Localized hepatocellular carcinoma: Therapeutic options

Hepatocellular carcinoma (HCC) is among the most common malignancies worldwide. Recent surveillance programs have allowed early detection and diagnosis, but overall survival of patients with HCC remains poor. This article provides a definition for localized HCC and summarizes the array of treatments that have emerged and the salient literature and findings for each. Among the treatments reviewed here are surgical resection, orthotopic liver transplantation, and local ablative therapies such as cryosurgery, percutaneous ethanol injection therapy, and transarterial chemoembolization.     

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。     

Imaging surveillance and multidisciplinary review improves curative therapy access and survival in HCC patients

Introduction. Imaging surveillance and multidisciplinary conference (MDC) review can potentially improve survival in patients with hepatocellular carcinoma (HCC) by increasing access to liver transplantation. Geographic disparities in donor organ availability may reduce this benefit. This study evaluated the impact of HCC surveillance on use of curative therapies and survival in a region with long transplant waiting times.Material and methods. 167 HCC patients were retrospectively studied. Subjects had an established HCC diagnosis or were diagnosed during hepatology follow-up. Collected data included patient demographics, HCC surveillance and MDC review status, portal hypertension complications, laboratory and radiologic parameters, tumor size, therapeutic interventions, tumor progression, and mortality. The primary outcome measures were use of curative treatments and survival. A Cox-regression model was constructed utilizing factors associated with survival in univariate analysis.Results. 58% of subjects underwent surveillance and MDC review of HCC. These patients were more likely to have received treatment with ablation or resection (16 vs. 3%, P = 0.006) and transplantation (23 vs. 4%, P = 0.001), and were less likely to develop tumor progression (45 vs. 68%, P = 0.005) or metastases (0 vs. 19%, P < 0.001). In multivariate analysis, surveillance and MDC review (P = 0.034, HR 0.520, 95% CI 0.284–0.952), tumor meeting Milan criteria (P < 0.001, HR 0.329, 95% CI 0.178–0.607), curative therapy application (P = 0.048, HR 0.130, 95% CI 0.017–0.979), and transplantation (P = 0.004, HR 0.236, 95% CI 0.088–0.632) were associated with survival.Conclusion. In conclusion, imaging surveillance and MDC review is associated with detection of early stage HCC, increased access to curative therapies and transplantation, and prolonged survival.     

Should a radiological diagnosis of hepatocellular carcinoma be routinely confirmed by a biopsy? Yes

Hepatocellular carcinoma (HCC) represents approximately 85 to 90% of all primary liver cancers (PLC) and every year, more than 560,000 people are diagnosed as affected by this cancer.The identification of risk factors for HCC prompted the creation of screening and surveillance programs in patients affected by chronic liver diseases with the aim of detecting HCC nodules as soon as possible and provide effective and hopefully curative therapyA correct diagnosis is of paramount importance for the surveillance program as well as for the choice of the appropriate therapy. Both in the diagnosis of small HCC and in the choice of the therapy for locally advanced HCC the diagnosis must be certain.Improvements of the radiological imagine techniques have surely enhanced both early diagnosis and tumor staging, allowing a reasonably accurate diagnosis, but cannot provide the certainty that in clinical practice is essential for an adequate workout.Therefore, the histopatological definition of the tumor is imperative both for an appropriate therapy and for an accurate prognostic evaluation.     

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.     

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.     

Current opinion on the role of resection and liver transplantation for hepatocellular cancer

Hepatocellular carcinoma (HCC) represents one of the most common cancers worldwide with rising incidence in developed countries. The best treatment options with curative intent for patients with HCC are liver resection or transplantation, although the role of hepatic ablative therapies has also been recognized. Surgical resection has emerged as the primary treatment in carefully selected patients of HCC. With the advances in surgical and radiological techniques, the perioperative mortality has been reduced to less than 5 % depending on the extent of resection and hepatic reserve. The role of liver transplantation (LT) as the mainstay of treatment for the majority of patients with HCC has evolved in the last few decades. Historically, the Milan criteria have been considered the gold standard for selecting patients; more expanded selection criteria to include those with more advanced tumors have been implemented in recent years. Living donor liver transplantation (LDLT) has emerged as a way to expand the donor pool and has influenced the role of transplantation for HCC, especially in communities with little access to cadaveric transplantation. Salvage transplantation is an alternative option as it allows a window for the biologically less favorable lesions to declare tumor behavior. Salvage transplantation also decreases the burden on transplant resources. Sirolimus, a novel immunosuppressant drug with anti-tumor effect, may have a role in limiting the severity of recurrent disease after transplantation for HCC, and play an important role in the future management of transplant recipients. This article examines the literature on current status of management of HCC.     

Treatment and outcomes of treating of hepatocellular carcinoma among Medicare recipients in the United States: a population-based study

BACKGROUND/AIMS: There are several treatment alternatives available for patients diagnosed with hepatocellular carcinoma (HCC). Yet, neither the extent to which potentially curative or palliative therapy is used to treat HCC, nor the determinants of using such therapies are known. Further, it is unclear how effective different modalities are for treating HCC. METHODS: We used the linked SEER-Medicare dataset to identify patients diagnosed with HCC between 1992 and 1999.We identified 2963 patients with continuous Medicare enrollment who were not enrolled in a Medicare-HMO. HCC treatments were categorized as potentially curative therapy (resection, transplant, local ablation), or palliative (trans-arterial chemoembolization (TACE), chemotherapy), and no therapy. Demographic (age, sex, race, geographic region), clinical (comorbidity, risk factors and severity of liver disease) and tumor factors (tumor size, extent of disease) were examined as potential determinants of therapy, as well as survival in univariate and multivariable analyses. Survival curves were also generated and compared among the different treatment modalities. RESULTS: The median age at diagnosis was 74 years (range: 32-105), and most patients (91%) were older than 65 years. Approximately 68% were White, 10% Black, 4% Hispanic, 8% Asian, and 9% were of other race. Thirteen percent of the patients received potentially curative therapy (transplant 0.9%, resection 8.2%, local ablation 4.1%), 4% received TACE, 57% received other palliative therapy, and 26% received no specific therapy. Only 34% of 513 patients with single lesions, and 34% of 143 patients with lesions <3.0 cm received potentially curative therapy. However, 19.2% of patients with unfavorable tumor features (lesion >10.0 cm) received such therapy. Among patients who received potentially curative therapy (n=392), resection was the most common procedure (n=243, 62%) followed by local ablation (n=122, 31%) and finally transplantation (n=27, 7%). In regression analyses, geographic variations in the extent and type of curative therapy persisted after adjusting for demographic, clinical, and tumor features. Median overall survival was 104 days following HCC diagnosis with the longest survival in the transplant group (852 days) and the shortest survival in the group with no treatment (58 days). In the survival analysis, transplantation led to the longest survival, followed by resection. Neither ablation nor TACE yielded prolonged survival (3 year survival was less than 10%). CONCLUSIONS: In this predominantly 65 years and older Medicare population, there are marked geographic variations in the management of HCC that seem to be at least as important as clinical and tumor-related features in determining the extent and type of HCC therapy. There is underutilization of potentially curative therapy, even among those with favorable tumor features.     

Application of surveillance programs for hepatocellular carcinoma in the Asia–Pacific Region

Hepatocellular carcinoma (HCC) is a potential target for cancer surveillance (or screening) as it occurs in well-defined, at-risk populations and curative therapy is possible only for small tumors. Surveillance has been recommended by regional liver societies and is practiced widely, but its benefits are not clearly established. Hepatic ultrasonography with or without alpha fetoprotein (AFP) performed every 6 months is the preferred program. Surveillance of HCC has been well shown to detect small tumors for curative treatment, which may be translated to improved patient survival. However, most studies are limited by lead-time bias, length bias for early diagnosis of small HCC, different tumor growth rates and poor compliance with surveillance. Cost-effectiveness of surveillance programs depends on the rate of small HCC detected 'accidentally' (routine imaging) in a comparator group, annual incidence of HCC with various etiologies, patient age and the availability of liver transplantation. The incremental cost-effectiveness for 6-monthly AFP and ultrasound has been estimated from approximately $US26 000–74 000/quality adjusted life years (QALY). All cirrhotic patients are therefore recommended for HCC surveillance unless the disease is too advanced for any curative treatment. As chronic hepatitis B can develop into HCC without going through liver cirrhosis, high-risk non-cirrhotic chronic hepatitis B patients are also recommended for HCC surveillance. In conclusion, HCC surveillance could be effective at reducing disease-specific mortality with acceptable cost-effectiveness among selected patient groups, provided it is a well-organized program.     

Treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third cause of cancer-related death. Despite therapeutic advances, the overall survival of patients with HCC has not significantly improved in the last two decades. In the majority of the cases there is underlying cirrhosis, so the prognosis of HCC depends on not only tumor stage but also liver function. There is not a widely accepted HCC staging system. In our group we have developed a new staging classification that stratifies HCC patients into four major categories and simultaneously links staging with treatment. Patients at an early stage are those who present with an asymptomatic single HCC with a maximum diameter of 5cm or up to three nodules each less than 3cm. They will benefit from curative therapies, including resection, liver transplantation (LT), and percutaneous ablation. Patients exceeding these limits, but who are free of cancer-related symptoms and vascular invasion or extrahepatic spread fit into the intermediate stage and may benefit from palliation with chemoembolization. The patients with mild cancer-related symptoms and/or vascular invasion or extrahepatic spread are included in the advanced stage. In this stage there is not effective therapy, and these patients may profit from new therapies in the setting of randomized controlled trials (RCTs). Finally, the patients with severe cancer-related symptoms or great tumor burden belong to the terminal stage and only benefit from symptomatic treatment.     

Treatment of hepatocellular carcinoma: Steps forward but still a long way to go

Hepatocellular carcinoma(HCC) is the fifth most common malignancy and the third cause of tumor associated deaths worldwide. HCC incidence rates are increasing in many parts of the world including developing and developed countries. Potentially curative treatments for HCC are resection and liver transplantation, but these are only suitable for patients with small tumors, meeting strict pre-defined criteria, or well-compensated liver disease. Early diagnosis of HCCcan be achieved by surveillance of at-risk populations. For patients with non-resectable disease treatments modalities include loco-ablative and systemic therapies. In this review we focus on treatment options in HCC and their allocation. Although significant research is in progress, to this date, the results are unsatisfactory with limited long-term survival. In the fight against this deadly disease, there is still a long way to go.     

Image-guided thermal ablation of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is increasingly diagnosed at an early, asymptomatic stage owing to surveillance of high-risk patients. Given the complexity of the disease, multidisciplinary assessment of tumor stage, liver function, and physical status is required for proper therapeutic planning. Patients with early-stage HCC should be considered for any of the available curative therapies, including surgical resection, liver transplantation and percutaneous image-guided ablation. Resection is currently indicated among patients with solitary HCC and extremely well-preserved liver function, who have neither clinically significant portal hypertension nor abnormal bilirubin. Liver transplantation benefits patients who have decompensated cirrhosis and one tumor smaller than 5 cm or up to three nodules smaller than 3 cm, but donor shortage greatly limits its applicability. This difficulty might be overcome by living donation that, however, is still at an early stage of clinical application. Image-guided percutaneous ablation is the best therapeutic choice for nonsurgical patients with early-stage HCC. While ethanol injection has been the seminal percutaneous technique, radiofrequency ablation has emerged as the most effective method for local tumor destruction and is currently used as the primary ablative modality at most institutions.     

Liver transplantation for hepatocellular carcinoma

The role of liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) has evolved over the past two decades, and transplantation has become one of the few curative treatment modalities for patients with HCC. Early results were poor, but the current restrictive selection criteria can yield excellent results. This review will discuss recent issues in the field, including (1) factors affecting the recurrence of HCC after LT; (2) the effect of downstaging HCC before LT, including transarterial catheter chemoembolization (TACE) and radiofrequency ablation (RFA); and (3) living-donor versus deceased-donor liver transplantation for HCC patients. The most important factors that have been described to affect LT survival include the tumor size, vascular invasion, and the degree of tumor differentiation. Recently, tumor markers, including alpha-fetoprotein and des-gamma carboxy prothrombin, were reported as predictors of HCC recurrence after LT. Furthermore, the experience accumulated with locoregional therapies such as TACE and RFA as bridging procedures to LT, along with the reduced waiting time under the HCC-adjusted MELD (model for endstage liver disease) system for organ allocation has led to improved outcomes. With the recent advances in adult living-donor liver transplantation (LDLT), there may be a marked change in the role of liver transplantation for hepatic malignancies, in particular for HCC.     

Stem Cell Origins and Animal Models of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a common malignant tumor that almost always occurs within a preexisting background of chronic liver disease and cirrhosis. Currently, medical therapy is not effective in treating most HCC, and the only hope of cure is either resection or liver transplantation. A small minority of patients is eligible for these therapies, which entail major morbidity at the very least. In spite of immense scientific advances during the past 3 decades, patient survival has improved very little. In order to reduce morbidity and mortality from HCC, improvements in early diagnosis and development of novel local and systemic therapies for advanced disease are essential, in addition to efforts geared towards primary prevention. Studies with experimental animal models that closely mimic human disease are very valuable in understanding physiological, cellular and molecular mechanisms underlying the disease. Furthermore, appropriate animal models have the potential to increase our understanding of the effects of image-guided minimally invasive therapies and thereby help to improve such therapies. In this review, we examine the evidence for stem cell origins of such tumors, critically evaluate existing models and reflect on how to develop new models for minimally invasive, image-guided treatment of HCC.     

Hepatocellular carcinoma surveillance:An evidence-based approach

Hepatocellular carcinoma(HCC) makes up 75%-85% of all primary liver cancers and is the fourth most common cause of cancer related death worldwide. Chronic liver disease is the most significant risk factor for HCC with 80%-90% of new cases occurring in the background of cirrhosis. Studies have shown that early diagnosis of HCC through surveillance programs improve prognosis and availability of curative therapies. All patients with cirrhosis and high-risk hepatitis B patients are at risk for HCC and should undergo surveillance. The recommended surveillance modality is abdominal ultrasound(US) given that it is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with non-alcoholic fatty liver disease(NAFLD). With the current obesity epidemic and rise in the prevalence of NAFLD, abdominal computed tomography or magnetic resonance imaging may be indicated as the primary screening modality in these patients. The addition of alpha-fetoprotein to a surveillance regimen is thought to improve the sensitivity of HCC detection.Further investigation of serum biomarkers is needed. Semiannual screening is the suggested surveillance interval. Surveillance for HCC is underutilized and low adherence disproportionately affects certain demographics such as nonCaucasian race and low socioeconomic status.     

Evaluating the current surgical strategies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Despite careful surveillance programs and the development of antiviral therapy for hepatitis virus infection, the occurrence rate of HCC remains high. Liver resection and liver transplantation are mainstay curative treatments. Most patients with HCC have impaired liver function, and surgical treatment is always accompanied by the risk of decompensation of the remnant liver, especially when the volume of the remnant liver is too small and the liver function too low to meet metabolic demands. The mortality of liver resection has dramatically decreased over the last three decades from 20% to less than 5% due to the accumulation of knowledge of liver anatomy, perioperative management and preoperative assessment of liver function. Here we provide an overview of the multidisciplinary treatments and current standard treatment strategies for HCC, to explore the possibility of expanding surgical treatments beyond the current standards.     

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.     

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.     

Role of radiotherapy in the management of hepatocellular carcinoma:A systematic review

Many patients with hepatocellular carcinoma(HCC) present with advanced disease,not amenable to curative therapies such as surgery,transplantation or radiofrequency ablation. Treatment options for this group of patients include transarterial chemoembolization(TACE) and radiation therapy. Especially TACE,delivering a highly concentrated dose of chemotherapy to tumor cells while minimizing systemic toxicity of chemotherapy,has given favorable results on local control and survival. Radiotherapy,as a therapeutic modality of internal radiation therapy with radioisotopes,has also achieved efficacious tumor control in advanced disease. On the contrary,the role of external beam radiotherapy for HCC has been limited in the past,due to the low tolerance of surrounding normal liver parenchyma. However,technological innovations in the field of radiotherapy treatment planning and delivery,have provided the means of delivering radical doses to the tumor,while sparing normal tissues. Advanced and highly conformal radiotherapy approaches such as stereotactic body radiotherapy and proton therapy,evaluated for efficacy and safety for HCC,report encouraging results. In this review,we present the role of radiotherapy in hepatocellular carcinoma patients not suitable for radical treatment.     

Non-surgical therapies of hepatocellular carcinoma

Early detection of hepatocellular carcinoma (HCC) through surveillance programmes allows potentially curative therapies such as resection, liver transplantation and percutaneous ablation to be applied in 40% of the patients. In non-surgical candidates, percutaneous treatments are the best therapeutic approach, and may improve survival in patients with well preserved liver function and small tumours that achieve initial complete response. Applying these criteria 5-year survival rates above 50% are achieved. Radio frequency thermal ablation provides slightly better objective response rates than ethanol injection, but no survival advantages have been reported. At more advanced stages, only chemoembolization has been shown to improve survival in well-selected candidates.