Combination approaches in hepatocellular carcinoma: How systemic treatment can benefit candidates to locoregional modalities

The management of hepatocellular carcinoma (HCC) is challenging because most patients have underlying cirrhosis, and the treatment provides, historically, a limited impact on the natural history of patients with advanced-stage disease. Additionally, recurrence rates are high for those patients who receive local and locoregional modalities, such as surgical (resection and transplantation) or image-guided (ablation and intra-arterial) therapies. Translational research has led to new concepts that are reshaping the current clinical practice. Substantial advancements were achieved in the understanding of the hallmarks that drive hepatocarcinogenesis. This has primed a successful incorporation of novel agents with different targets, such as anti-angiogenic drugs, targeted-therapies, and immune-checkpoint inhibitors. Although clinical trials have proven efficacy of systemic agents in advanced stage disease, there is no conclusive evidence to support their use in combination with loco-regional therapy. While novel local modalities are being incorporated (e.g., radioembolization, microwave ablation, and irreversible electroporation), emerging data indicate that locoregional treatments may induce tumor microenvironment changes, such as hyperexpression of growth factors, release of tumor antigens, infiltration of cytotoxic lymphocytes, and modulation of adaptative and innate immune response. Past trials that evaluated the use of antiangiogenic drugs in the adjuvant setting after ablation or chemoembolization fail to demonstrate a substantial improvement. Current efforts are directed to investigate the role of immunotherapy-based regimens in this context. The present review aims to describe the current landscape of systemic and locoregional treatments for HCC, present evidence to support combination approaches, and address future perspectives.     

Combined locoregional treatment of patients with hepatocellular carcinoma: state of the art

In recent years, a combination of intervention therapies has been widely applied in the treatment of hepatocellular carcinoma(HCC). One such combined strategy is based on the combination of the percutaneous approach, such as radiofrequency ablation(RFA), and the intra-arterial locoregional approach, such as trans-arterial chemoembolization(TACE). Several types of evidence have supported the feasibility and benefit of combined therapy, despite some studies reporting conflicting results and outcomes. The aim of this review was to explain the technical aspects of different combined treatments and to comprehensively analyze and compare the clinical efficacy and safety of this combined treatment option and monotherapy, either as TACE or RFA alone, in order to provide clinicians with an unbiased opinion and valuable information. Based on a literature review and our experience, combined treatment seems to be a safe and effective option in the treatment of patients with early/intermediate HCC when surgical resection is not feasible; furthermore, this approach provides better results than RFA and TACE alone for the treatment of large HCC, defined as those exceeding 3 cm in size. It can also expand the indication for RFA to previously contraindicated "complex cases", with increased risk of thermal ablation related complications due to tumor location, or to "complex patients" with high bleeding risk.     

Risk factors for hepatocellular carcinoma in cirrhosis due to nonalcoholic fatty liver disease: A multicenter,case-control study

AIM To identify risk factors associated with hepatocellular carcinoma(HCC), describe tumor characteristics and treatments pursed for a cohort of individuals with nonalcoholic steatohepatitis(NASH) cirrhosis. METHODS We conducted a retrospective case-control study of a well-characterized cohort of patients among five liver transplant centers with NASH cirrhosis with(cases) and without HCC(controls).RESULTS Ninety-four cases and 150 controls were included. Cases were significantly more likely to be male than controls(67% vs 45%, P 0.001) and of older age(61.9 years vs 58 years, P = 0.002). In addition, cases were more likely to have had complications of end stage liver disease(83% vs 71%, P = 0.032). On multivariate analysis, the strongest association with the presence of HCC were male gender(OR 4.3, 95%CI: 1.83-10.3, P = 0.001) and age(OR = 1.082, 95%CI: 1.03-1.13, P = 0.001). Hispanic ethnicity was associated with a decreased prevalence of HCC(OR = 0.3, 95%CI: 0.09-0.994, P = 0.048). HCC was predominantly in the form of a single lesion with regional lymph node(s) and distant metastasis in only 2.6% and 6.3%, respectively. Fifty-nine point three percent of individuals with HCC underwent locoregional therapy and 61.5% underwent liver transplantation for HCC. CONCLUSION Male gender, increased age and non-Hispanic ethnicity are associated with HCC in NASH cirrhosis. NASH cirrhosis associated HCC in this cohort was characterized by early stage disease at diagnosis and treatment with locoregional therapy and transplant.     

Selection criteria for liver resection in patients with hepatocellular carcinoma and chronic liver disease

Hepatocellular carcinoma （HCC） is one of the most common malignancies worldwide with an annual occurrence of one million new cases. An etiologic association between HBV infection and the development of HCC has been established with a relative risk 200-fold greater than in non-infected individuals. Hepatitis C virus is also proving an important predisposing factor for this malignancy with an incidence rate of 7% at 5 years and 14% at 10 years. The prognosis depends on tumor stage and degree of liver function, which affect the tolerance to invasive treatments. Although surgical resection is generally accepted as the treatment of choice for HCC, new treatment strategies, such as local ablative therapies, transarterial embolization and liver transplantation, have been developed nowadays. With increasing detection of small HCCs from screening programs for cirrhotic patients, it is foreseen that locoregional therapy will play an important role 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.     

Hepatocellular carcinoma Liver Imaging Reporting and Data Systems treatment response assessment: Lessons learned and future directions

Hepatocellular carcinoma(HCC) is a leading cause of morbidity and mortality worldwide, with rising clinical and economic burden as incidence increases. Thereare a multitude of evolving treatment options, including locoregional therapies which can be used alone, in combination with each other, or in combination with systemic therapy. These treatment options have shown to be effective in achieving remission, controlling tumor progression, improving disease free and overall survival in patients who cannot undergo resection and providing a bridge to transplant by debulking tumor burden to downstage patients. Following locoregional therapy(LRT), it is crucial to provide treatment response assessment to guide management and liver transplant candidacy. Therefore, Liver Imaging Reporting and Data Systems(LI-RADS) Treatment Response Algorithm(TRA) was created to provide a standardized assessment of HCC following LRT. LIRADS TRA provides a step by step approach to evaluate each lesion independently for accurate tumor assessment. In this review, we provide an overview of different locoregional therapies for HCC, describe the expected post treatment imaging appearance following treatment, and review the LI-RADS TRA with guidance for its application in clinical practice. Unique to other publications, we will also review emerging literature supporting the use of LI-RADS for assessment of HCC treatment response after LRT.     

Epidemiology and management of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major world health problem because of the high incidence and case fatality rate. In most patients, the diagnosis of HCC is made at an advanced stage, which limits the application of curative treatments. Most HCCs develop in patients with underlying chronic liver disease. Chronic viral hepatitis B and C are the major causes of liver cirrhosis and HCC. Recent improvements in treatment of viral hepatitis and in methods for surveillance and therapy for HCC have contributed to better survival of patients with HCC. This article reviews the epidemiology, cause, prevention, clinical manifestations, surveillance, diagnosis, and treatment approach for HCC.     

Survival impact of delayed treatment in patients with hepatocellular carcinoma undergoing locoregional therapy: is there a lead-time bias?

OBJECTIVE: Many reports indicate the importance of active treatment for hepatocellular carcinoma (HCC), but there are few studies available that address the impact of delayed therapy on survival or take the lead-time bias into account. The objective of this study was to investigate whether patients with delayed locoregional therapy for HCC truly have a shortened survival from the time of diagnosis. MATERIAL AND METHODS: Survival rates were compared between 48 HCC patients with treatment delay and 96 age- and gender-matched controls without delay. All patients underwent transarterial chemoembolization or percutaneous ethanol or acetic acid injection for HCC. Treatment delay was defined as a >2 months' time interval between diagnosis and treatment. RESULTS: Baseline comparison showed that patients with treatment delay had higher scores in the model for endstage liver disease compared with those of patients without delay (12.3+/-1.8 versus 11.1+/-2.5, p=0.01). In the Cox multivariate model, advanced cancer stage (relative risk (RR): 2.66, p=0.001), Child-Turcotte-Pugh class B (RR: 3.81, p<0.001), tumor size >5 cm (RR: 2.02, p=0.011) and treatment delay (RR: 2.91, p=0.001) were independent poor prognostic predictors. Among patients with treatment delay, disease progression was registered in 30 (63%) patients. Patients with prolonged treatment delay (>3 months) were more likely to have tumor progression (p=0.013). In the Cox model, a treatment delay of >3 months independently predicted a poor rate of survival (RR: 3.67, p=0.002). CONCLUSIONS: Delayed HCC treatment is linked with shortened overall survival unrelated to the lead-time bias in patients undergoing locoregional therapy. Prolonged treatment delay of more than 3 months in these patients may worsen the long-term outcome.     

Percutaneous ablation for perivascular hepatocellular carcinoma: Refining the current status based on emerging evidence and future perspectives

Various therapeutic modalities including radiofrequency ablation, cryoablation, microwave ablation, and irreversible electroporation have attracted attention as energy sources for effective locoregional treatment of hepatocellular carcinoma(HCC); these are accepted non-surgical treatments that provide excellent local tumor control and favorable survival. However, in contrast to surgery, tumor location is a crucial factor in the outcomes of locoregional treatment because such treatment is mainly performed using a percutaneous approach for minimal invasiveness; accordingly, it has a limited range of ablation volume. When the index tumor is near large blood vessels, the blood flow drags thermal energy away from the targeted tissue, resulting in reduced ablation volume through a socalled "heat-sink effect". This modifies the size and shape of the ablation zone considerably. In addition, serious complications including infarction or aggressive tumor recurrence can be observed during follow-up after ablation for perivascular tumors by mechanical or thermal damage. Therefore, perivascular locations of HCC adjacent to large intrahepatic vessels can affect post-treatment outcomes. In this review, we primarily focus on physical properties of perivascular tumor location, characteristics of perivascular HCC,potential complications, and clinical outcomes after various locoregional treatments; moreover, we discuss the current status and future perspectives regarding percutaneous ablation for perivascular HCC.     

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.     

Immunotherapy for hepatocellular carcinoma:Current and future

Hepatocellular carcinoma(HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However,there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy,either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.     

Management of patients with hepatocellular carcinoma and extrahepatic metastasis

Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) has recently been paradoxically increasing due to increased survival with effective locoregional therapies. The intrahepatic stage of the tumor is important for determining the risk of an extrahepatic lesion. Almost all patients with intrahepatic stage T(3-4), with or without EHM, die of progressive intrahepatic HCC but not due to EHM; thus, the majority of patients with HCC and EHM need to undergo concurrent treatment for intrahepatic HCC. There is no convincing evidence, to date, that systemic chemotherapy improves overall survival. Sorafenib is the first systemic agent that has demonstrated a significant survival benefit in patients with advanced HCC; however, the modest improvement of 3 months is far from satisfactory. Therefore, most hepatologists still rely on the conventional multidisciplinary approach to treat patients with EHM. The concept of the multidisciplinary treatment is the combination of locoregional therapies for both the intrahepatic HCC and symptomatic EHM when confined to a single organ. Targeted therapy may be considered for patients with advanced intrahepatic HCC and multiple EHM, however the potential efficacy of this approach requires confirmation. The outcome of ongoing clinical trials of the multidisciplinary approach, combining conventional locoregional therapy and targeted systemic therapy, is pending.     

Salvage locoregional therapies for recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the second most common cause of cancerrelated death worldwide. Despite the advent of screening efforts and algorithms to stratify patients into appropriate treatment strategies, recurrence rates remain high. In contrast to first-line treatment for HCC, which relies on several factors, including clinical staging, tumor burden, and liver function, there is no consensus or general treatment recommendations for recurrent HCC(R-HCC). Locoregional therapies include a s...     

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.     

Deep learning in hepatocellular carcinoma: Current status and future perspectives

Hepatocellular carcinoma (HCC) is among the leading causes of cancer incidence and death. Despite decades of research and development of new treatment options, the overall outcomes of patients with HCC continue to remain poor. There are areas of unmet need in risk prediction, early diagnosis, accurate prognostication, and individualized treatments for patients with HCC. Recent years have seen an explosive growth in the application of artificial intelligence (AI) technology in medical research, with the field of HCC being no exception. Among the various AI-based machine learning algorithms, deep learning algorithms are considered state-of-the-art techniques for handling and processing complex multimodal data ranging from routine clinical variables to high-resolution medical images. This article will provide a comprehensive review of the recently published studies that have applied deep learning for risk prediction, diagnosis, prognostication, and treatment planning for patients with HCC.     

Is there still a role for the hepatic locoregional treatment of metastatic neuroendocrine tumors in the era of systemic targeted therapies?

Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs) frequently present with distant metastases at the time of diagnosis and the liver is the most frequent site of spreading. The early identification of metastatic disease represents a major prognostic factor for GEP-NENs patients. Radical surgical resection, which is feasible for a minority of patients, is considered the only curative option, while the best management for patients with unresectable liver metastases is still being debated. In the last few years, a number of locoregional and systemic treatments has become available for GEP-NEN patients metastatic to the liver. However, to date only a few prospective studies have compared those therapies and the optimal management option is based on clinical judgement. Additionally, locoregional treatments appear feasible and safe for disease control for patients with limited liver involvement and effective in symptoms control for patients with diffuse liver metastases. Considering the lack of randomized controlled trials comparing the locoregional treatments of liver metastatic NEN patients, clinical judgment remains key to set the most appropriate therapeutic pathway. Prospective data may ultimately lead to more personalized and optimized treatments. The present review analyzes all the locoregional therapy modalities(i.e., surgery, ablative treatments and transarterial approach) and aims to provide clinicians with a useful algorithm to best treat GEP-NEN patients metastatic to the liver.     

Indications of external radiotherapy for hepatocellular carcinoma from updated clinical guidelines: Diverse global viewpoints

significantly vary among regions.Modern standard treatments commonly require multidisciplinary approaches,including applications of up-to date medicine and advanced procedures,and necessitate the support of socioeconomic systems.For these reasons,a number of clinical guidelines for HCC from different associations and regions have been presented.External beam radiation therapy was contraindicated for HCC until a few decades ago,but with the development of new technologies,its application has rapidly increased as selective irradiation for tumorous lesions became possible.Most of the guidelines had been opposed or indifferent to radiotherapy in the past,but several guidelines have introduced indications and recommendations for radiotherapy in their updated versions.This review will discuss the characteristics of important guidelines and their contents regarding radiotherapy and will also provide guidance to physicians who are considering applications of locoregional modalities that include radiotherapy.     

Loco-regional treatment of hepatocellular carcinoma: Role of contrast-enhanced ultrasonography

Hepatocellular carcinoma (HCC) is one of the few cancers for which locoregional treatments (LRTs) are included in international guidelines and are considered as a valid alternative to conventional surgery. According to Barcelona Clinic Liver Cancer classification, percutaneous treatments such as percutaneous ethanol injection, radiofrequency ablation and microwave ablation are the therapy of choice among curative treatments in patients categorized as very early and early stage, while transcatheter arterial chemoembolization is considered the better option for intermediate stage HCC. A precise assessment of treatment efficacy and surveillance is essential to optimize survival rate, whereas residual tumor requires additional treatment. Imaging modalities play a key role in this task. Currently, contrast-enhanced computed tomography/magnetic resonance imaging are considered the standard imaging modalities for this purpose. Contrast enhanced ultrasound (CEUS), using second generation contrast agents, plays an increasingly important role in detecting residual disease after LRTs. CEUS is a straightforward to perform, repeatable and cost-effective imaging modality for patients with renal failure or iodine allergies. Due to the ability to focus on single regions, CEUS can also provide high temporal resolution. Moreover, several studies have reported the same or better diagnostic accuracy as contrast-enhanced computed tomography for assessing tumor vascularity 1 mo after LRTs, and recently three-dimensional (3D)-CEUS has been reported as a promising technique to improve the evaluation of tumor response to therapy. Furthermore, CEUS could be used early after procedures in monitoring HCC treatments, but nowadays this indication is still debated, and data from literature are conflicting, especially after transcatheter arterial chemoembolization procedure.     

Effects of loco regional treatments before living donor liver transplantation on overall survival and recurrence-free survival in South Korean patients with hepatocellular carcinoma

Background

We evaluated the effects of pre-transplant locoregional treatment on survival in living donor liver transplantation (LDLT), and the most accurate method for predicting survival after LDLT in patients who received pre-transplant locoregional treatment.

Methods

From December 2003 to December 2012, 234 patients underwent LDLT for hepatocellular carcinoma (HCC) at our transplant center. We retrospectively reviewed 86 patients newly diagnosed with HCC and who received pre-transplant locoregional treatments at our hospital.

Results

Of the 33 patients with HCC initially beyond the Milan criteria, 12 experienced successful down-staging after locoregional treatments, and the 5-year recurrence-free survival was 81.8%, which was comparable to those in patients with HCC initially within the Milan criteria. A bad responder according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) [HR, 4.874 (1.059–22.442), p = 0.042], and increased AFP levels [HR 4.002 (1.540–10.397), p = 0.004] during pre-transplant locoregional treatments were independent risk factors for HCC recurrence after LDLT in multivariate analysis.

Conclusions

Liver transplantation may be considered after successful down-staging in patients with HCC initially beyond the Milan criteria. The mRECIST and serum AFP level changes are better selection criteria for LDLT in patients who have received locoregional treatments.