Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be?

Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death. In the U.S., 18,510 new cancers of the liver and intrahepatic bile duct are expected in 2006, with an estimated 16,200 deaths. The incidence rates for HCC in the U.S. continued to rise steadily through 1998 and doubled during the period 1975-1995. Unresectable or metastatic HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit. A majority of HCC patients (>80%) presents with advanced or unresectable disease. Even for those with resected disease, the recurrence rate can be as high as 50% at 2 years. Because of the poor track record of systemic therapy in HCC, there has been a sense of nihilism for this disease in the oncology community for decades. However, with the arrival of newly developed molecularly targeted agents and the success of some of these agents in other traditionally challenging cancers, like renal cell carcinoma, there has recently been renewed interest in developing systemic therapy for HCC. This review attempts to concisely summarize the historical perspective and the current status of systemic therapy development in HCC.     

肝癌的靶向治疗

肝癌（HCC）是全球最富有挑战性的恶性肿瘤之一。HCC需要综合治疗，目前尚无特效的治疗药物。分子靶向药物的发展，使HCC的全身治疗有了新的希望。阐述了分子靶向药物的现状，多激酶抑制剂、抗血管生成和抗表皮生长因子受体药物在临床上的进展，认为索拉芬尼是晚期HCC的新的标准治疗药物。     

Traitement systémique du carcinome hépatocellulaire

Systemic cytotoxic treatments provide marginal benefit in unresectable or metastatic HCC. With the arrival of molecularly targeted agents, there has been renewed interest in developing novel systemic treatments for HCC. For the first time, results of a phase III randomized, placebo-controlled trial were recently presented in which sorafenib demonstrated improved survival in patients with advanced HCC. Therefore, sorafenib is now the new standard for the first-line treatment of advanced HCC. The identification of predictive factors and the search for new molecules remain major challenges for this poor prognostic disease.     

Molecularly targeted therapy for advanced hepatocellular carcinoma in 2012: current status and future perspectives

Improving the overall survival for patients with advanced hepatocellular carcinoma (HCC) requires development of effective systemic therapy. Despite the successful approval and extensive application of sorafenib, the prognosis for patients with advanced HCC remains poor and the benefits with sorafenib are modest. In the past few years, there have been renewed and continued interests and active research in developing other molecularly targeted agents in HCC. While the initial efforts are focusing on anti-angiogenic therapy, other agents targeting the epidermal growth factor-receptor, mammalian target of rapamycin (mTOR), hepatocyte growth factor/c-Met among others have entered HCC clinical trials. Combining different molecularly targeted agents or combining targeted agents with chemotherapy represent other strategies under investigation. This review will attempt to summarize the current status of other molecularly targeted agents or regimens beyond sorafenib under development in advanced HCC and the future perspectives.     

肝癌的分子靶向治疗研究进展

不能手术和已转移的原发性肝细胞癌预后很差,放化疗难以使患者受益。近年来,分子靶向治疗对一些肿瘤已取得突破性进展,肝癌的分子靶向治疗也在临床试验中取得了令人鼓舞的结果。目前的肝癌临床研究主要针对EGFR、VEGF/VEGFR、Raf/MAPK-ERK、HGF、乙肝表面抗原等靶点。本文针对肝癌的分子靶向治疗的研究进展进行了综述。     

Targeted agents for the systemic treatment of advanced hepatocellular carcinoma

The prognosis for advanced hepatocellular carcinoma is poor and systemic therapy has historically been of limited benefit. However, novel targeted agents offer promise in improving patient outcomes. In a recent phase III study the oral multi-tyrosine kinase inhibitor sorafenib was demonstrated to have a survival advantage over a placebo in advanced hepatocellular carcinoma. Similar efficacy was demonstrated in a phase III trial limited to an Asian–Pacific group of patients. While these results are encouraging, it is vital to make further progress. In this review we examine current knowledge of targeted agents in advanced hepatocellular carcinoma. We also address some of the key issues that require exploration regarding the use of targeted agents in advanced hepatocellular carcinoma.     

Novel systemic therapy options for hepatocellular carcinoma

Hepatocellular carcinoma, a common malignancy globally, has been increasing in incidence in the United States, mostly due to the rising incidence of Hepatitis C viral (HCV) infection. The prognosis of patients with this cancer has been poor and even tumor resection has rarely been curative. However, orthotopic liver transplantation (OLT) has been associated with long-term survival benefit and cures, provided rigorous patient-selection criteria were adhered to. Liver cirrhosis is the most common precursor for HCC, and attempts have been made to prevent the progression from liver cirrhosis to HCC. Post resection adjuvant therapies have included interferon, polyprenoic acid, and adoptive immunotherapy. Finding effective systemic treatments for non-resectable HCC has been challenging and quite frustrating. The presence of liver cirrhosis and the associated volume expansion, electrolyte imbalances, decreased liver synthetic and metabolic reserve, and portal hypertension has made the design of systemic therapy for HCC a major challenge. Additionally staging of HCC using the Tumor Node Metastases (TNM) system, but ignoring the underlying liver disease made it extremely difficult to compare results of different trials. However by and large it would seem, that the more aggressive chemotherapy agents and combinations were associated with median survival times of 3-5 months. Considering the vascular nature of HCC it may be reasonable to combine tolerable chemotherapy with newly released agents with angiogenesis inhibiting properties. Thus, systemic therapy of HCC is a work in progress that calls for additional trials of tolerable newer agents and combinations.     

Current status of molecularly targeted therapy for hepatocellular carcinoma: basic science

Conventional systemic chemotherapy has been developed with so-called anti-cancer agents, essentially screened for cytotoxicity to cultured cancer cells. However, in patients with hepatocellular carcinoma (HCC), the role of chemotherapy is quite limited because most anti-cancer agents are ineffective and relatively toxic to HCC patients with chronic liver diseases. On the other hand, accumulated understanding of the molecular mechanisms regulating cancer progression has led to novel development of molecularly targeted therapies with cytostatic agents. Recently, a phase III clinical trial revealed a multi-kinase inhibitor, Sorafenib, as the first agent leading to improved overall survival of patients with advanced HCC. A new era of HCC treatment has arrived, based on identification of deranged signaling pathways of cancer cells or their microenvironment. This review summarizes the molecular hallmarks of HCC with a focus on angiogenesis, growth signals, and mitotic stress, and a novel concept “synthetic lethality” for the targeted therapy strategy.     

A narrative review of systemic treatment options for hepatocellular carcinoma: state of the art review

Hepatocellular carcinoma (HCC) is an aggressive cancer that typically develops in the setting of underlying cirrhosis of the liver. HCC commonly presents in advanced stages and if eligible orthotopic liver transplantation (OLT) and surgical resection/ablation remain as the only curative options. Prior to 2007, no systemic therapy was available that demonstrated an improvement in survival. Underlying cirrhosis and poor synthetic hepatic function provides a major challenge into effective systemic options contributing to the poor success of cytotoxic chemotherapy in HCC. The first drug to achieve clinical success was sorafenib despite the underwhelming overall survival of 3 months. Since then, other targeted therapies have shown modest benefit as well. Most recently, immunotherapy advances have come to the forefront in the management of HCC and combination therapy with immunotherapy and monoclonal antibodies have now surpassed sorafenib as first line treatment. This article will review the various approved and emerging therapies that have had a significant clinical impact and highlight the future directions and ongoing research that will hopefully translate into better outcomes in the treatment approach of advanced HCC.     

Targeted therapy for renal cell carcinoma: a new therapeutic paradigm

Renal cell carcinoma is the most common tumor of the kidney. It has an unpredictable behavior and poor response to systemic therapy. Developing newer therapy for this disease is a priority considering the high recurrence rate and the small subset of patients who benefit from the use of cytokines such as interferon-alpha or interleukin-2. Identifying molecular targets and targeting various biomarkers has revolutionized the therapeutic approach to advanced and metastatic renal cell carcinoma. Although some of the antiangiogenic agents and receptor tyrosine kinase inhibitors appear promising, further understanding of their mechanism of action and the patient population who would benefit most from such agents is still being explored. As numerous targeted agents are entering the clinical investigation arena in a relatively short period of time, newer challenges in renal cell carcinoma therapeutics are emerging. Some of the future challenges in using targeted antineoplastic agents in renal cell carcinoma will include evaluating their long-term safety and benefit, using the particular drug in the appropriate patient population after appropriate stratification and studying the combination of some of these drugs for synergy or additive effects.     

HCC and angiogenesis: possible targets and future directions

Hepatocellular carcinoma (HCC), the most common primary liver tumor, is notoriously resistant to systemic therapies, and often recurs even after aggressive local therapies. HCCs rely on the formation of new blood vessels for growth, and VEGF is critical in this process. A hallmark of new vessel formation in tumors is their structural and functional abnormality. This leads to an abnormal tumor microenvironment characterized by low oxygen tension. The liver is perfused by both arterial and venous blood and the resulting abnormal microenvironment selects for more-aggressive malignancies. Anti-VEGF therapy with sorafenib was the first systemic therapy to demonstrate improved survival in patients with advanced-stage HCC. This important development in the treatment of HCC raises hope as well as critical questions on the future development of targeted agents including other antiangiogenic agents, which hold promise to further increase survival in this aggressive disease.     

ASCO 2006 highlights: targeted therapy for renal cell carcinoma

In the past few years, advances in the understanding of the pathogenesis of renal cell carcinoma (RCC) have resulted in the identification of new therapeutic targets, and ultimately, the development of new targeted agents for the treatment of the disease. This paper reviews latest data in RCC for the recently approved agents sunitinib and sorafenib, as well as other molecularly targeted drugs, presented at the annual meeting of the American Society for Clinical Oncology, held in Atlanta, Georgia, in June 2006. Clinical findings to date show that these new agents are challenging the role of cytokines in this setting, and for some (e.g. sunitinib) a substantially improved efficacy profile (progression-free survival and response) over conventional cytokine therapy has been reported. While challenges remain with regard to optimal use of these agents, the outlook for patients with advanced RCC has improved considerably and there is great hope for continuing progress.     

The impact of new data in the treatment of advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, causing 500,000 deaths yearly. The risk factors mostly responsible for the rising incidence of HCC in the Western hemisphere are hepatitis C, alcoholic cirrhosis, and nonalcoholic steatohepatitis, which most commonly leads to HCC in the setting of cirrhosis. Over the past 30 years, several chemotherapeutic single agents and combinations have been tested in HCC, yet none have demonstrated any improvement in survival. Recently, the multitargeted anti-angiogenic and Raf kinase inhibitor sorafenib has shown a survival advantage as a single agent and improved outcomes in combination with doxorubicin. Other novel agents have also shown intriguing outcomes as single agents (sunitinib) or in combination (bevacizumab and erlotinib). The encouraging results and clinical information gathered in recent trials are generating important clinical questions regarding which patients to treat, how to accommodate concurrent cirrhosis, and which parameters to use to monitor efficacy and the potential benefit from therapy.     

Molecular pathogenesis and targeted therapy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) constitutes the 5th most frequent cancer worldwide, and due to a lack of treatment options, HCC represents the 3rd most lethal cancer worldwide. The incidence of HCC is continuously rising in Europe and Northern America, which can be explained by spreading of hepatitis C virus infections. Systemic chemotherapy is not an option for most patients with HCC. The most promising strategy for systemic treatment of HCC is targeted therapy. Successful targeted therapy has to inhibit pathways which are necessary for tumor growth, even in the late stages of carcinogenesis. The p16/Rb, p53, and IGF2R checkpoints as well as oncogenic alterations of telomerase, c-myc, Wnt/beta-catenin, PI3K/Akt, hedgehog, and c-met/HGF are most frequently involved in human hepatocarcinogenesis. However, currently, the most attractive target for molecular therapy of HCC appears to be the vascular endothelial growth factor (VEGF). Phase I/II studies showed high progression-free survival rates with antibodies or small molecules targeting the VEGF receptor pathway. Recently, a randomized placebo-controlled phase III study showed that the multikinase inhibitor sorafenib, which inhibits VEGF and Raf, significantly improves survival of patients with advanced HCC and Child A cirrhosis. As a consequence of this study, sorafenib is now the first available drug for effective systemic treatment of patients with advanced HCC.     

Hepatocellular Carcinoma: Review of Targeted and Immune Therapies

Background

Hepatocellular carcinoma is the fifth most common cancer globally and the second leading cause of cancer-related mortality worldwide. Despite the established efficacy of screening programs for at-risk individuals, most patients are diagnosed at later stages of disease, wherein the tumor characteristics or liver disease progressions do not allow for curative interventions. Many cytotoxic chemotherapeutic agents have been tested in patients with advanced disease with disappointing outcomes and poor tolerance; therefore, no standard systemic therapy emerged until the approval of sorafenib in 2006.

Conclusion

Despite the toxicity and low response rate, sorafenib had shown a significant survival benefit in phase III clinical trials, thus encouraging clinical research aimed at advancing the field of molecular therapy. Disrupted signaling pathways related to hepatocellular carcinoma (HCC) include the Wnt/β-catenin, Ras/Raf/MAPK, phosphatidyl inositol 3-kinase/Akt/mechanistic target of rapamycin, hepatocyte growth factor/c-mesenchymal–epithelial transition, IGF, vascular endothelial growth factor, and platelet-derived growth factor pathways, and a variety of agents targeting these pathways are currently under investigation. Additionally, better comprehension of the complex mechanisms underlying the ability of tumor cells to escape immune surveillance has led to impressive results with immunotherapy in many types of cancer, and this treatment strategy is currently being developed for HCC patients. Previous and ongoing targeted therapy and immunotherapy trials for HCC are discussed in this review.

     

Systemic therapy in metastatic or recurrent endometrial cancer

Endometrial cancer is one of the most common gynecologic malignancies. In patients with advanced or recurrent endometrial cancer survival is greatly diminished. Hormonal therapy and chemotherapy play a major role in the management of advanced or recurrent endometrial cancer. Endocrine therapy provides a 10-20% response rate (RR) and survival of less than 1 year. Combination chemotherapy offers a RR of 40-60%, but the survival is still less than 1 year. The combination of cisplatin plus doxorubicin is the most commonly used regimen, but carboplatin plus paclitaxel represents an efficacious, low toxicity regimen in advanced or recurrent endometrial cancer. The addition of paclitaxel to cisplatin plus doxorubicin appears to improve response rates, progression-free survival and overall survival, but to worsen toxicity profile. At this time the focus of future research should be on the use of novel targeted agents, since it is unlikely that further significant advances could be made with chemotherapy and endocrine therapy. mTOR inhibitors represent a promising therapeutic strategy for endometrial cancer. Anti-HER-2/neu targeted therapy might be a novel and attractive therapeutic option in patients with biologically aggressive variants (uterine serous papillary carcinoma, clear cell carcinoma) of endometrial cancer. Research in better understanding the signal transduction pathways in endometrial carcinogenesis will allow the development of specific and selective molecularly targeted inhibitors.     

From molecular biology to targeted therapies for hepatocellular carcinoma: the future is now

Hepatocellular carcinoma (HCC) is characterized as a highly chemoresistant cancer with no effective systemic therapy. Despite surgical or locoregional therapies, prognosis remains poor because of high tumor recurrence or tumor progression, and currently there are no well-established effective adjuvant therapies. The molecular biology of carcinogenesis and tumor progression of HCC has been increasingly understood with intense research in recent years. Several important intracellular signaling pathways such as the Ras/Raf/Mek/Erk pathway and PI3k/Akt/mTOR pathway have been recognized, and the role of several growth factors and angiogenic factors such as EGF and VEGF has been confirmed. Effective agents targeting these molecular abnormalities have been developed and widely tested in preclinical studies of HCC cell lines or xenograft models. Several agents have entered clinical trials in HCC patients, and recent data indicated that a multikinase inhibitor targeting Ras kinase and VEGFR-2, sorafenib, is effective in prolonging survival of patients with advanced HCC. The management of advanced HCC is entering the era of molecular targeting therapy, which is of particular significance for HCC in view of the lack of existing effective systemic therapy for this cancer.     

Current approach in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common malignant hepatobiliary disease; it is responsible for about 1 million deaths per year. Risk factors include hepatitis B and C, hepatic cirrhosis, including alcohol related hepatitis, metabolic and nutritional hepatic damage. The main modality of diffusion is intrahepatic in the natural course of the disease. There are two leading types of treatment: local and systemic. Surgical resection and liver transplantation constitute the most appropriate local treatments and are considered the only real possibility for recovery. Other local approaches include: radiofrequency ablation, percutaneous ethanol ablation, hepatic endoarterial chemoembolization and intrahepatic radiotherapy (SIRT: selective internal radiation therapy). These last treatments are used to control the disease when surgery or transplantation is not achievable; in some cases they are able to prolong survival while they constitute mainly a palliative treatment. Systemic treatments include: chemotherapy, immunological and hormonal therapies and, more recently, the introduction of new specific molecular target drugs. At the moment, in this group, the only drug that has given positive results during phase III trials (SHARP study) is Sorafenib. Sorafenib represents the only primary systemic therapy that has demonstrated, unlike the other treatments previously described, an increase in survival rate in patients affected with advanced HCC. Currently, other studies are taking place that are further developing the potential of this drug. These studies, including phase III trials, are directed in order to test the activity and safety of new emerging drugs with targeted activity. Examples of these new agents are: Sunitinib, Gefitinib, Cetuximab, Bevacizumab and Erlotinib.     

Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials

Hepatocellular carcinoma (HCC) is common worldwide, and its incidence is increasing. Liver resection or transplantation is potentially curative, although subsequent recurrence and death are common. We reviewed randomised trials on the role of adjuvant therapy in resectable HCC. We identified 13 randomised trials with recurrence or survival endpoints reported at 3 years or longer. Three studies involved predominantly systemic adjuvant chemotherapy; four involved predominantly hepatic-artery-based chemotherapy or embolisation; and six used other therapeutic modalities including immunological, radiation, and differentiation agents. A therapeutic benefit in terms of disease-free or overall survival was noted in six trials, five of which involved modalities other than systemic or hepatic-artery chemotherapy or embolisation. We conclude that systemic and hepatic-artery chemotherapy or chemoembolisation have not been shown to improve overall or disease-free survival after resection of HCC, although there has been no definitive trial comparing adjuvant systemic chemotherapy with no treatment. Other adjuvant modalities (mostly tested in small, preliminary settings) may confer benefit after potentially curative resection of HCC.     

90 Y微球选择性内放射治疗在肝细胞癌中的应用及研究进展

肝细胞癌（hepatocellular carcinoma,HCC）是中国癌症相关死亡第二大常见原因。中国约85%的HCC患者在确诊时已是中晚期,系统治疗（包括化疗、靶向治疗、免疫治疗）联合局部微创治疗（如介入治疗、放射治疗等）是目前主要的治疗方式。钇-90（yttrium-90, ⁹⁰ Y）微球选择性内放射治疗（selective internal radiation therapy,SIRT）作为主要局部微创治疗手段在国外已有近20年的临床使用经验,临床研究证明了其治疗肝脏肿瘤的疗效和安全性。相关研究证实了 ⁹⁰ Y微球SIRT单用在HCC中的局部控制作用,以及其与手术、免疫药物、靶向药物联用的有效性及安全性,同时, ⁹⁰ Y微球SIRT对于肝段产生的“放射性切除”效应初步显示出其在HCC根治性治疗方面的应用前景。从HCC姑息治疗、转化治疗、放射性肝段切除等方面综述SIRT在HCC中的应用及研究进展。