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.     

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…     

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.     

New sonographic techniques for the diagnosis and treatment of hepatocellular carcinoma

Ultrasound (US) contrast agents such as Levovist and Sonazoid are now commercially available in Japan. Innovative contrast agents and ultrasound technologies have dramatically changed both diagnostic and treatment strategies for hepatocellular carcinoma (HCC). Contrast-enhanced US is extremely useful in the differential diagnosis of hepatic tumors as well as in evaluation of post-treatment response of HCC after lipiodol transarterial chemoembolization and radio frequency ablation. Harmonic US sensitively detects residual cancer cells in HCC patients after treatment, to facilitate accurate guidance for needle insertion for US monitoring; no other imaging modalities, including computed tomography (CT) or magnetic resonance imaging (MRI), have such capability. In 2005, the breakthrough technology of pure arterial phase imaging, which depicts only intranodular arterial accumulated maximum intensity projection images, was developed from advanced raw data storing and accumulation technologies. This technique can clearly identify whether blood supplyin the tumor is of arterial or portal origin, to facilitate the non-invasive characterization of nodular lesions associated with liver cirrhosis. Again, CT or MRI do not have such capabilities. This innovative technique can help differentiate premalignant lesions from overt HCC. Concurrent real-time imaging of multi-detector CT and US, known as real-time virtual sonography, has recently become available. This technique greatly facilitates the treatment guidance for HCC. These newly introduced sonographic techniques are dramatically changing the diagnostic and therapeutic strategies for HCC, which are expected to improve the prognosis of HCC patients.     

Surveillance and diagnosis of hepatocellular carcinoma in patients with cirrhosis

Early identification of hepatocellular carcinoma (HCC) is more frequent because of surveillance programs for HCC worldwide. The optimal strategy of surveillance in cirrhosis is a current topical issue. In terms of diagnosis, recent advances in non-invasive imaging technology, including various techniques of harmonic ultrasound, new ultrasound contrast agents, multi-slice helical computed tomography and rapid high quality magnetic resonance, have all improved the accuracy of diagnosis. Consequently the role of liver biopsy in diagnosis of HCC has declined. The imaging diagnosis relies on the hallmark of arterial hypervascularity with portal venous washout. However, with recent advances in genomics and proteomics a great number of potential serum and tissue markers have been identified and are being developed as new candidate markers for both diagnosis and prognosis of hepatocellular carcinoma, and may increase the need for liver biopsy.     

Liver transplantation for hepatocellular carcinoma beyond the Milan criteria: A review

Liver transplantation(LT) has been accepted as an effective therapy for hepatocellular carcinoma(HCC). The Milan criteria(MC) are widely used across the world to select LT candidates in HCC patients. However, the MC may be too strict because a substantial subset of patients who have HCC exceed the MC and who would benefit from LT may be unnecessarily excluded from the waiting list. In recent years, many extended criteria beyond the MC were raised, which were proved to be able to yield similar outcomes compared with those patients meeting the MC. Because the simple use of tumor size and number was insufficient to indicate HCC biological features and to predict the risk of tumor recurrence, some biological markers such as Alphafetoprotein, Des-Gamma-carboxy prothrombin and the neutrophil-to-lymphocyte ratio were useful in selecting LT candidates in HCC patients beyond the MC. For patients with advanced HCC, downstaging therapy is an effective way to reduce the tumor stage to fulfill the MC by using liver-directed therapy such as transarterial chemoembolization, radiofrequency ablation and percutaneous ethanol injection. This article reviews the recent advances in LT for HCC beyond the MC.     

Early detection of liver cancer: Diagnosis and management

Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer deaths worldwide, and the incidence is rising. Despite a wide array of treatment options, fewer than half of candidates for potentially curative treatments receive them. The diagnosis and management of HCC require a multidisciplinary approach involving various clinical specialties. The foundation of diagnosis is high-quality imaging, with MRI being the test of choice. Some patients also require guided biopsy when MRI is equivocal. Treatment options depend upon the tumor stage and the degree of underlying synthetic dysfunction. Potentially curative treatments include surgical resection and transplantation. Other treatments that prolong survival include percutaneous ablation and transarterial chemoembolization. A new oral agent, sorafenib, was recently shown to prolong survival in patients with advanced HCC. By increasing surveillance and treatment of HCC, outcomes for these patients may be improved.     

Clinical features,histology,and histogenesis of combined hepatocellular-cholangiocarcinoma

Combined hepatocellular-cholangiocarcinoma(CHC) is a rare tumor with poor prognosis,with incidence ranging from 1.0%-4.7% of all primary hepatic tumors.This entity will be soon renamed as hepato-cholangiocarcinoma.The known risk factors for hepatocellular carcinoma(HCC) have been implicated for CHC including viral hepatitis and cirrhosis.It is difficult to diagnose this tumor pre-operatively.The predominant histologic component within the tumor largely determines the predominant radiographic features making it a difficult distinction.Heterogeneous and overlapping imaging features of HCC and cholangiocarcinoma should raise the suspicion for CHC and multiple core biopsies(from different areas of tumor) are recommended before administering treatment.Serum tumor markers CA19-9 and alpha-fetoprotein can aid in the diagnosis,but it remains a challenging diagnosis prior to resection.There is sufficient data to support bipotent hepatic progenitor cells as the cell of origin for CHC.The current World Health Organization classification categorizes two main types of CHC based on histo-morphological features:Classical type and CHC with stem cell features.Liver transplant is one of the available treatment modalities with other management options including transarterial chemoembolization,radiofrequency ablation,and percutaneous ethanol injection.We present a review paper on CHC highlighting the risk factors,origin,histological classification and therapeutic modalities.     

Surgical management of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the second most common cause of death from cancer worldwide. Standard potentially curative treatments are either resection or transplantation. The aim of this paper is to provide an overview of the surgical management of HCC, as well as highlight current issues in hepatic resection and transplantation. In summary, due to the relationship between HCC and chronic liver disease, the management of HCC depends both on tumourrelated and hepatic function-related considerations. As such, HCC is currently managed largely through nonsurgical means as the criteria, in relation to the above considerations, for surgical management is still largelyrestrictive. For early stage tumours, both resection and transplantation offer fairly good survival outcomes(5 years overall survival of around 50%). Selection therefore would depend on the level of hepatic function derangement, organ availability and local expertise. Patients with intermediate stage cancers have limited options, with resection being the only potential for cure. Otherwise, locoregional therapy with transarterial chemoembolization or radiofrequency ablation are viable options. Current issues in resection and transplantation are also briefly discussed such as laparoscopic resection, ablation vs resection, anatomical vs non-anatomical resection, transplantation vs resection, living donor liver transplantation and salvage liver transplantation.     

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.     

肝癌的局部区域治疗

局部区域治疗在影像学引导下靶向杀伤肿瘤,是原发性肝癌最主要的非手术治疗方法,包括放射介入治疗（主要为肝动脉化疗栓塞）和局部消融治疗（瘤内乙醇注射、射频、微波、激光、高强度聚焦超声、冷冻等治疗）。肝动脉化疗栓塞主要应用于不能手术切除的中晚期肝癌,局部消融治疗适用于直径5cm以下的小肝癌。肝癌局部区域治疗强调针对具体病情选择合适的方法进行规范治疗。本文简要评述各种局部区域治疗方法的指征、治疗原则、技术要点和疗效,并讨论手术切除与局部消融治疗小肝癌的选择。     

Treatment for hepatocellular carcinoma in Japan over the last three decades: Our experience and published work review

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer‐related mortality worldwide. In the last few decades, there has been a marked increase in therapeutic options for HCC and epidemiological characteristics at HCC diagnosis have also significantly changed. With these changes and advances in medical technology and surveillance program for detecting earlier stage HCC, survival in patients with HCC has significantly improved. Especially, patients with liver cirrhosis are at high risk of HCC development, and regular surveillance could enable early detection of HCC and curative therapy, with potentially improved clinical outcome. However, unfortunately, only 20% of HCC patients are amenable to curative therapy (liver transplantation, surgical resection or ablative therapies). Locoregional therapies such as radiofrequency ablation, percutaneous ethanol injection, microwave coagulation therapy and transcatheter arterial chemoembolization play a key role in the management of unresectable HCC. Currently, molecular‐targeted agents such as sorafenib have emerged as a promising therapy for advanced HCC. The choice of the treatment modality depends on the size of the tumor, tumor location, anatomical considerations, number of tumors present and liver function. Furthermore, new promising therapies such as gene therapy and immunotherapy for HCC have emerged. Approaches to the HCC diagnosis and adequate management for patients with HCC are improving survival. Herein, we review changes of epidemiological characteristics, prognosis and therapies for HCC and refer to current knowledge for this malignancy based on our experience of approximately 4000 HCC cases over the last three decades.     

Surgical Treatment for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is an epithelial tumor derived from hepatocytes; it accounts for 80% of all primary liver cancers and ranks globally as the fourth leading cause of cancer-related deaths. HCC treatment is a multidisciplinary and a multimodal task, with surgery in the form of liver resection and liver transplantation (LT) representing the only potentially curative modality. However, there are variable opinions and discussions about applying these surgical options and using other supporting treatments. This article is a narrative review that includes articles published from 1984 to 2013 located by searching scientific databases such as PubMed, SCOPUS, and Elsevier, with the main keyword of hepatocellular carcinoma in addition to other keywords such as liver transplantation, liver resection, transarterial chemoembolization, portal vein embolization, bridging therapy, and downstaging. In this review, we focus mainly on the surgical treatment options offered for HCC, in order to illustrate the current relevant data available in the literature to help in applying these surgical options and to use other supporting treatment modalities when appropriate.     

Is percutaneous ethanol injection therapy still effective for hepatocellular carcinoma in the era of radiofrequency ablation?

Percutaneous ethanol injection (PEI) therapy has been replaced by more-effective thermal ablation techniques that have lower local recurrence rates. However, PEI therapy remains useful in certain settings. Since PEI can be performed in any portion of the liver, PEI therapy can be valuable when tumors are located in close proximity to intestinal loops or other positions that are risky for thermal local ablative techniques. PEI therapy is also valuable in other situations where radiofrequency ablation (RFA) is difficult, including technically difficult masses that are not detected with ultrasound (US), are located in the hepatic dome, in the subcapsular area, and exophytically, or are surrounded by large vessels. PEI therapy contributes to combination therapy with transcatheter arterial chemoembolization or RFA in advanced-stage hepatocellular carcinoma (HCC), and also to the treatment of large HCC or extrahepatic metastasis from HCC. These roles of PEI therapy should be stressed for the treatment of HCCs in appropriate clinical situations. This comprehensive review of articles related to PEI therapy illustrates the recent role and indications of this therapy, which is currently valuable for HCC in the era of RFA.     

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.     

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.     

Hypofractionated stereotactic radiotherapy with and without transarterial chemoembolization for small hepatocellular carcinoma not eligible for other ablation therapies: Preliminary results for efficacy and toxicity

Aim: To investigate the efficacy and toxicity of hypofractionated stereotactic radiotherapy for the treatment of patients presenting with hepatocellular carcinoma (HCC) in a single institutional setting. Methods: Sixteen patients who presented with solitary HCC, including two patients with a tumor thrombus of the portal veins, were treated with stereotactic radiotherapy with or without transarterial chemoembolization. The criteria for stereotactic radiotherapy were existence of technical difficulties for other ablation therapies, inoperable disease or refusal to undergo surgery, tumor staged as Grade A or B according to the Child-Pugh classification, and solitary tumor distant from the gastrointestinal tract and kidney with a tumor volume <100 cm(3). In 14 of 16 patients, a total dose of 35- 50 Gy was delivered in 5-7 fractions over 5-9 days. Results: At the end of a mean follow-up of 612 days (median 611 days; range 244-994 days), all patients were alive. Eight of 16 patients had complete responses and seven others were judged as stable with lipiodol accumulation. In one patient, local recurrence developed after 489 days. Intrahepatic recurrences developed outside the treated volume in six patients and no extrahepatic metastases developed during follow-up. No serious treatment-related toxic manifestations developed. Conclusions: Stereotactic radiotherapy for HCC with or without transarterial chemoembolization is feasible therapy and provides good local control with a short treatment period. Stereotactic radiotherapy may be of clinical benefit in patients who are inoperable or for whom there are difficulties in other ablation therapies.     

Treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. The major etiologies and risk factors for HCC development 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 early HCC detection in patients at risk, patient survival has not improved during the last three decades. This is due in part to the advanced stage of the disease at the time of clinical presentation, in part due to the limited therapeutic options. These fall into four main categories: (1) surgical interventions, including tumour resection and liver transplantation, (2) percutaneous interventions, including ethanol injection and radiofrequency thermal ablation, (3) transarterial interventions, including embolisation and chemoembolisation and (4) drugs as well as gene and immune therapies. These therapeutic strategies have been evaluated in part in randomised controlled clinical trials that are the basis for therapeutic recommendations. While surgery and percutaneous as well as 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 morbidity and mortality from HCC, therefore, 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. Further, 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 further elucidate the molecular events underlying HCC development and identify novel diagnostic markers as well as therapeutic and preventive targets.     

索拉非尼联合肝移植、射频消融、肝动脉化疗栓塞治疗肝细胞癌的研究进展

肝细胞癌(HCC)是世界上最常见的恶性肿瘤之一,传统的手术及化疗效果局限。多酶抑制剂索拉非尼在HCC的Ⅲ期临床试验中证明对晚期肝癌有效,开创了肝癌治疗新领域。近年来,索拉非尼联合其他方法治疗HCC的研究正在世界各地开展,并取得令人鼓舞的结果。总结了索拉非尼联合肝移植、射频消融术及肝动脉化疗栓塞术治疗肝癌的研究进展,认为索拉非尼与其他抗肝癌治疗的综合运用,有望成为肝癌靶向治疗的新途径。