第24届亚太地区肝脏研究协会年会（APASL 2014）于2014年3月12～15日在澳大利亚布里斯班召开。会上奥地利维也纳医科大学胃肠道与肝病系医学博士Markus Peck教授介绍了索拉非尼及其他口服抗肿瘤药物的研究进展。 
 

 Markus Peck教授
 

索拉非尼（Sorafenib）是一种针对RAF-， VEGF-， PDGF-和其他酪氨酸激酶的多重激酶抑制剂，是目前治疗晚期肝癌的一线药物。索拉非尼的适应证有：肿瘤体积大、多个肿瘤、血管侵犯、远处转移、Child Pugh 评分A级、一般状态良好。研究表明白种人服用索拉非尼，可延长10.7个月的生存期，安慰剂组为7.9个月。另一项研究也表明亚洲的晚期肝癌患者服用索拉非尼后，其生存期中位数从平均4.2个月延长到了6.5个月。

一项来自欧盟的大型观察性研究（Bridge）研究表明，尽管索拉非尼可以显著改善患者的生存率，但只有大约10%的晚期肝癌患者接受索拉非尼治疗。大部分患者接受了其他治疗，且这些治疗标准有时并不是被大家广泛认可的。但这项研究同时也指出，如果病人先前得到了正规、系统性治疗，那么90%的患者会应用索拉非尼。索拉非尼改善了患者生存期，虽然不是很明显，但却是肝癌治疗的一大进步，同时也激发了晚期肝癌一线治疗药物的开发。

不幸的是，随后的几个大型三期药物临床试验比较了索拉非尼与其他口服抗肿瘤药物的疗效，结果显示Sunitinib、Linifanib、Brivanib、Sorafenib联合Erlotinib都不能有效延长患者生存率，甚至疗效还不如索拉非尼，因此这些临床试验被视为是失败的。这些负面结果虽然减弱了研究者开发治疗肝癌一线药物的热情，但仍有一些药物，如Lenvatinib、Nintedanib、Refametinib正在进行二期及三期药物临床试验。
 

另一个主要问题是索拉非尼平均应用17.6周后就会失效，而目前尚无二线药物能在患者无法耐受索拉非尼或对索拉非尼抵抗后进行补救治疗。两个三期药物临床试验评估了多重激酶抑制剂Brivanib和m-Tor激酶抑制剂Erlotinib在索拉非尼治疗失败后进行补救治疗的疗效，结果发现两者都无效。VEGF-R2拮抗剂单克隆抗体—Ramucirumab的研究数据值得期待。另外，一种HGF-受体阻滞剂— Tivantinib（肝细胞生长因子受体抑制剂）的二期药物临床试验结果显示其可明显延长高表达肝细胞生长因子受体患者的生存期，目前这种药物正在进行三期药物临床试验。

目前很多治疗晚期肝癌的药物正在进行一期和二期试验。除传统的针对生长因子受体及其信号传导通路所开发的药物外，一些针对端粒酶活性和免疫治疗的新药物也初步显示了很好的疗效，但这需要进一步在临床试验中评估。现在需要深入发展生物学标志物鉴定的研究，从而以患者特有的生物学标志物为依据，为患者提供个体化的、最佳的治疗药物。

原文阅读》》》The Role of Sorafenib and Other Oral Agents
 

Markus Peck, MD, Department of Gastroenterology and Hepatology , the Medizinische Universität Wien, Austria.
 

Sorafenib, a multikinase inhibitor targeting RAF-, VEGF-, PDGF-, and other tyrosine kinases, is the current standard of care for the treatment of advanced stage liver cancer. Patients with large multifocal tumours, with vascular invasion or extrahepatic spread, Chi ld Pugh A and good per formance s tatus are typical candidates for this drug. Sorafenib prolongs the survival of these patients from a median of 7.9 months in a placebo group to 10.7 months in the treatment group in a mostly Caucasian population, while in a group of Asian patients with more advanced tumours, the median survival was improved from 4.2 to 6.5 months. 
 

Data from the large observational BRIDGE study from the EU show that, despite this significant improvement in patient survival, only around 10% of all patients with advanced stage HCC in Europe receive treatment with sorafenib. The majority of patients get all kinds of other treatments, which often times are not consistent with the suggested treatment standard. But the same study shows that if patients get systemic treatment, then 90% of the patients get treatment with sorafenib. Th e improvement insurvival facilitated by sorafenib, even though modest, was a major advance for the treatment of HCC, and stimulated drug development in first line treatment of HCC. 
 

Unfortunately, in the next several large phase III trials comparing sorafenib with other drugs, neither sunitinib, linifanib, brivanib, nor the combination of sorafenib and erlotinib were able to show a survival advantage or even non-inferiority to treatment with sorafenib and have to be regarded as fai led cl inical trials. These negative results have slowed down the enthusiasm for drug development in the first line treatment for HCC considerably. Nevertheless, several substances like lenvatinib, nintedanib or refametinib are currently undergoing phase II or phase III testing in the first line setting. 
 

Another major chal lenge is the fact that after a median of 17.6 weeks, treatment with sorafenib fails. Currently, there is no second line treatment established to date that could be offered as standard of care for patients who are intolerant to sorafenib or treatment failures. Two phase III studies testing the multikinase inhibitor brivanib and the m-Tor inhibitor everolimus versus placebo in the second line setting after sorafenib failure showed negative results. The data on ramucirumab, a VEGF-R2 antagonist monoclonal antibody are eagerly awaited, while treatment with the HGF-receptor blocker tivantinib (c-MET inhibitor) showed a significant survival benefit in a phase II trial in patients with high c-MET expression compared to placebo and is currently undergoing phase III testing.
 

A considerable number of drugs are under development in the first and second line setting for advanced stage liver cancer. In addition to traditional approaches targeting growth factor receptors and their pathways , novel approaches targeting telomerase activity or immunotherapy show promising experimental results but need urther evaluation in preclinical and clinical settings. Additionally, identificat ion of biomarkers for patient selection for different drugs needs development in order to use novel drugs in the best way possible.