Emerging curative-intent minimally-invasive therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common cause of liver malignancy and the fourth leading cause of cancer deaths universally. Cure can be achieved for early stage HCC, which is defined as 3 or fewer lesions less than or equal to 3 cm in the setting of Child-Pugh A or B and an ECOG of 0. Patients outside of these criteria who can be down-staged with loco-regional therapies to resection or liver transplantation (LT) also achieve curative outcomes. Traditionally, surgical resection, LT, and ablation are considered curative therapies for early HCC. However, results from recently conducted LEGACY study and DOSISPHERE trial demonstrate that transarterial radio-embolization has curative outcomes for early HCC, leading to its recent incorporation into the Barcelona clinic liver criteria guidelines for early HCC. This review is based on current evidence for curative-intent loco-regional therapies including radioembolization for early-stage HCC.     

Hepatocellular carcinoma locoregional therapies: Outcomes and future horizons

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and has an overall five-year survival rate of less than twenty percent. For patients with unresectable disease, evolving liver-directed locoregional therapies provide efficacious treatment across the spectrum of disease stages and via a variety of catheter-directed and percutaneous techniques. Goals of locoregional therapies in HCC may include curative intent in early-stage disease, bridging or downstaging to surgical resection or transplantation for early or intermediate-stage disease, and local disease control and palliation in advanced-stage disease. This review explores the outcomes of chemoembolization, bland embolization, radioembolization, and percutaneous ablative therapies. Attention is also given to prognostic factors related to each of the respective techniques, as well as future directions of locoregional therapies for HCC.     

High rate of complete histopathological response in hepatocellular carcinoma patients after combined transarterial chemoembolization and stereotactic body radiation therapy

BACKGROUNDLiver transplantation (LT) presents a curative treatment option in patients with early stage hepatocellular carcinoma (HCC) who are not eligible for resection or ablation therapy. Due to a risk of up 30% for waitlist drop-out upon tumor progression, bridging therapies are used to halt tumor growth. Transarterial chemoembolization (TACE) and less commonly stereotactic body radiation therapy (SBRT) or a combination of TACE and SBRT, are used as bridging therapies in LT. However, it remains unclear if one of those treatment options is superior. The analysis of explant livers after transplantation provides the unique opportunity to investigate treatment response by histopathology.AIMTo analyze histopathological response to a combination of TACE and SBRT in HCC in comparison to TACE or SBRT alone. METHODSIn this multicenter retrospective study, 27 patients who received liver transplantation for HCC were analyzed. Patients received either TACE or SBRT alone, or a combination of TACE and SBRT as bridging therapy to liver transplantation. Liver explants of all patients who received at least one TACE and/or SBRT were analyzed for the presence of residual vital tumor tissue by histopathology to assess differences in treatment response to bridging therapies. Statistical analysis was performed using Fisher-Freeman-Halton exact test, Kruskal-Wallis and Mann-Whitney-U tests.RESULTSFourteen patients received TACE only, four patients SBRT only, and nine patients a combination therapy of TACE and SBRT. There were no significant differences between groups regarding age, sex, etiology of underlying liver disease or number and size of tumor lesions. Strikingly, analysis of liver explants revealed that almost all patients in the TACE and SBRT combination group (8/9, 89%) showed no residual vital tumor tissue by histopathology, whereas TACE or SBRT alone resulted in significantly lower rates of complete histopathological response (0/14, 0% and 1/4, 25%, respectively, P value < 0.001). CONCLUSIONOur data suggests that a combination of TACE and SBRT increases the rate of complete histopathological response compared to TACE or SBRT alone in bridging to liver transplantation.     

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.     

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.     

Effective Biliary Drainage and Proper Treatment Improve Outcomes of Hepatocellular Carcinoma with Obstructive Jaundice

Background/Aims

We investigated the treatment outcomes and prognostic factors of hepatocellular carcinoma (HCC) with obstructive jaundice.

Methods

Among 2,861 patients newly diagnosed with HCC between 2002 and 2011, a total of 63 patients who initially presented with obstructive jaundice were analyzed. Only four patients presented with resectable tumors and underwent curative resection. In the other patients who presented with unresectable tumors, 5, 8, 9, and 18 patients received transarterial chemoembolization (TACE), chemotherapy, radiotherapy, and combined treatment, respectively. Both the clinical and the treatment factors that affect overall survival (OS) were analyzed.

Results

The median OS was 4 months, and the 1-year OS rate was 23%. Patients who received treatment for HCC had a significantly improved OS rate compared with the patients who received supportive care only (1-year OS, 32% vs 0%; p<0.01). Responders to treatment showed a better OS than nonresponders (1-year OS, 52% vs 0%; p<0.01). TACE and radiotherapy resulted in relatively good treatment responses of 64% and 67%, respectively. In multivariate analyses, treatment of HCC (p=0.02) and the normalization of serum bilirubin by biliary drainage (p=0.02) were significantly favorable prognostic factors that affected the OS.

Conclusions

Unresectable HCC with obstructive jaundice has a poor prognosis. However, effective biliary drainage and treatment of HCC such as with TACE or radiotherapy improves survival.     

Chinese expert consensus on neoadjuvant and conversion therapies for hepatocellular carcinoma

The low resection and high recurrence rates in hepatocellular carcinoma (HCC) are the major challenges to improving prognosis. Neoadjuvant and conversion therapies are underlying strategies to overcome these challenges. To date, no guideline or consensus has been published on the neoadjuvant and conversion therapies in HCC. Recent studies showed that neoadjuvant therapy for resectable HCC and conversion therapy for unresectable HCC are safe, feasible, and effective. Neoadjuvant and conversion therapies have the following advantages in treating HCC: R0 resection with sufficient volume of future liver remnant, relatively simple operation, and wide applicability. Therefore, it was necessary to conduct a widely accepted consensus among the experts in China who have extensive expertise and experience in treating HCC using neoadjuvant and conversion therapies, which is important to standardize the application of neoadjuvant and conversion therapies for the management of HCC. The strategies of neoadjuvant therapy include the selection of the eligible patients, therapy regimen, cycles, effect evaluations, and multidisciplinary treatment. The management of patients with insufficient volume of future liver remnant and patients who cannot achieve R0 resection is the key to the strategies of conversion therapy. Here, we present the resultant evidence- and experience-based consensus to guide the application of neoadjuvant and conversion therapies in clinical practice.     

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: Current Status and Future Directions

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. This cancer commonly arises against a background of chronic liver disease. As a result, a patient with HCC requires multidisciplinary care. Treatment options vary widely based on tumor burden and metastases. The most widely utilized staging system is the Barcelona Clinic Liver Cancer staging system, which recommends treatments based on tumor size and the underlying liver disease and functional status of the patient. Treatment options range from surgical resection or transplantation to locoregional therapies with modalities such as radiofrequency ablation and transarterial chemoembolization to systemic chemotherapies. Future care involves the development of combination therapies that afford the best tumor response, further clarification of the patients best suited for therapies and the development of new oral chemotherapeutic agents.     

Management of recurrent hepatocellular carcinoma after liver transplant

Hepatocellular carcinoma(HCC) is the leading cause of deaths in patients with hepatitis B or C, and its incidence has increased considerably over the past decade and is still on the rise. Liver transplantation(LT) provides the best chance of cure for patients with HCC and liver cirrhosis. With the implementation of the MELD exception system for patients with HCC waitlisted for LT, the number of recipients of LT is increasing, so is the number of patients who have recurrence of HCC after LT. Treatments for intrahepatic recurrence after transplantation and after other kinds of surgery are more or less the same, but long-term cure of posttransplant recurrence is rarely seen as it is a "systemic" disease. Nonetheless, surgicalresection has been shown to be effective in prolonging patient survival despite the technical difficulty in resecting graft livers. Besides surgical resection, different kinds of treatment are also in use, including transarterial chemoembolization, radiofrequency ablation, highintensity focused ultrasound ablation, and stereotactic body radiation therapy. Targeted therapy and modulation of immunosuppressants are also adopted to treat the deadly disease.     

Neoadjuvant and adjuvant treatment strategies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common liver malignancy worldwide and a major cause of cancer-related mortality for which liver resection is an important curative-intent treatment option. However, many patients present with advanced disease and with underlying chronic liver disease and/or cirrhosis, limiting the proportion of patients who are surgical candidates. In addition, the development of recurrent or de novo cancers following surgical resection is common. These issues have led investigators to evaluate the benefit of neoadjuvant and adjuvant treatment strategies aimed at improving resectability rates and decreasing recurrence rates. While high-level evidence to guide treatment decision making is lacking, recent advances in locoregional and systemic therapies, including antiviral treatment and immunotherapy, raise the prospect of novel approaches that may improve the outcomes of patients with HCC. In this review, we evaluate the evidence for various neoadjuvant and adjuvant therapies and discuss opportunities for future clinical and translational research.     

肝细胞癌非手术治疗的现状和进展

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

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.     

Antiviral therapies for hepatitis B virus-related hepatocellular carcinoma

Chronic hepatitis B virus(HBV) infection is a critical risk factor for the carcinogenesis and progression of hepatocellular carcinoma(HCC). It promotes HCC development by inducing liver fibrogenesis, genetic and epigenetic alterations, and the expression of active viral-coded proteins. Effective antiviral treatments inhibit the replication of HBV, reduce serum viral load and accelerate hepatitis B e antigen serum conversion. Timely initiation of antiviral treatment is not only essential for preventing the incidence of HCC in chronic hepatitis B patients, but also important for reducing HBV reactivation, improving liver function, reducing or delaying HCC recurrence, and prolonging overall survival of HBV-related HCC patients after curative and palliative therapies. The selection of antiviral drugs, monitoring of indicators such as HBV DNA and hepatitis B surface antigen, and timely rescue treatment when necessary, are essential in antiviral therapies for HBVrelated HCC.     

Immunotherapy for hepatocellular carcinoma: A promising therapeutic option for advanced disease

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and its incidence continues to increase. Despite improvements in both medical and surgical therapies, HCC remains associated with poor outcomes due to its high rates of recurrence and mortality. Approximately 50% of patients require systemic therapies that traditionally consist of tyrosine kinase inhibitors. Recently, however, immune checkpoint inhibitors have revolutionized HCC management, providing new therapeutic options. Despite these major advances, the different factors involved in poor clinical responses and molecular pathways leading to resistance following use of these therapies remain unclear. Alternative strategies, such as adoptive T cell transfer, vaccination, and virotherapy, are currently under evaluation. Combinations of immunotherapies with other systemic or local treatments are also being investigated and may be the most promising opportunities for HCC treatment. The aim of this review is to provide updated information on currently available immunotherapies for HCC as well as future perspectives.     

肝癌微创介入治疗进展

原发性肝癌的治疗方法一直是许多学者研究的重点,近年来尽管新兴治疗方法层出不穷,但由于病变多发生于进展期肝病或肝硬化的基础上,因此目前原发性肝癌仍然是一种难治性恶性肿瘤。在治疗方面,外科手术切除及肝移植虽是根治性治疗方法,但由于移植相关问题的复杂性及原发性肝癌本身的隐匿性,使得上述两种治疗方法并不能适用于大多数患者。近些年,随着设备和技术水平的提高,原发性肝癌的微创介入治疗得到了越来越多的重视,其中应用最为广泛的就是肝动脉化疗栓塞术(TACE)和组织消融术(TA)。该文主要讨论上述两种介入疗法联合应用治疗原发性肝癌的有效性、可行性,以及近年来介入治疗在原发性肝癌治疗领域的研究进展。     

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.     

Hepatocellular carcinoma after locoregional therapy: Magnetic resonance imaging findings in falsely negative exams

AIM: To elucidate causes for false negative magnetic resonance imaging (MRI) exams by identifying imaging characteristics that predict viable hepatocellular carcinoma (HCC) in lesions previously treated with locoregional therapy when obvious findings of recurrence are absent. METHODS: This retrospective institutional review board-approved and Health Insurance Portability and Accountability Act-compliant study included patients who underwent liver transplantation at our center between 1/1/2000 and 12/31/2012 after being treated for HCC with locoregional therapy. All selected patients had a contrast-enhanced MRI after locoregional therapy within 90 d of transplant that was prospectively interpreted as without evidence of residual or recurrent tumor. Retrospectively, 2 radiologists, blinded to clinical and pathological data, independently reviewed the pre-transplant MRIs for 7 imaging features. Liver explant histopathology provided the reference standard, with clinically significant tumor defined as viable tumor ≥ 1.0 cm in maximum dimension. Fisher’s exact test was first performed to identify significant imaging features. RESULTS: Inclusion criteria selected for 42 patients with 65 treated lesions. Fourteen of 42 patients (33%) and 16 of 65 treated lesions (25%) had clinically significant viable tumor on explant histology. None of the 7 imaging findings examined could reliably and reproducibly determine which treated lesion had viable tumor when the exam had been prospectively read as without evidence of viable HCC. CONCLUSION: After locoregional therapy some treated lesions that do not demonstrate any MRI evidence of HCC will contain viable tumor. As such even patients with a negative MRI following treatment should receive regular short-term imaging surveillance because some have occult viable tumor. The possibility of occult tumor should be a consideration when contemplating any action which might delay liver transplant.