Management of HCC

Hepatocellular carcinoma (HCC) is a highly prevalent and lethal neoplasia, the management of which has significantly improved during the last few years. A better knowledge of the natural history of the tumor and the development of staging systems that stratify patients according to the characteristics of the tumor, the liver disease, and the performance status, such as the BCLC (Barcelona Clinic Liver Cancer) system, have led to a better prediction of prognosis and to a most appropriate treatment approach. Today curative therapies (resection, transplantation, ablation) can improve survival in patients diagnosed at an early HCC stage and offer a potential long-term cure. Patients with intermediate stage HCC benefit from chemoembolization and those diagnosed at advanced stage benefit from sorafenib, a multikinase inhibitor with antiangiogenic and antiproliferative effects. In this article we review the current management in HCC and the new advances in this field.     

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

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

Treatment of hepatocellular carcinoma with portal venous tumor thrombosis: A comprehensive review

The natural history of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is dismal (approximately 2-4 mo), and PVTT is reportedly found in 10%-40% of HCC patients at diagnosis. According to the Barcelona Clinic Liver Cancer (BCLC) Staging System (which is the most widely adopted HCC management guideline), sorafenib is the standard of care for advanced HCC (i.e., BCLC stage C) and the presence of PVTT is included in this category. However, sorafenib treatment only marginally prolongs patient survival and, notably, its therapeutic efficacy is reduced in patients with PVTT. In this context, there have been diverse efforts to develop alternatives to current standard systemic chemotherapies or combination treatment options. To date, many studies on transarterial chemoembolization, 3-dimensional conformal radiotherapy, hepatic arterial chemotherapy, and transarterial radioembolization report better overall survival than sorafenib therapy alone, but their outcomes need to be verified in future prospective, randomized controlled studies in order to be incorporated into current treatment guidelines. Additionally, combination strategies have been applied to treat HCC patients with PVTT, with the hope that the possible synergistic actions among different treatment modalities would provide promising results. This narrative review describes the current status of the management options for HCC with PVTT, with a focus on overall survival.     

Prognosis prediction and staging

Staging and prognosis assessment are critical steps in the management of patients with hepatocellular carcinoma. This cancer is a complex disease usually associated with chronic liver disease, and any attempt to assess the prognosis should consider tumour burden, degree of liver function impairment and evaluation of cancer-related symptoms. In addition, for any staging system to be meaningful it has to link staging with treatment indication and this should be based on robust scientific data. Currently, the only proposal that serves both aims is the Barcelona Clinic Liver Cancer (BCLC) staging system. It divides patients into very early/early, intermediate, advanced and end-stage. Very early/early stage HCC patients should be considered for potentially curative options such as resection, transplantation and ablation. Patients at intermediate stage benefit from chemoembolization, while patients at an advanced stage or who cannot benefit of options of higher priority have sorafenib as standard of care. Finally, patients at end-stage should receive best supportive care.     

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.     

Indications and Best Practices for Intra-arterial Therapies to Treat Hepatocellular Carcinoma

Purpose of Review

The purpose of this review is to re-evaluate the role of intra-arterial therapies for hepatocellular carcinoma (HCC) recommended by contemporary staging systems.

Recent Findings

Currently, intra-arterial therapies are recommended by the Barcelona Clinic Liver Cancer (BCLC) staging system only for patients with BCLC B HCC in the form of trans-arterial chemoembolization. Recently, randomized controlled trials in patients with BCLC C HCC without metastatic disease have suggested a potential role for trans-arterial radioembolization (TARE) with fewer adverse events and better quality of life compared to sorafenib. Randomized controlled trials have also demonstrated the benefit of using combination therapy of trans-arterial chemoembolization (TACE) with ablation for patients with BCLC A HCC [single tumors (3–7 cm)] compared to ablation alone. Finally, promising results from single-center studies indicate that TARE using a radiation segmentectomy technique may be a potentially curative therapy for tumors less than 3 cm, supporting its use in patients with BCLC A HCC that are not amenable to surgical or ablative therapies.

Summary

Recent randomized clinical trials have demonstrated the benefit of intra-arterial therapies in subpopulations of BCLC stages A, B, and C. These studies highlight the need for careful patient assessment, staging, and multidisciplinary discussion to consider treatments that are not currently included in guidelines but can improve patient outcomes for HCC.

     

Usefulness of staging systems and prognostic scores for hepatocellular carcinoma treatments

Therapeutic management of hepatocellular carcinoma(HCC) is quite complex owing to the underlying cirrhosis and portal vein hypertension. Different scores or classification systems based on liver function and tumoral stages have been published in the recent years. If none of them is currently "universally" recognized, the Barcelona Clinic Liver Cancer(BCLC) staging system has become the reference classification system in Western countries. Based on a robust treatment algorithm associated with stage stratification, it relies on a high level of evidence. However, BCLC stage B and C HCC include a broad spectrum of tumors but are only matched with a single therapeutic option. Some experts have thus suggested to extend the indications for surgery or for transarterial chemoembolization. In clinical practice, many patients are already treated beyond the scope of recommendations. Additional alternative prognostic scores that could be applied to any therapeutic modality have been recently proposed. They could represent complementary tools to the BCLC staging system and improve the stratification of HCC patients enrolled in clinical trials, as illustrated by the NIACE score. Prospective studies are needed to compare these scores and refine their role in the decision making process.     

Medical treatments: in association or alone, their roles and their future perspectives

Management of hepatocellular carcinoma (HCC) is a complex issue, as it needs to take into account the liver disease, the cancer stage and the performance status of the patient. The treatment decision has to be based on robust scientific evidence and for this it is instrumental to have a proper staging system linked to the treatment indication. The BCLC proposal serves these two purposes and has been validated worldwide and endorsed by several scientific associations. The sole systemic therapy that has shown efficacy in improving the survival of HCC patients is sorafenib, an oral kinase inhibitor that blocks the Raf/MEK/ERK pathway and the receptor for VEGFR 2 and PDGFR-beta. Sorafenib has been recognized as the standard of care for patients who cannot benefit from treatments of higher priority and established efficacy, such as surgical resection, transplantation, ablation and transarterial chemoembolization. Sorafenib has changed the management of HCC, opening the path to combination therapies for patients at advanced stages and to evaluation as an adjuvant for those in earlier evolutionary stages.     

肝细胞癌四种临床分期系统预后判断和治疗指导价值的比较

目的 比较4个分期系统[巴塞罗那临床肝癌分期标准(BCLC)、日本综合分期积分(JIS)、意大利肝癌评分(CLIP)和国内分期]对中国肝癌患者预后判断和对治疗方案选择的指导意义.方法 回顾性分析2001年至2002年复旦大学附属中山医院收治的861例初发肝细胞癌患者的临床资料,分别按4个分期系统分期或评分,比较各期患者的生存情况以及不同治疗方案对其生存的影响.结果 在判断预后方面,BCLC、JIS和国内分期系统的各分期间生存率差异均有统计学意义;而在CLIP分期的一些评分间的生存率差异无统计学意义.在指导治疗方面,BCLC C期,CLIP 3、4分以及国内分期ⅢA期的患者接受手术治疗与接受肝动脉化学治疗栓塞(TACE)和(或)肝动脉栓塞(TAE)治疗的生存率差异无统计学意义;而比这些更早期的患者接受手术治疗的生存率优于接受TACE和(或)TAE治疗的生存率.结论 BCLC、JIS和国内分期系统在判断预后方面适用于中国患者;但仅国内分期和BCLC分期同时兼备了判断预后和指导治疗两方面的作用.     

Current systemic treatment of hepatocellular carcinoma: A review of the literature

Hepatocellular carcinoma (HCC) is the fifth most common form of human cancer worldwide and the third most common cause of cancer-related deaths. The strategies of various treatments for HCC depend on the stage of tumor, the status of patient’s performance and the reserved hepatic function. The Barcelona Clinic Liver Cancer (BCLC) staging system is currently used most for patients with HCC. For example, for patients with BCLC stage 0 (very early stage) and stage A (early stage) HCC, the curable treatment modalities, including resection, transplantation and radiofrequency ablation, are taken into consideration. If the patients are in BCLC stage B (intermediate stage) and stage C (advanced stage) HCC, they may need the palliative transarterial chemoembolization and even the target medication of sorafenib. In addition, symptomatic treatment is always recommended for patients with BCLC stage D (end stage) HCC. In this review, we will attempt to summarize the historical perspective and the current developments of systemic therapies in BCLC stage B and C in HCC.     

Comparative effectiveness of traditional chemoembolization with or without sorafenib for hepatocellular carcinoma

AIM: To compare the overall survival (OS) and progression-free survival (PFS) with associated adverse events (AE) in patients with unresectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) + sorafenib vs TACE alone. METHODS: In this retrospective cohort study we collected data on all consecutive patients with a diagnosis of unresectable HCC between 2007 and 2011 who had been treated with TACE + sorafenib or TACE alone. We hypothesized that the combination therapy is superior to TACE alone in improving the survival in these patients. Data extracted included patient’s demographics, etiology of liver disease, histology of HCC, stage of liver disease with respect to model of end stage liverdisease score and Child-Turcotte-Pugh (CTP) classification and Barcelona Clinic Liver Cancer (BCLC) staging for HCC. Computed tomography scan findings, alpha fetoprotein levels, number of treatments and related AE were also recorded and analyzed. RESULTS: Of the 43 patients who met inclusion criteria, 13 were treated with TACE + sorafenib and 30 with TACE alone. There was no significant difference in median survival: 20.6 mo (95%CI: 13.4-38.4) for the TACE + sorafenib and 18.3 mo (95%CI: 11.8-32.9) for the TACE alone (P = 0.72). There were also no statistically significant differences between groups in OS (HR = 0.82, 95%CI: 0.38-1.77; P = 0.61), PFS (HR = 0.93, 95%CI: 0.45-1.89; P = 0.83), and treatment-related toxicities (P = 0.554). CTP classification and BCLC staging for HCC were statistically significant (P = 0.001, P = 0.04 respectively) in predicting the survival in patients with HCC. The common AE observed were abdominal pain, nausea, vomiting and mild elevation of liver enzymes. CONCLUSION: Combination therapy with TACE + sorafenib is safe and equally effective as TACE alone in patients with unresectable HCC. CTP classification and BCLC staging were the significant predictors of survival. Future trials with large number of patients are needed to further validate this observation.     

Diagnosis and treatment of hepatocellular carcinoma

The diagnosis and treatment of hepatocellular carcinoma (HCC) have witnessed major changes over the past decade. Until the early 1990s, HCC was a relatively rare malignancy, typically diagnosed at an advanced stage in a symptomatic patient, and there were no known effective palliative or therapeutic options. However, the rising incidence of HCC in several regions around the world coupled with emerging evidence for efficacy of screening in high-risk patients, liver transplantation as a curative option in select patients, ability to make definitive diagnosis using high-resolution imaging of the liver, less dependency on obtaining tissue diagnosis, and proven efficacy of transarterial chemoembolization and sorafenib as palliative therapy have improved the outlook for HCC patients. In this article, we present a summary of the most recent information on screening, diagnosis, staging, and different treatment modalities of HCC, as well as our recommended management approach.     

Intermediate hepatocellular carcinoma: How to choose the best treatment modality?

Intermediate stage, or stage B according to Barcelona Clinic Liver Cancer classification, of hepatocellular carcinoma (HCC) comprises a heterogeneous population with different tumor burden and liver function. This heterogeneity is confirmed by the large variability of treatment choice and disease-relate survival. The aim of this review was to highlight the existing evidences regarding this specific topic. In a multidisciplinary evaluation, patients with large (> 5 cm) solitary HCC should be firstly considered for liver resection (LR). When LR is unfeasible, locoregional treatments are evaluable therapeutic options, being transarterial chemoembolization (TACE), the most used procedure. Percutaneous ablation can be an evaluable treatment for large HCC. However, the efficacy of all ablative procedures decrease as tumor size increases over 3 cm. In clinical practice, a combination treatment strategy [TACE or transarterial radioembolization (TARE)-plus percutaneous ablation] is “a priori” preferred in a relevant percentage of these patients. On the other hands, sorafenib is the treatment of choice in patients who are unsuitable to surgery and/or with a contraindication to locoregional treatments. In multifocal HCC, TACE is the first-line treatment. The role of TARE is still undefined. Surgery may have also a role in the treatment of multifocal HCC in selected cases (patients with up to three nodules, multifocal HCC involving 2-3 adjacent liver segments). In some patients with bilobar disease the combination of LR and ablative treatment may be a valuable option. The choice of the best treatment in the patient with intermediate stage HCC should be “patient-tailored” and made by a multidisciplinary team.     

From liver cirrhosis to HCC

Hepatocellular carcinoma represents the main cause of death in patients with Child-A cirrhosis. Surveillance programs aimed at the early diagnosis of hepatocellular carcinoma, at potentially treatable stages, are mandatory in Child-A cirrhotic patients and in Child-B cirrhotic patients, provided liver transplantation can be pursued. Surveillance allows stage migration and in definite subgroups of patients, it improves survival as well. Even though several circulating markers have been tested, none of them, including serum AFP determination, is actually recommended in the setting of surveillance. Thus ultrasound scan is the only recommended test, and it should be performed at 6-month intervals. Upon detection of a new nodule, a diagnostic algorithm based on the size of the nodule should be applied. In the western countries, the BCLC proposal is the most widely used and validated staging system and it helps to choice of the best treatment option even though each patient deserves a multidisciplinary evaluation due to the complexity of the coexistence of two diseases: hepatocellular carcinoma and liver cirrhosis.     

From liver cirrhosis to HCC

Hepatocellular carcinoma represents the main cause of death in patients with Child-A cirrhosis. Surveillance programs aimed at the early diagnosis of hepatocellular carcinoma, at potentially treatable stages, are mandatory in Child-A cirrhotic patients and in Child-B cirrhotic patients, provided liver transplantation can be pursued. Surveillance allows stage migration and in definite subgroups of patients, it improves survival as well. Even though several circulating markers have been tested, none of them, including serum AFP determination, is actually recommended in the setting of surveillance. Thus ultrasound scan is the only recommended test, and it should be performed at 6-month intervals. Upon detection of a new nodule, a diagnostic algorithm based on the size of the nodule should be applied. In the western countries, the BCLC proposal is the most widely used and validated staging system and it helps to choice of the best treatment option even though each patient deserves a multidisciplinary evaluation due to the complexity of the coexistence of two diseases: hepatocellular carcinoma and liver cirrhosis.     

Effective treatment strategies other than sorafenib for the patients with advanced hepatocellular carcinoma invading portal vein

Patients with hepatocellular carcinoma(HCC) accompanying portal vein tumor thrombosis(PVTT) have relatively few therapeutic options and an extremely poor prognosis. These patients are classified into barcelonaclinic liver cancer stage C and sorafenib is suggested as the standard therapy of care. However, overall survival(OS) gain from sorafenib is unsatisfactory and better treatment modalities are urgently required. Therefore, we critically appraised recent data for the various treatment strategies for patients with HCC accompanying PVTT. In suitable patients, even surgical resection can be considered a potentially curative strategy. Transarterial chemoembolization(TACE) can be performed effectively and safely in a carefully chosen population of patients with reserved liver function and sufficient collateral blood flow nearby the blocked portal vein. A recent metaanalysis demonstrated that TACE achieved a substantial improvement of OS in HCC patients accompanying PVTT compared with best supportive care. In addition, transarterial radioembolization(TARE) using yttrium-90 microspheres achieves quality-of-life advantages and is as effective as TACE. A large proportion of HCC patients accompanying PVTT are considered to be proper for TARE. Moreover, TACE or TARE achieved comparable outcomes to sorafenib in recent studies and it was also reported that the combination of radiotherapy with TACE achieved a survival gain compared to sorafenib in HCC patients accompanying PVTT. Surgical resectionbased multimodal treatments, transarterial approaches including TACE and TARE, and TACE-based appropriate combination strategies may improve OS of HCC patients accompanying PVTT.     

Role of liver resection in the management of multinodular hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide. Various treatment modalities have been applied to HCC depending on the tumor load, functional capacity of the liver and the general condition of the patient. According to Barcelona Clinic Liver Cancer staging strategy and The American Association for the Study of Liver Disease guidelines, surgical resection is not advocated in the tretment of multinodular HCC. Despite this, many recent clinical studies show that, resection can achieve good results in patients with multinodular HCC and 5-year survival rate around 40% can be reached. If resection or transplantation is not performed, these patients are usually managed with palliative procedures such as transarterial chemoembolization, radioembolization and cytotoxic chemotherapy and 5-year survival of this group of patients will be extremely low. Although survival rates are lower and complications may be increased in this group of patients, liver resection can safely be performed in selected patients in experienced centers for the management of multinodular HCC.     

Current management of hepatocellular carcinoma:An Eastern perspective

Hepatocellular carcinoma(HCC) is one of the leading causes of cancer death, especially in Eastern areas. With advancements in diagnosis and treatment modalities for HCC, the survival and prognosis of HCC patients are improving. However, treatment patterns are not uniform between areas despite efforts to promote a common protocol. Although many hepatologists in Asian countries may adopt the principles of the Barcelona Clinic Liver Cancer staging system, they are also independently making an effort to expand the indications of each treatment and to combine therapies for better outcomes. Several expanded criteria for liver transplantation in HCC have been developed in Asian countries. Living donor liver transplantation is much more commonly performed in these countries than deceased donor liver transplantation, and it may be preceded by other treatments such as the down-staging of tumors. Local ablation therapies are often combined with transarterial chemoembolization( TACE) and the outcome is comparable to that of surgical resection. The indications of TACE are expanding, and there are new types of transarterial therapies. Although data on drug-eluting beads, TACE, and radioembolization in Asian countries are still relatively sparse compared with Western countries, these methods are gradually gaining popularity because of better tolerability and the possibility of improved response rates. Hepatic arterial infusion chemotherapy and radiotherapy are not included in Western guidelines, but are currently being used actively in several Asian countries. For more advanced HCCs, appropriate combinations of TACE, radiotherapy, and sorafenib can be considered, and emerging data indicate improved outcomes of combination therapies compared with single therapies. To include these paradigm shifts into newer treatment guidelines, more studies may be needed, but they are certainly in progress.     

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.     

Neo-adjuvant therapy for hepatocellular carcinoma before liver transplantation: Where do we stand?

Liver transplantation(LT)for hepatocellular carcinoma(HCC)within Milan criteria is a widely accepted optimal therapy.Neo-adjuvant therapy before transplantation has been used as a bridging therapy to prevent dropout during the waiting period and as a down-staging method for the patient with intermediate HCC to qualify for liver transplantation.Transarterial chemoembolization and radiofrequency ablation are the most commonly used method for locoregional therapy.The data associated with newer modalities including drugeluting beads,radioembolization with Y90,stereotactic radiation therapy and sorafenib will be discussed as a tool for converting advanced HCC to LT candidates.The concept"ablate and wait"has gained the popularity where mandated observation period after neoadjuvant therapy allows for tumor biology to become apparent,thus has been recommended after downstaging.The role of neo-adjuvant therapy with conjunction of"ablate and wait"in living donor liver transplantation for intermediate stage HCC is also discussed in the paper.