial in our aim to improve the outcome for patients with pancreatic cancer.     

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.     

Advanced hepatocellular carcinoma. Review of targeted molecular drugs

Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world in terms of incidence, accounting for approximately 630 thousand new cases per year; in addition, HCC is the third most common cause of cancer death. Worldwide, the greatest risk factors for HCC are the infections caused by hepatitis B and C viruses, which increase the risk of developing the disease by about 20 times. The standard treatment in the early stages of the disease, such as surgical resection, local ablation and liver transplantation, are able to cure a proportion of patients, but most cases of HCC present in advanced stages, precluding the use of such treatments with curative intent. In these advanced stages, systemic treatments are commonly used. Unfortunately, chemotherapy with conventional cytotoxic agents is ineffective and does not seem to modify the natural history of disease. Treatment options for patients with advanced HCC are extremely limited, but the identification of signaling pathways, and the recognition of the role of these pathways in the pathogenesis of the disease resulted in the development of drugs directed at specific therapeutic targets. One such drug is Sorafenib, a kinase inhibitor with antiangiogenic and antiproliferative properties. In conclusion, Sorafenib has demonstrated survival benefits in patients with advanced HCC, thus representing a new standard reference for systemic treatment in these cases.     

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.     

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...     

Expanding TACTICS trial into a different setting in hepatocellular carcinoma

Systemic treatment for hepatocellular carcinoma (HCC) is recommended for patients with advanced stage and for those who progressed on locoregional modalities. The first agent approved for advanced HCC was sorafenib, and it remains one of the cornerstones of systemic treatment. In the past years, immunotherapy has shown promising results and has been incorporated into the treatment armamentarium. The rates of recurrence and progression after locoregional therapies are significant, what highlights the need to explore systemic agents for preventing or delaying these negative outcomes. Recently, sorafenib was shown to benefit patients with unresectable HCC under transarterial chemoembolization (TACE) by delaying tumor progression and prolonging time to vascular invasion and extrahepatic spread. Although this result was reported in patients with intermediate stage, it provides background to test the strategy of combining systemic treatment plus TACE as a bridge therapy to HCC patients awaiting liver transplantation, for which the risk of dropout due to tumor progression impairs the possibility of cure.     

Hepatocellular carcinoma: Understanding molecular mechanisms for defining potential clinical modalities

Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year. The diagnosis of hepatocellular carcinoma (HCC) has relied on scanning techniques and serum-based markers such as α-fetoprotein. These measures have limitations due to their detection limits and asymptomatic conditions during the early stages, resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is offered. However, the aid of conventional therapy for patients in the advanced stage of HCC has limited outcomes. Thus, it is essential to seek a new treatment strategy and improve the diagnostic techniques to manage the disease. Researchers have used the omics profile of HCC patients for sub-classification of tissues into different groups, which has helped us with prognosis. Despite these efforts, a promising target for treatment has not been identified. The hurdle in this situation is genetic and epigenetic variations in the tumor, leading to disparities in response to treatment. Understanding reversible epigenetic changes along with clinical traits help to define new markers for patient categorization and design personalized therapy. Many clinical trials of inhibitors of epigenetic modifiers (also known as epi-drugs) are in progress. Epi-drugs like azacytidine or belinostat are already approved for other cancer treatments. Furthermore, epigenetic changes have also been observed in drug-resistant HCC tumors. In such cases, combinatorial treatment of epi-drugs with systemic therapy or trans-arterial chemoembolization might re-sensitize resistant cells.     

Progress in systemic therapy of advanced hepatocellular carcinoma

Primary liver cancer, mainly consisting of hepatocellular carcinoma (HCC), is one of common malignancies worldwide, and prevalent among the Chinese population. A diagnosis of early stage HCC has proven to be very difficult because of its insidious feature in onset and development. At the time of diagnosis, most HCC cases are locally advanced and/or distant metastatic, which results in difficulty to be treated and poor prognosis. For advanced HCC, systemic therapy is frequently adopted as an important palliative method. In recent years, clinical studies and observations have often reported about systemic anti-cancer therapy of advanced HCC, including molecular target therapy, systemic chemotherapy and immunotherapy. In this article, we review these treatment modalities to provide a reference for clinicians.     

Will the collaboration of surgery and external radiotherapy open new avenues for hepatocellular carcinoma with portal vein thrombosis?

Portal invasion of hepatocellular carcinoma(HCC)occurs in 12.5%-40%of patients diagnosed with cancer and yields poor clinical outcomes.Since it is a common cause of inoperability,sorafenib was regarded as the standard treatment for HCC in the Barcelona Clinic of Liver Cancer guidelines.However,the median survival of the Asian population was only approximately 6 mo,and the tumor response rate was less than moderate(<5%).Various locoregional modalities were performed,including external beam radiotherapy(EBRT),transarterial chemoembolization,hepatic arterial infusion chemotherapy,and surgery,alone or in combination.Among them,EBRT is a noninvasive method and can safely treat tumors involving the major vessels.Palliative EBRT has been commonly performed,especially in East Asian countries,where locally invasive HCC is highly prevalent.Although surgery is not commonly indicated,pioneering studies have demonstrated encouraging results in recent decades.Furthermore,the combination of neo-or adjuvant EBRT and surgery has been recently used and has significantly improved the outcomes of HCC patients,as reported in a few randomized studies.Regarding systemic modality,a combination of novel immunotherapy and vascular endothelial growth factor inhibitor showed results superior to that of sorafenib as a first-line agent.Future clinical trials investigating the combined use of these novel agents,surgery,and EBRT are expected to improve the prognosis of HCC with portal invasion.     

Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges

Primary liver cancer is one of the commonest causes of death. Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers. For patients with unresectable or metastatic HCC, conventional chemotherapy is of limited or no benefit. Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit, leading to an era of targeted agents. Many clinical trials of targeted drugs have been carried out with many more in progress. Some drugs like PTK787 showed potential benefits in the treatment of HCC. Despite these promising breakthroughs, patients with HCC still have a dismal prognosis. Recently, both a phase III trial of everolimus and a phase II clinical trial of trebananib failed to demonstrate effective antitumor activity in advanced HCC. Sorafenib still plays a pivotal role in advanced HCC, leading to further explorations to exert its maximum efficacy. Combinations targeted with chemotherapy or transarterial chemoembolization is now being tested and might bring about advances. New targeted agents such as mammalian target of rapamycin inhibitors are under investigation, as well as further exploration of the mechanism of hepatocarcinogenesis.     

Conventional vs drug-eluting beads transarterial chemoembolization for hepatocellular carcinoma

Transarterial chemoembolization(TACE) is the current standard of therapy for patients with intermediatestage hepatocellular carcinoma(HCC) according to the Barcelona Clinic Liver Cancer classification. The concept of conventional TACE(cTACE) is the selective obstruction of tumor-feeding artery by injection of chemotherapeutic agents, leading to ischemic necrosis of the target tumor via cytotoxic and ischemic effects. Drugeluting beads(DEBs) have been imposed as novel drugdelivering agents for TACE, which allows for higher concentrations of drugs within the target tumor and lower systemic concentrations compared with cTACE. Despite the theoretical advantages of DEB-TACE, it is still controversial in clinical practice as to whether DEBTACE is superior to cTACE in regard to overall survival and treatment response. In this review article, we summarize the clinical efficacy and safety of DEB-TACE for patients with intermediate or advanced stage HCC in comparison with cTACE.     

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 hepatocellular carcinoma

Hepatocellular carcinoma (HCC) ranks fifth in frequency worldwide among all malignancies and causes 1 million deaths annually. The management of HCC begins with diagnostic confirmation by radiologic imaging or histology. Staging is essential, as the choice of therapy depends on the functional state of the liver and the extent of tumor growth. Surgery, in the form of either hepatic resection or orthotopic liver transplantation, is the only potentially curative treatment. Transarterial chemoembolization is commonly used as either palliative treatment or adjunctive therapy to surgery, and a survival benefit with this therapy has just recently been demonstrated in a randomized, controlled trial. Patients with inoperable HCC may benefit from local ablative therapy that may still have curative potential in those with sufficiently small lesions and adequate liver function. For patients with advanced HCC, systemic chemotherapy has been widely employed, despite low efficacy and significant complication rate. Tamoxifen did not improve survival in large clinical trials. Gene therapy is an exciting approach to treating HCC but is still largely confined to preclinical and experimental settings.     

Molecular targeted therapy for advanced hepatocellular carcinoma: current status and future perspectives

Sorafenib, a multikinase inhibitor targeting vascular endothelial growth factor (VEGF)-mediated angiogenesis, is the first drug found to prolong survival of patients with advanced hepatocellular carcinoma (HCC). This advance has shifted the paradigm of systemic treatment for HCC toward molecular targeted therapy (MTT). However, the disease-stabilizing effect of VEGF signaling-targeted MTT normally lasts only for a few months, suggesting a rapid emergence of resistance in the majority of patients. To overcome the resistance to VEGF signaling-targeted MTT, strategies incorporating inhibition of either compensatory pro-angiogenic pathways or recruitment of bone marrow-derived circulating endothelial progenitors, as well as suppression of other oncogenic pathways, are currently being investigated. The combination of multiple molecular targeted agents or the use of multi-target agents may enhance the efficacy at the expense of increased toxicities. To facilitate the development of MTT for HCC, current methodologies for pharmacodynamic assessment, patient selection and target identification need to be improved. Patient selection according to the individual molecular signature of the tumor and correlative biomarker studies are encouraged while planning a clinical trial of novel MTT.     

Growth factors as therapeutic targets in HCC

Despite various effective local treatments for hepatocellular carcinoma (HCC), some patients do not meet the treatment criteria because of extrahepatic metastases or macroscopic vascular invasion at the time of their diagnosis. Furthermore, many patients treated with successful local treatments develop recurrences after treatment. Although these patients receive systemic treatment including chemotherapy, HCC is generally recognized as a chemo-resistant tumor. Recently, new molecular targets have been confirmed and various targeted agents are now being investigated for the treatment of HCC. Epidermal growth factor receptor (EGFR) is frequently expressed in human hepatoma cells, and EGF may be one of the mitogens that are needed for the growth of hepatoma cells. HCC is generally hypervascular, and vascular endothelial growth factor (VEGF) promotes HCC development and metastasis. Various inhibitors targeting EGFR and/or VEGF, VEGF receptor (VEGFR) have been developed as treatments of HCC. In phase-II studies of these growth factor inhibitors, the response rates are relatively low; however, high rates of disease control, enabling a good time to progression, have been achieved. Recently, a randomized phase III trial of sorafenib versus placebo conducted in patients with advanced HCC demonstrated the beneficial effects of this drug on the time-to-progression and overall survival of the patients, and the drug could become established as the standard chemotherapeutic agent for advanced HCC. Further clinical trials using biologic agents are warranted to prolong the survival in HCC patients.