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.     

Outcome of transarterial chemoembolization monotherapy, and in combination with percutaneous ethanol injection, or radiofrequency ablation therapy for hepatocellular carcinoma

Aim:  Hepatocellular carcinoma (HCC) is one of the most commonly occurring malignances worldwide. Curative therapies such as resection, percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA) have been applied to patients with early-stage HCC. Patients with more advanced cancers require local or systemic therapies. We present the results of our retrospective review conducted to evaluate whether transarterial chemoembolization (TACE) alone and combined TACE with percutaneous ablation for HCC exhibited superior efficacy to palliative treatment.
Methods:  The effects of TACE and of the combined therapies (TACE + PEI or TACE + RFA) on the long-term survival rates were evaluated in 268 untreated HCC patients by various statistical analyses.
Results:  The cumulative survival rates in the TACE alone group were significantly superior to those in the palliative treatment group. Further, the cumulative survival rates in the combined TACE + PEI/RFA group were significantly superior to those in the TACE alone group. When the comparison among the groups was restricted to patients with two or three tumors fulfilling the Milan criteria, significantly greater prolongation of survival was observed in the combined TACE + PEI/RFA group than in the PEI/RFA alone group.
Conclusions:  The aforementioned treatment modalities yielded greater improvements of the survival rate and survival duration as compared to palliative treatment in HCC patients. Furthermore, in terms of the effect on the survival period, combined TACE + PEI/RFA therapy was more effective than TACE monotherapy, and also more effective than PEI or RFA monotherapy in cases with multiple tumors fulfilling the Milan criteria.     

Liver resection for intermediate hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common malignant tumors in China. The Barcelona Clinic Liver Cancer(BCLC) staging system is regarded as the gold standard staging system for HCC, classifying HCC as early, intermediate, or advanced. For intermediate HCC, trans-catheter arterial chemoembolization(TACE) is recommended as the optimal strategy by the BCLC guideline. This review investigates whether liver resection is better than TACE for intermediate HCC. Based on published studies, we compare the survival benefits and complications of liver resection and TACE for intermediate HCC. We also compare the survival benefits of liver resection in early and intermediate HCC. We find that liver resection can achieve better or at least comparable survival outcomes compared with TACE for intermediate HCC; however, we do not observe a significant difference between liver resection and TACE in terms of safety and morbidity. We conclude that liver resection may improve the short- and long-term survival of carefully selected intermediate HCC patients, and the procedure may be safely performed in the management of intermediate HCC.     

Imaging appearance of treated hepatocellular carcinoma

Surgical resection and imaging guided treatments play a crucial role in the management of hepatocellular carcinoma(HCC).Although the primary end point of treatment of HCC is survival,radiological response could be a surrogate end point of survival,and has a key role in HCC decision-making process.However,radiological assessment of HCC treatment efficacy is often controversial.There are few doubts on the evaluation of surgical resection;in fact,all known tumor sites should be removed.However,an unenhancing partial linear peripheral halo,in most cases,surrounding a fluid collection reducing in size during follow-up is demonstrated in successfully resected tumor with bipolar radiofrequency electrosurgical device.Efficacy assessment of locoregional therapies is more controversial and differs between percutaneous ablation(e.g.,radiofrequency ablation and percutaneous ethanol injection)and transarterial treatments(e.g.,conventional transarterial chemoembolization,transarterial chemoembolization with drug eluting beads and radioembolization).Finally,a different approach should be used for new systemic agent that,though not reducing tumor mass,could have a benefit on survival by delaying tumor progression and death.The purpose of this brief article is to review HCC imaging appearance after treatment.     

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.     

Interventional treatments for hepatocellular carcinoma

Introduction Hepatocellular carcinoma (HCC) ranks thefifth in overall frequency (the fifth in men and the eighth in women) and fourth inannual mortality. About 372 000 new cases of HCC are diagnosed each year, constituting 4.6% of all new human cancers (6.3% in men and 2.7% in women).[1] Surgical treatments including hepatic resection and liver transplantation are considered the most effective treatments of HCC. However, less than 20% of HCC can be treated surgically because of multi- foc…     

Radiofrequency ablation,PEIT, and TACE for hepatocellular carcinoma

At detection or over time, hepatocellular carcinoma (HCC) is multicentric in origin, against a background of chronic hepatic disease at different stages. Orthotopic liver transplantation (OLT) is the only therapy able to definitely cure both diseases. When OLT is not feasible, all other options can be only palliative. Owing to the multicentricity, surgical resection may be one possible option at the initial detection in selected patients, whereas percutaneous interventional techniques (percutaneous ethanol injection [PEI], radiofrequency ablation [RFA], selected transcatheter arterial chemoembolization [TACE]) are the options more often used. The range of their indications is becoming wider. Although it is understood that partial resection assures the greatest local control, the survival rates after surgery are roughly comparable with those obtained with PEI. The explanation for this result reflects a balance among the advantages and disadvantages of the two therapies. PEI survival curves are better than curves of resected patients who present with adverse prognostic factors, and this means that a better selection of the patients for surgery is needed. An open question remains the choice among percutaneous techniques. In our department we currently use RFA in most patients but consider PEI and selected TACE complementary, and use them according to the features of the disease and the response.     

Hemobilia immediately after transcatheter arterial chemoembolization using drug‐eluting beads for hepatocellular carcinoma with intrahepatic bile duct invasion

Transcatheter arterial chemoembolization (TACE) is used as a palliative treatment for unresectable hepatocellular carcinoma (HCC) worldwide. Recently, a novel drug delivery–embolic agent, the drug‐eluting bead (DEB), was introduced for TACE. There are a few reports of tumor hemorrhage after TACE using DEB (DEB‐TACE) for HCC. However, there have not been any reports of hemobilia immediately after DEB‐TACE for HCC with intrahepatic bile duct invasion. Here, the first such case is reported. A 71‐year‐old woman was admitted to our hospital to undergo DEB‐TACE for multiple HCCs with worsening left intrahepatic bile duct dilatation. She was diagnosed with HCC that extensively invaded the left hepatic duct. After DEB‐TACE through the left hepatic artery, a hepatic arteriogram showed extra flow of the contrast agent to the left hepatic and common bile ducts. Therefore, transcatheter arterial embolization (TAE) of the responsible vessel was carried out using coils, and no extra flow of the contrast agent was identified. The patient was discharged 14 days after TAE without deterioration of liver function. Although hemobilia immediately after DEB‐TACE is rare, there may be increased potential for hemobilia when DEB‐TACE is carried out for HCC with extensive bile duct invasion. We suggest that DEB‐TACE may be contraindicated for such cases.     

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.     

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.     

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.     

Efficacy of transcatheter embolization/chemoembolization （TAE/TACE） for the treatment of single hepatocellular carcinoma

AIM: To investigate the efficacy of transcatheter embolization/chemoembolization (TAE/TACE) in cirrhotic patients with single hepatocellular carcinoma (HCC) not suitable for surgical resection and percutaneous ablation therapy. METHODS: A cohort of 176 consecutive cirrhotic patients with single HCC undergoing TAE/TACE was reviewed; 162 patients had at least one image examination (helical CT scan or triphasic contrast-enhanced MRI) after treatment and were included into the study. TAE was performed with Lipiodol followed by Gelfoam embolization; TACE was performed with Farmorubicin prepared in sterile drip at a dose of 50 mg/m(2), infused over 30 min using a peristaltic pump, and followed by Lipiodol and Gelfoam embolization. RESULTS: Patients characteristics were: mean age, 62 years; male/female 117/45; Child-Pugh score 6.2 +/- 1.1; MELD 8.7 +/- 2.3; mean HCC size, 3.6 (range 1.0-12.0) cm. HCC size class was 6.0 cm, n = 14. Patients received a total of 368 TAE/TACE (mean 2.4 +/- 1.7). Complete tumor necrosis was obtained in 94 patients (58%), massive (90%-99%) necrosis in 16 patients (10%), partial (50%-89%) necrosis in 18 patients (11%) and poor (< 50%) necrosis in the remaining 34 patients (21%). The rate of complete necrosis according to the HCC size class was: 69%, 69%, 52%, 68%, 50% and, 13% for lesions of 6.0 cm, respectively. Kaplan-Mayer survival at 24-mo was 88%, 68%, 59%, 59%, 45%, and 53% for lesions of 6.0 cm, respectively. CONCLUSION: Our study showed that in cirrhotic patients with single HCC smaller than 6.0 cm, TAE/TACE produces complete local control of tumor in a significant proportion of patients. TAE/TACE is an effective therapeutic option in patients with single HCC not suitable for surgical resection or percutaneous ablation therapies. Further studies should investigate if the new available embolization agents or drug eluting beads may improve the effect on tumor necrosis.     

Hepatocellular carcinoma and octreotide: treatment results in prospectively assigned patients with advanced tumor and cirrhosis stage

BACKGROUND AND AIM: Treatment of inoperable hepatocellular carcinoma (HCC) remains a major clinical problem. The only efficient treatment options are percutaneous ethanol injection (PEI), radiofrequency ablation (RF) and transarterial chemoembolization (TACE), but these therapies are only applicable to patients with limited tumor spread and sufficient liver function. For patients with advanced tumor and poor liver function a systemic therapy is required. Octreotide, a somatostatin analog with antimitotic activity, is a controversial treatment option. METHODS: In the current study we prospectively assigned a group of 41 HCC patients with advanced HCC and cirrhosis stage to treatment with octreotide. The clinical and laboratory parameters were monitored and survival was analyzed using a Cox regression model. RESULTS: The medium survival in the group of all patients was 571 days. Using the Cox regression there was a significant difference in survival for alpha-fetoprotein (P = 0.026) and Quick's test (P = 0.009) in consideration of the tumor dimension compared to the other characteristics. The tumor remained stable in 26 patients over a mean follow-up of 21 months and progressed in 14 patients. One patient showed a partial response. There was no incidence of severe side-effects (WHO grade 3-4). During the follow-up time, 14 patients died because of their underlying disease. CONCLUSIONS: Treatment with octreotide appears safe and patients show similar survival compared to a group of patients with advanced HCC treated with TACE. Further studies are necessary to investigate somatostatin receptor subtypes or receptor mutations of patients with advanced HCC in relation to their response.     

Radiation therapy has been shown to be adaptable for various stages of hepatocellular carcinoma

In addition to surgical procedures, radiofrequency ablation is commonly used for the treatment of hepatocellular carcinomas(HCCs) of limited size and number. Transcatheter arterial chemoembolization(TACE), using iodized poppy seed oil, Lipiodol and anticancer drugs, has been actively performed for the treatment of unresectable HCC, particularly in Asian countries. Recently, Sorafenib become available for advanced HCCs when the liver is still sufficiently functional. Sorafenib is an oral multikinase inhibitor with antiproliferative and antiangiogenic effects. However, the effect of sorafenib seems to be inadequate to control the progression of HCC. Radiation therapy(RT)for HCC has a potential role across all stages of HCC. However, RT is generally not considered an option in HCC consensus documents or national guidelines, primarily because of insufficient supporting evidence. However, the method of RT has much improved because of advances in technology. Moreover, combined treatment of RT plus other treatments(TACE, sorafenib and chemotherapy etc.) has become one of the alternative therapies for HCC. Therefore, we should understand the various kinds of RT available for HCC. In this review, we focus on various kinds of external beam radiation therapy.     

Combined interventional therapies of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, responsible for an estimated one million deaths annually. It has a poor prognosis due to its rapid infiltrating growth and complicating liver cirrhosis. Surgical resection, liver transplantation and cryosurgery are considered the best curative options, achieving a high rate of complete response, especially in patients with small HCC and good residual liver function. In nonsurgery, regional interventional therapies have led to a major breakthrough in the management of unresectable HCC, which include transarterial chemoembolization (TACE), percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave coagulation therapy (MCT), laser-induced thermotherapy (LITT), etc. As a result of the technical development of locoregional approaches for HCC during the recent decades, the range of combined interventional therapies has been continuously extended. Most combined multimodal interventional therapies reveal their enormous advantages as compared with any single therapeutic regimen alone, and play more important roles in treating unresectable HCC.     

Short-term interval combined chemoembolization and radiofrequency ablation for hepatocellular carcinoma

AIM: To investigate hepatic function after combined transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) with a short-term interval (0-2 d).METHODS: A total of 115 patients with compensated liver cirrhosis underwent RFA combined with TACE at a time-interval of 0-2 d for the treatment of hepatocellular carcinoma (HCC) < 5.0 cm. There were 21 patients who received further hepatic directed treatment altering liver function within 12 mo after the combined therapy for HCC-recurrence, and were excluded. The remaining 94 patients who survived without HCC-recurrence were included in this retrospective study.RESULTS: At 1 mo after treatment, Child-Pugh scores (CPs) remained unchanged in 89 of 94 patients (94.7%), and transiently increased by one-point in 5 patients (5.3%). However, the score returned to baseline score at 3 mo and was maintained until 6 mo in all patients. The baseline CPs of 8 or more was identified as a factor for transient rise of CPs after the treatment (CPs 8/9 vs 5/6/7; 21.4% vs 2.5%; P = 0.022). At 12 mo follow-up, CPs was unchanged in 90 patients (95.7%), and increased by one-point in 4 patients (4.3%). The rise of CPs at 12 mo was not statistically associated with the initial transient rise of CPs. There were procedure-related complications in 3 patients (3.2%), but the complications were resolved by medical and interventional treatments without hepatic functional sequelae.CONCLUSION: The combined TACE and RFA with an interval of 0-2 d are safe for the management of HCC < 5 cm in cirrhotic patients.     

Interventional therapies of unresectable liver metastases

Liver metastases are the major cause of mortality in patients with gastrointestinal carcinomas and other malignant tumors, carrying a poor prognosis and presenting considerable management. Surgical resection remains the only curative therapy for liver metastases up to now. However, only a small percentage of patients are suitable for curative resection due to many factors: multi-centric tumors, extrahepatic metastases, early vascular invasion, and coexisting advanced liver cirrhosis. In non-surgical cases, regional interventional therapies have led to a major break through in the treatment of unresectable liver metastases, which include transarterial chemoembolization (TACE), radiofrequency ablation (RFA), laser-induced thermotherapy (LITT), cryosurgical ablation (CSA), microwave coagulation therapy (MCT), percutaneous ethanol injection (PEI), and others. As a result of the technical development of locoregional approaches for unresectable liver metastases during recent decades, the range of combined interventional therapies has been continuously enlarged. The current roles of these treatment options for liver metastases are discussed in this review.     

Advances in non-surgical management of primary liver cancer

Hepatocellular carcinoma(HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. There have been great improvements in the diagnosis and treatment of HCC in recent years, but the problems, including difficult diagnosis at early stage, quick progression, and poor prognosis remain unsolved. Surgical resection is the mainstay of the treatment for HCC. However, 70%-80% of HCC patients are diagnosed at an advanced stage when most are ineligible for potentially curative therapies such as surgical resection and liver transplantation. In recent years, non-surgical management for unrespectable HCC, such as percutaneous ethanol injection, percutaneous microwave coagulation therapy, percutaneous radiofrequency ablation, transcatheter arterial chemoembolization, radiotherapy, chemotherapy, biotherapy, and hormonal therapy have been developed. These therapeutic options, either alone or in combination, have been shown to control tumor growth, prolong survival time, and improve quality of life to some extent. This review covers the current status and progress of non-surgical management for HCC.     

Comparison of hepatic resection and transarterial chemoembolization for solitary hepatocellular carcinoma

AIM: To compare the outcomes of hepatic resection and transarterial chemoembolization (TACE) for solitary hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer (BCLC) staging system.METHODS: A consecutive sample of 540 patients with solitary HCC who underwent liver resection (n = 312) or TACE (n = 128) were included in the present study. Baseline characteristics, tumor characteristics, and post-operative complications were compared between the two groups. The Kaplan-Meier method was used for long-term survival analysis. Independent prognostic predictors were identified using the Cox proportional hazards model (univariate and multivariate analyses).RESULTS: The TACE and liver resection groups had similar baseline demographic and clinicopathological characteristics. The TACE group showed a significantly lower rate of major complications than the liver resection group (3.9% vs 17.4%, P < 0.001). Univariate and multivariate analyses indicated that TACE did not contribute to poor overall survival compared with liver resection; however, a solitary tumor diameter of greater than 6 cm should be considered a risk factor for poor overall survival (HR = 1.328, 95%CI: 1.002-1.783, P = 0.048). The liver resection and TACE groups had comparable overall survival rates at 1 year, 3 years, and 5 years (86.2%, 62.8%, and 44.0% vs 88.3%, 59.8%, and 40.6%, respectively, P = 0.419). In cases with tumor diameters equal to or less than 6 cm, the liver resection group showed a survival benefit compared with the TACE group at 1 year, 3 years, and 5 years (P = 0.030). The 1-, 3-, and 5-year overall survival rates of HCC cases with tumor diameters of more than 6 cm were similar among the liver resection and TACE groups (P = 0.467).CONCLUSION: A tumor diameter of 6 cm should be the cutoff for deciding between liver resection and TACE.     

Management of hepatocellular carcinoma: Enlightening the gray zones

Management of hepatocellular carcinoma (HCC) has been continuously evolving during recent years. HCC is a worldwide clinical and social issue and typically a complicates cirrhosis. The incidence of HCC is increasing, not only in the general population of patients with cirrhosis, but particularly in some subgroups of patients, like those with human immunodeficiency virus infection or thalassemia. Since a 3% annual HCC incidence has been estimated in cirrhosis, a bi-annual screening is generally suggested. The diagnostic criteria of HCC has recently had a dramatic evolution during recent years. HCC diagnosis is now made only on radiological criteria in the majority of the cases. In the context of cirrhosis, the universally accepted criteria for HCC diagnosis is contrast enhancement in arterial phase and washout in venous/late phase at imaging, the so called “typical pattern”. However, recently updated guidelines slightly differ in diagnostic criteria. Apart from liver transplantation, the only cure of both HCC and underlying liver cirrhosis, all the other treatments have to match with higher rate of HCC recurrence. The latter can be classified into curative (resection and percutaneous ablation) and palliative treatments. The aim of this paper was to review the current knowledge on management of HCC and to enlighten the areas of uncertainty.