Systemic therapy in hepatocellular carcinoma

Many potential systemic therapies are being investigated for the treatment of hepatocellular carcinoma (HCC). The incidence of this malignancy is rising sharply and the vast majority of patients present at advanced stages. Although the earlier dismal results with cytotoxic chemotherapies made way for the development of locoregional therapies that provided improved overall survival, truly personalized therapy will require the selection of phenotypically similar stages of disease and populations, an understanding of the complex molecular and genetic pathways leading to HCC, and a keen understanding of the pathobiology of cirrhosis. Only then will we understand how to offer a particular patient at a specific stage of disease the appropriate therapy to truly prolong survival.     

程序性细胞死亡受体1及其配体抑制剂在肝细胞癌治疗中的应用进展

肝细胞癌(HCC)是我国最常见的恶性肿瘤之一,由于缺乏特异性表现,超过一半的患者在初诊时已处于进展期。靶向治疗和系统化疗是进展期HCC的主要治疗方法,疗效有限。近年来,免疫治疗迅速发展。介绍了免疫检查点抑制剂——程序性细胞死亡受体1及其配体(PD-1/PD-L1)抑制剂在HCC治疗中的现状,归纳了多项临床试验的数据结果,分析了单药治疗及联合治疗的安全性及有效性。通过分析表明,免疫治疗已成为全身系统治疗的重要方法之一,尤其是联合治疗可显著提高HCC的疗效,其安全性亦在可控范围内,是未来发展的重要方向。     

Recent advances in the surgical treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The treatment of HCC is complex and complicated by the severity of associated chronic liver disease, the stage of HCC, and the clinical condition of the patient. Liver resection (LR) is one of the most efficient treatments for patients with HCC, with an expected 5-year survival of 38%-61% depending on the stage of the disease. Improved liver function assessment, increased understanding of segmental liver anatomy from advanced imaging studies, and surgical technical progress are important factors that have led to reduced mortality in patients with HCC. The indication for LR may be expanded due to emerging evidences from laparoscopic hepatectomies and combined treatments with newly developed chemotherapies. Liver transplantation (LT) is considered as an ideal treatment for removal of existing tumors and the injured/preneoplastic underlying liver tissue with impaired liver function and the risk of multicentric carcinogenesis that results from chronically injured liver. However, LT is restricted to patients with minimal risk of tumor recurrence under immunosuppression. The expansion of criteria for LT in HCC patients is still under trial and discussion. Limited availability of grafts, as well as the risk and the cost of transplantation have led to considerable interest in expansion of the donor pool, living donor-related transplantation, and combined treatment involving LR and LT. This highlight presents evidence concerning recent studies evaluating LR and LT in HCC patients. In addition, alternative therapies for the treatment of early stage tumors and the management of patients on transplant waiting lists are discussed.     

Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus statement

Although surgical resection and liver transplantation are the only treatment modalities that enable prolonged survival in patients with hepatocellular carcinoma (HCC), the majority of HCC patients presents with advanced disease and do not undergo resective or ablative therapy. Transarterial chemoembolization (TACE) is indicated in intermediate/advanced stage unresectable HCC even in the setting of portal vein involvement (excluding main portal vein). Sorafenib has been shown to improve survival of patients with advanced HCC in two controlled randomized trials. Yttrium 90 is a safe microembolization treatment that can be used as an alternative to TACE in patients with advanced liver only disease or in case of portal vein thrombosis. External beam radiation can be helpful to provide local control in selected unresectable HCC. These different treatment modalities may be combined in the treatment strategy of HCC and also used as a bridge to resection or liver transplantation. Patients should undergo formal multidisciplinary evaluation prior to initiating any such treatment in order to individualize the best available options.     

Advanced hepatocellular carcinoma. Review of targeted molecular drugs

Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world in terms of incidence, accounting for approximately 630 thousand new cases per year; in addition, HCC is the third most common cause of cancer death. Worldwide, the greatest risk factors for HCC are the infections caused by hepatitis B and C viruses, which increase the risk of developing the disease by about 20 times. The standard treatment in the early stages of the disease, such as surgical resection, local ablation and liver transplantation, are able to cure a proportion of patients, but most cases of HCC present in advanced stages, precluding the use of such treatments with curative intent. In these advanced stages, systemic treatments are commonly used. Unfortunately, chemotherapy with conventional cytotoxic agents is ineffective and does not seem to modify the natural history of disease. Treatment options for patients with advanced HCC are extremely limited, but the identification of signaling pathways, and the recognition of the role of these pathways in the pathogenesis of the disease resulted in the development of drugs directed at specific therapeutic targets. One such drug is Sorafenib, a kinase inhibitor with antiangiogenic and antiproliferative properties. In conclusion, Sorafenib has demonstrated survival benefits in patients with advanced HCC, thus representing a new standard reference for systemic treatment in these cases.     

Regorafenib治疗肝癌的临床研究进展

Regorafenib是1种新型的多激酶抑制剂,已被批准用于转移性结肠癌和胃肠道间质瘤的治疗。旨在总结Regorafenib治疗肝癌的临床研究进展。Ⅰ期和Ⅱ期临床试验已证实Regorafenib在肝癌患者中的安全性。Ⅱ期临床试验也显示Regorafenib作为肝癌患者的二线治疗手段可以较好地控制肿瘤的进展。1项正在进行的Ⅲ期随机对照试验将比较Regorafenib与安慰剂之间作为晚期肝癌的二线治疗手段的安全性和有效性。研究分析表明Regorafenib可以有效地控制肝癌进展,有望成为晚期肝癌的二线治疗手段。     

Treatment of hepatocellular carcinoma with portal venous tumor thrombosis: A comprehensive review

The natural history of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is dismal (approximately 2-4 mo), and PVTT is reportedly found in 10%-40% of HCC patients at diagnosis. According to the Barcelona Clinic Liver Cancer (BCLC) Staging System (which is the most widely adopted HCC management guideline), sorafenib is the standard of care for advanced HCC (i.e., BCLC stage C) and the presence of PVTT is included in this category. However, sorafenib treatment only marginally prolongs patient survival and, notably, its therapeutic efficacy is reduced in patients with PVTT. In this context, there have been diverse efforts to develop alternatives to current standard systemic chemotherapies or combination treatment options. To date, many studies on transarterial chemoembolization, 3-dimensional conformal radiotherapy, hepatic arterial chemotherapy, and transarterial radioembolization report better overall survival than sorafenib therapy alone, but their outcomes need to be verified in future prospective, randomized controlled studies in order to be incorporated into current treatment guidelines. Additionally, combination strategies have been applied to treat HCC patients with PVTT, with the hope that the possible synergistic actions among different treatment modalities would provide promising results. This narrative review describes the current status of the management options for HCC with PVTT, with a focus on overall survival.     

Traditional Chinese herbal medicines for treatment of liver fibrosis and cancer: from laboratory discovery to clinical evaluation.

Liver disease afflicts over 10% of the world population. This includes chronic hepatitis, alcoholic steatosis, fibrosis, cirrhosis and hepatocellular carcinoma (HCC), which are the most health-threatening conditions drawing considerable attention from medical professionals and scientists. Patients with alcoholism or viral hepatitis are much more likely to have liver cell damage and cirrhosis, and some may eventually develop HCC, which is unfortunately, and very often, a fatal malignancy without cure. While liver surgery is not suitable in many of the HCC cases, patients are mostly given palliative support cares or transarterial chemoembolization or systemic chemotherapies. However, HCC is well known to be a highly chemoresistant tumour, and the response rate is <10-20%. To this end, alternative medicines are being actively sought from other sources with hopes to halt the disease's progression or even eliminate the tumours. Traditional Chinese herbal medicine has begun to gain popularity worldwide for promoting healthcare as well as disease prevention, and been used as conventional or complementary medicines for both treatable and incurable diseases in Asia and the West. In this article, we discuss the laboratory findings and clinical trial studies of Chinese herbal medicines (particularly small molecule compounds) for the treatment of liver disease ranging from fibrosis to liver cancer.     

中晚期肝癌临床治疗进展

肝癌的发病隐匿,早期诊断困难,进展较快,临床上仅有不足30%的患者就诊时可获得手术治疗的机会,因此非手术疗法是中晚期肝癌的主要治疗方式。总结了几种主要的非手术治疗方式———血管介入治疗、分子靶向和化疗药物治疗、放疗以及局部消融治疗在肝癌治疗中的地位。认为尽管综合治疗已成为肝癌治疗的共识,但是他们在综合治疗中的地位及次序等仍未形成共识,还需要进行更多的临床研究,从而为中晚期肝癌患者的治疗提供更好的选择。     

New chemotherapy for patients with advanced hepatocellular carcinoma: Pilot study of β-interferon and doxorubicin one-shot intra-arterial chemotherapy

Background: Patients with advanced hepatocellular carcinoma (HCC) need an effective treatment modality because of the poor prognosis of the disease. From an in vitro study, beta-interferon (IFN-beta) has been reported to enhance the antiproliferative effects of doxorubicin on HCC cell lines. In the present study, we investigated the therapeutic effects of combined IFN-beta and doxorubicin intra-arterial injection therapy on patients with advanced HCC. Methods: IFN-beta (3 MIU) and doxorubicin (10 mg/bodyweight) were given by one-shot intra-arterial injection through an arterial port to patients with advanced HCC. One treatment course consisted of three intra-arterial injections per week for 4 weeks. Three courses were conducted and evaluation was done monthly. Results: Eleven patients with advanced HCC were treated with combined IFN-beta and doxorubicin. One patient enteredcomplete remission (CR), seven patients were evaluated as having stable disease (SD) and three as having progressive disease (PD). The mean overall survival was 10 months. The mean survival for CR and SD patients was 15 months, and that for PD patients was 6 months (P = 0.0464, log-rank test). Decrease of serum total bilirubin was observed for all patients. Conclusion: Combined IFN-beta and doxorubicin intra-arterial therapy offers an effective chemotherapy option for patients with advanced HCC by improving liver function and having tolerable side-effects.     

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.     

德氮吡格影响人肝癌细胞株QGY-7701亚细胞的蛋白质组学研究

目的 观察德氮吡格(TNBG)对人肝癌细胞QGY-7701亚细胞蛋白表达的影响,探讨其影响脂代谢的分子机制. 方法 分别提取TNBG处理前后人肝癌细胞QGY-7701的细胞质、细胞膜和细胞核蛋白进行双向电泳,PDQuest 7.4.0软件分析比对图像,采用基质辅助激光解吸电离飞行时间质谱技术(MALDI-TOF-MS)鉴定差异蛋白质点. 结果 TNBG作用于人肝癌细胞QGY-770172h后,细胞质的差异表达蛋白质点有56个,细胞膜的差异表达蛋白质点有65个,细胞核的差异表达蛋白质点有34个,共计155个.利用MALDI-TOF-MS技术鉴定出其中33个差异表达蛋白质点,其中包括与脂质合成有关的10个蛋白质点和与脂质降解、转运有关的7个蛋白质点,如3-羟基-3甲基戊二酸单酰辅酶A还原酶、角鲨烯合成酶、低密度脂蛋白受体、三磷酸腺柠檬酸裂解酶、甘油醛-3-磷酸脱氢酶、甘油-3-磷酸酰基转移酶、长链酯 辅酶A脱氢酶等,这些都是固醇调节元件结合蛋白调控的靶基因.结论 TNBG可能通过固醇调节元件结合蛋白途径增加胆固醇和甘油三酯合成,导致肿瘤细胞内脂滴大量聚积.     

Hepatic artery infusion chemotherapy for advanced hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common cancers worldwide. Surgery, percutaneous ablation and liver transplantation are the only curative treatment modalities for HCC. However, the majority of patients have unresectable disease at diagnosis. Therefore, effective treatment options for patients with advanced HCC are required. In advanced HCC, according to current international guidelines, sorafenib, a molecular targeted agent, is the standard treatment. However, alternative treatment modalities are required because of the low response rates and unsuitability of molecular agents in real practice. In various treatment modalities, mostly in Asia, hepatic arterial infusion chemotherapy(HAIC) has been applied to advanced HCC with a view to increasing the therapeutic efficacy. HAIC provides direct drug delivery into the tumor feeding vessels and also minimizes systemic toxicities through a greater first-pass effect in the liver. However, the sample sizes of studies on HAIC have been small and large randomized trials are still lacking. In this article, we describe the treatment efficacy of HAIC for advanced stage HCC and discuss future therapeutic possibilities.     

Second-line treatment of advanced hepatocellular carcinoma: Time for more individualized treatment options?

Hepatocellular carcinoma (HCC) is the most frequently diagnosed primary tumor of the liver and is usually detected as advanced disease. It is an aggressive disease that often progresses rapidly when it fails to respond to treatment. As such, patients have limited opportunities to try different subsequent-line treatment regimens. In the last 5 years, the number of agents and/or regimens available for the treatment of advanced HCC has significantly increased, which has made treatment choices for this patient population increasingly complex. In the second-line setting, several phase III trials of regorafenib (RESORCE), ramucirumab (REACH/REACH-2), and cabozantinib (CELESTIAL) have demonstrated clinically meaningful survival benefits in patients with the disease. However, the median overall survival of patients with advanced HCC remains unchanged at approximately 12 mo from the start of systemic second-line therapy, with a limited duration of response. Evidence from the REACH/REACH-2 trials demonstrated for the first time that baseline alpha-fetoprotein (AFP) levels can be used as an identification factor to select those who are likely to benefit the most from ramucirumab treatment. Ramucirumab is both well tolerated and efficacious and has a clinically acceptable safety profile. Therefore, it should be considered an option for patients with AFP levels ≥ 400 ng/mL.     

肝癌微创介入治疗进展

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

Complete response to sorafenib in a patient with recurrent hepatocellular carcinoma

Partial hepatectomy is still the treatment of choice aiming at a cure for patients with hepatocellular carcinoma (HCC), provided that the patient can tolerate the treatment. For patients with multiple recurrent HCC after partial hepatectomy which cannot be treated by re-hepatectomy or local ablative therapy, the prognosis is extremely poor. Sorafenib is a molecular-targeted agent which has been demonstrated in two global phase III randomized controlled trials to show survival benefit for advanced HCC. Here, we present a 56-year-old patient with HCC who showed complete clinical response after sorafenib was used for tumor recurrence which developed 3 mo after partial hepatectomy. There was no evidence of progression of disease for 60 mo till now after continuous treatment with sorafenib.     

Treatment of hepatocellular carcinoma

Opinion statement The incidence of hepatocellular carcinoma (HCC) is increasing in the United States. Several modalities are available for the treatment of HCC, and decisions regarding the optimal choice of therapy are based on tumor burden and severity of liver disease. Classification systems are helpful for prognostic purposes and to guide in the choice of therapy. Surgical resection is a mainstay of therapy for patients with solitary small tumors and preserved liver function (noncirrhotic or Child-Pugh class A cirrhotic patients without portal hypertension). Unfortunately, a minority of patients is eligible for resection, and postoperative recurrence or de novo HCC is common. Liver transplantation offers the best chance of curing HCC in cirrhotic patients. Patients with a solitary tumor less than 5 cm or no more than three tumors each 3 cm or less have a survival rate of 70% with less than 20% recurrence at 5 years. Access to liver transplantation is limited by organ availability, and tumor progression during the waiting period can lead to ineligibility. Ethanol injection and radiofrequency ablation are effective modalities to ablate small tumors (generally <5 cm) in patients who are not candidates for resection or liver transplantation. These modalities can also be used to treat HCC prior to liver transplantation. Transarterial chemoembolization is used to treat patients with multifocal or large HCC who are ineligible for other therapies. Chemotherapeutic agents are infused into the tumor via the hepatic artery along with embolic material in order to induce tumor necrosis. This technique should be used in selective patients with relatively preserved liver function, absence of portal vein thrombosis, or encephalopathy. Limited data exist to support the use of this modality as a primary treatment option for small HCC. Chemotherapeutic or hormonal therapies have a limited role in the management of patients with HCC. Despite mixed outcomes, we routinely use the somatostatin analog octreotide in advanced, multifocal HCC. Emerging therapies should focus on treatment of small tumors and targeted pharmacologic therapy for advanced disease.     

Immunotherapy for hepatocellular carcinoma: Current status and future perspectives

Hepatocellular carcinoma(HCC) is one of the world’s deadliest and fastestgrowing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery(liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying live...     

肝细胞癌生物标志物的研究进展:对于临床诊断及预后的意义

肝细胞癌(HCC)是2020年癌症死亡的第三大原因,也是全球第六大常见癌症。大多数肝癌患者在就诊时已发展为晚期癌症,尽管HCC发病率很高,但对于晚期患者的治疗方案并不多,所以提高HCC患者的早期发现率非常必要。本文总结HCC中已发现的生物标志物,希望能够为肝癌的早期诊断和预后判断提供新的视角。