Targeted systemic therapies for hepatocellular carcinoma: clinical perspectives, challenges and implications

Hepatocellular carcinoma(HCC) is a lethal disease in most patients,due to its aggressive course and a lack of effective systemic therapies for advanced disease.Surgical resection and liver transplantation remain the only curative options for a small subset of patients.Few patients with HCC are diagnosed early enough to be eligible for curative treatment.Angiogenesis inhibition is a natural therapeutic target for all solid tumors,but particularly for the highly vascularized HCC tumors.With the approval of the targeted agent sorafenib,there are now additional options for patients with HCC.Although sorafenib does produce some improvement in survival in HCC patients,the responses are not durable.In addition,there are significant dermatologic,gastrointestinal,and metabolic toxicities,and,as importantly,there is still limited knowledge of its usefulness in special subpopulations with HCC.Other angiogenesis inhibitors are in development to treat HCC both in the first-line setting and for use following sorafenib failure;the furthest in development is brivanib,a dual fibroblast growth factor pathway and vascular endothelial growth factor receptor inhibitor.Additional agents with antiangiogenic properties also in phase Ⅱ and Ⅲ development for the treatment of patients with HCC include bevacizumab,ramucirumab,ABT-869,everolimus and ARQ 197.     

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.     

Effect of interferon therapy on first and second recurrence after resection of hepatitis C virus-related hepatocellular carcinoma

Aim: Several investigators have shown that interferon (IFN) therapy can suppress the recurrence of hepatocellular carcinoma (HCC) after curative treatment. We investigated the effect of IFN therapy on the first and second HCC recurrence following hepatic resection of hepatitis C virus (HCV)-related HCC. Methods: Subjects included 166 patients who had undergone curative resection for a single HCV-related HCC. We analyzed the outcome after initial hepatic resection and risk factors of a second HCC recurrence following treatment for the first HCC recurrence. Results: Using multivariate analysis, a non-sustained virological response (non-SVR) was significantly associated with a high incidence of first HCC recurrence. The rate of second HCC recurrence tended to be higher in the non-SVR group than in the SVR group. In the patients with recurrence of multiple tumors or who received non-curative treatment for recurrent HCC, the second HCC recurrence rates were significantly higher. Multivariate analysis demonstrated that non-curative treatment for first HCC recurrence was an independent risk factor for a second HCC recurrence. Among the patients who received curative treatment for their first HCC recurrence, the rates of second recurrence were significantly higher in the non-SVR group than in the SVR group. Multivariate analysis also revealed that SVR was independently associated with prevention of a second HCC recurrence. Conclusions: These results suggest that on first HCC recurrence, a curative treatment should be considered in order to prevent a second recurrence if possible. In addition, IFN therapy contributes to improved prognosis after curative treatment, even in patients with recurrent HCC.     

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。     

Current status and prospect of treatments for recurrent hepatocellular carcinoma

Owing to its heterogeneous and highly aggressive nature, hepatocellular carcinoma (HCC) has a high recurrence rate, which is a non-negligible problem despite the increasing number of available treatment options. Recent clinical trials have attempted to reduce the recurrence and develop innovative treatment options for patients with recurrent HCC. In the event of liver remnant recurrence, the currently available treatment options include repeat hepatectomy, salvage liver transplantation, tumor ablation, transcatheter arterial chemoembolization, stereotactic body radiotherapy, systemic therapies, and combination therapy. In this review, we summarize the strategies to reduce the recurrence of high-risk tumors and aggressive therapies for recurrent HCC. Additionally, we discuss methods to prevent HCC recurrence and prognostic models constructed based on predictors of recurrence to develop an appropriate surveillance program.     

Efficacy of antiviral therapy with lamivudine after initial treatment for hepatitis B virus-related hepatocellular carcinoma

AIM: The aim of this study was to determine whether antiviral therapy with lamivudine is beneficial in patients after initial treatment for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: Forty-nine consecutive patients with HBV-related HCC completely treated by hepatic resection or radiofrequency ablation were retrospectively enrolled in this study. Comparison was made between 16 patients who received lamivudine therapy at a dose of 100 mg/day after treatment for HCC (lamivudine group) and 33 patients who did not (control group) in terms of changes in remnant liver function, HCC recurrence and survival. RESULTS: Cumulative recurrence rates of HCC did not significantly differ between the two groups (P = 0.622). However, median Child-Pugh score at the time of HCC recurrence was significantly different; 5 (range 5-6) in the lamivudine group versus 7 (range 5-12) in the control group (P = 0.005). All patients in the lamivudine group were able to receive curative treatment for recurrent HCC. In contrast, 10 of 15 patients in the control group were unable to receive curative optimal therapy for recurrent HCC due to deterioration of remnant liver function. The cumulative survival rates of patients in the lamivudine group tended to be higher than those of patients in the control group (P = 0.063). CONCLUSION: It is suggested that lamivudine therapy is beneficial for patients after initial treatment for HBV-related HCC because it contributes to improving remnant liver function, thus decreasing the risk of liver failure and increasing the chances of receiving available treatment modalities for recurrent HCC.     

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.     

Interferon therapy for hepatitis C virus (HCV)-related advanced chronic hepatitis after treatment of recurrent hepatocellular carcinoma: a successful case

A complete response was obtained by interferon (IFN) therapy for hepatitis C virus (HCV)-related advanced chronic hepatitis after curative treatment of initial and recurrent hepatocellular carcinoma (HCC). The patient is alive 73 months after diagnosis of initial HCC and is in a tumor-free state 53 months after diagnosis of the last HCC. This case suggest that it is possible to suppress recurrence and to prolong the life of patients with HCV-related advanced chronic hepatitis, if a complete response is obtained by means of IFN therapy after the curative treatment of the recurrent HCC.     

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.     

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.     

Strategy for improving survival and reducing recurrence of HCV-related hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the sixth most common cancer and the third leading cause of cancerrelated death in the world.With advances in imaging diagnostics,accompanied by better understanding of high-risk patients,HCC is now frequently detected at an early stage;however,the prognosis remains poor.The recurrence rate after treatment of HCC is higher than that associated with cancers of other organs.This may be because of the high incidence of intrahepatic distant recurrence and multicentric recurrence,especially with hepatitis C virus(HCV)-related hepatocellular carcinoma.The Barcelona Clinic Liver Cancer(BCLC)classification has recently emerged as the standard classification system for the clinical management of patients with HCC.According to the BCLC staging system,curative therapies(resection,transplantation,transcatheter arterial chemoembolization,percutaneous ethanol injection therapy,percutaneous microwave coagulation therapy and percutaneous radiofrequency ablation)can improve survival in HCC patients diagnosed at an early stage and offer a potential long-term cure.However,treatment strategies for recurrent disease are not mentioned in the BCLC classsification.The strategy for recurrence may differ according to the recurrence pattern,i.e.,intrahepatic distant recurrence vs multicentricrecurrence.In this article,we review recurrent HCC and the therapeutic strategies for reducing recurrent HCC,especially HCV-related HCC.     

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.     

The current role of neoadjuvant/adjuvant/chemoprevention therapy in partial hepatectomy for hepatocellular carcinoma:a systematic review

BACKGROUND:Following curative treatment for hepato-cellular carcinoma(HCC),50%-90% of postoperative death is due to recurrent disease.Intra-hepatic recurrence is frequently the only site of recurrence.Thus,any neoadjuvant or adjuvant therapy,which can decrease or delay the incidence of intra-hepatic recurrence,or any cancer chemoprevention which can prevent a new HCC from developing in the liver remnant,will improve the results of liver resection.This article systematically reviewed the current evidence of ...     

HBcrAg is a predictor of post‐treatment recurrence of hepatocellular carcinoma during antiviral therapy

Background/Aims: The recurrence rate of hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) is high even in patients receiving curative therapy. In this study, we analysed the risk factors for tumour recurrence after curative therapy for HBV‐related HCC while under treatment with nucleot(s)ide analogues (NAs) by measuring serum HBcrAg and intrahepatic covalently closed circular DNA (cccDNA) levels to elucidate the viral status associated with HCC recurrence. Methods: We enrolled 55 patients who developed HCC during NA therapy and underwent either curative resection or percutaneous ablation for HCC. Results: Hepatocellular carcinoma recurred in 21 (38%) of the patients over a period of 2.2 (range, 0.2–7.4) years. In multivariate analysis, serum HBcrAg levels ≥4.8log U/ml at the time of HCC diagnosis (hazard ratio, 8.96; 95% confidential interval, 1.94–41.4) and portal vein invasion (3.94, 1.25–12.4) were independent factors for HCC recurrence. The recurrence‐free survival rates of the high cccDNA group were significantly lower than those of the low cccDNA group only in patients who underwent resection (P=0.0438). A positive correlation (P=0.028; r=0.479) was observed between the intrahepatic cccDNA and the serum HBcrAg levels at the incidence of HCC. Conclusion: HBcrAg is a predictor of the post‐treatment recurrence of HCC during antiviral therapy. Serum HBcrAg and intrahepatic cccDNA suppression by NAs may be important to prevent HCC recurrence.     

Low-dose intermittent interferon-alpha therapy for HCV-related liver cirrhosis after curative treatment of hepatocellular carcinoma

AIM: To assess the efficacy of low-dose intermittent interferon (IFN) therapy in patients with hepatitis C virus (HCV)-related compensated cirrhosis who had received curative treatment for primary hepatocellular carcinoma (HCC). METHODS: We performed a prospective case controlled study. Sixteen patients received 3 MIU of natural IFN- alpha intramuscularly 3 times weekly for at least 48 wk (IFN group). They were compared with 16 matched historical controls (non-IFN group). RESULTS: The cumulative rate of first recurrence of HCC was not significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 68.6% vs 80% at 1- and 3-year, P = 0.157, respectively). The cumulative rate of second recurrence was not also significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 35.9% vs 67% at 1- and 3-year, P = 0.056, respectively). Although the difference in the Child-Pugh classification score between the groups at initial treatment of HCC was not signifi cant, the score was signifi cantly worse at the time of data analysis in the non-IFN group than IFN group (7.19 ± 1.42 vs 5.81 ± 0.75, P = 0.0008). The cumulative rate of deviation from objects of any treatment for recurrentHCC was also higher in the non-IFN group than IFN group (6.7% and 27% vs 0 and 0% at 1- and 3-year, P = 0.048, respectively). CONCLUSION: Low-dose intermittent IFN-alpha therapy for patients with HCV-related compensated cirrhosis after curative HCC treatment was effective by making patients tolerant to medical or surgical treatment for recurrent HCC in the later period of observation.     

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related 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.     

Evidence-based diagnosis and locoregional therapy for hepatocellular carcinoma

Early identification of hepatocellular carcinoma (HCC) is crucial to improving the results of therapy and for patients to be eligible for liver transplantation. Recent advances in noninvasive imaging technology include various techniques of harmonic ultrasound, new ultrasound contrast agents, multislice helical computed tomography and rapid high-quality magnetic resonance. The imaging diagnosis relies on the hallmark of arterial hypervascularity with portal venous washout. Since the use of better radiological techniques has improved the accuracy of noninvasive diagnosis, the role of liver biopsy in the diagnosis of HCC has declined. With recent advances in genomics and proteomics, a great number of potential markers have been identified and developed as new candidate markers for HCC. Locoregional therapies currently constitute the best options for early nonsurgical treatment of HCC. Percutaneous ethanol injection shows similar results to resection surgery for single tumors less than 3 cm in diameter. Radiofrequency ablation is superior to percutaneous ethanol injection in terms of local recurrence. Transarterial chemoembolization is currently the most common approach for the management of HCC without curative options since it improves patient survival, but the optimal embolizing agent, length of interval between sessions and whether the chemotherapeutic agent has any effect have not yet been determined. Combining transarterial chemoembolization with antiangiogenic agents, as well as with other techniques, such as radiofrequency ablation, may improve the results. Injection of radioisotopes such as yttrium-90, via the hepatic artery, may be particularly useful in patients with portal vein thrombosis. Comparisons with other transarterial techniques are needed.     

Das hepatozelluläre Karzinom

Hepatocellular cancer (HCC) is the most common cause of death among patients with liver cirrhosis. Screening programs for high-risk patients allow diagnosis at an early stage, when curative treatment options can be offered. Contrast-enhanced imaging modalities are used for diagnosis, with a typical finding in the respective imaging technique being sufficient to establish the diagnosis for lesions >2 cm. Depending on the imaging results, biopsy for histological confirmation of the diagnosis has to be considered for lesions 1–2 cm in diameter. Lesions <1 cm should be controlled after 3 months. In patients without chronic liver disease, histological confirmation is always required. According to stage-dependent treatment algorithms, surgical options are the primary treatment for early-stage disease (resection, orthotopic liver transplantation). In the case of contraindications, radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) can also be considered. The latter is the treatment modality of choice for intermediate-stage disease in which curative options are no longer available. Further ablative and radiological interventional therapy modalities are under current evaluation in clinical studies, also in combination with systemic therapies. For advanced-stage disease in patients with good liver function, systemic therapy with sorafenib is indicated. Further targeted therapies are currently not available. Data of a phase-III trial that has been recently published as abstract confirm the efficacy of Regorafenib as second line treatment. Additionally new data from international multicentric genome sequencing projects suggest further promising therapeutic targets. An effect of sorafenib in an adjuvant setting could not be confirmed.