仑伐替尼治疗肝细胞癌的研究进展

肝细胞癌（hepatocellular carcinoma,HCC）是严重威胁人类生命健康的疾病之一,其发病率和死亡率逐年上升,具有发展迅速、高侵袭性和高复发性等特点。大多数患者确诊时已是进展期,而靶向治疗作为进展期肝癌的主要治疗策略,已广泛应用于临床。以往该类患者的一线治疗药物仅有索拉菲尼,但其不良反应大,肿瘤应答率低,对乙型肝炎病毒（hepatitis B virus,HBV）阳性患者的总生存率并无明显改善。近年来,新的靶向治疗药物仑伐替尼在肝癌的治疗研究中取得了良好的疗效,成为继索拉菲尼后治疗进展期肝癌的第2个一线药物。本文就仑伐替尼在治疗HCC中的研究进展进行综述。      

晚期肾癌分子靶向治疗新进展

肾癌是泌尿系最常见的恶性肿瘤,透明细胞癌是常见病理类型,约占全部肾癌的 85 %～90 %。既往主要以化疗、白介素及干扰素药物等治疗肾癌。近年来随着肿瘤诊治水平的提高,对肾癌的认识和诊治取得重要突破,特别是分子靶向治疗为患者提供了新的治疗手段。以索拉非尼、舒尼替尼、帕唑帕尼、贝伐珠单抗、替西罗莫司、依维莫司、阿西替尼和卡博替尼等分子靶向治疗多种药物已应用于临床,为患者带来明显生存获益且耐受性较好。本文主要对晚期肾癌分子靶向治疗方面的最新进展进行综述。      

胃癌分子靶向治疗的研究新进展

分子靶向治疗是近几年来胃癌治疗领域的热点。目前,西妥昔单抗、帕尼单抗、吉非替尼、拉帕替尼、曲妥珠单抗等为胃癌治疗的主要靶向药物。本文结合最新研究报道对胃癌分子靶向治疗的最新进展作如下综述。     

吉非替尼治疗老年晚期非小细胞肺癌55例

老年局部晚期(Ⅲb期)和转移性(Ⅳ期)非小细胞肺癌(NSCLC)患者在肺癌人数中约占70%左右 [1],目前推荐的治疗标准是第3代化疗药物的单药治疗,部分体能评分较好的老年患者可接受标准的以铂类为基础的两药联合化疗.但是老年患者在一线化疗失败后大多不能耐受继续化疗,甚至很多患者因为体能评分差、化疗反应或不愿接受细胞毒药物治疗等而不能化疗 [2].吉非替尼是治疗晚期非小细胞肺癌(NSCLC)分子靶向药物,其有效性和良好的耐受性为此类患者带来了希望 [3].本文回顾总结我院于2007年1月至2009年1月用吉非替尼治疗的老年局部晚期和转移性非小细胞肺癌(NSCLC)患者的疗效、不良反应,旨在更好地认识吉非替尼对老年非小细胞肺癌患者的有效性与安全性.     

HER-2改变在非小细胞肺癌靶向治疗中的研究进展

肺癌是恶性程度和死亡率最高的恶性肿瘤之一,非小细胞肺癌(NSCLC)约占85%。靶向治疗是NSCLC的首选治疗方案。靶向治疗显著改善了ALK、ROS1、BRAF、NTRK、MET和大多数EGFR突变的NSCLC患者的临床结果。但自从发现异常激活的人类表皮生长因子受体2(HER-2)对EGFR抑制剂有耐药性并且其对化疗并不敏感以来,便促进了对HER-2改变的NSCLC患者靶向治疗的深入研究。HER-2改变包括基因突变、扩增和蛋白过表达。HER-2改变的不同类型针对不同的靶向治疗药物,其中HER-2第20外显子突变是NSCLC中具有功能意义的最为重要的驱动突变。本文针对HER-2改变的NSCLC患者的靶向治疗药物：阿法替尼、波齐替尼、吡咯替尼、曲妥珠单抗-美坦新偶联物、溴他替尼等的研究进展进行了详细综述。     

阿昔替尼与索拉非尼一线治疗晚期肾癌的临床疗效

目的:比较阿昔替尼与索拉非尼一线治疗晚期肾癌的临床疗效,探讨分子靶向药物阿昔替尼能否作为一线治疗晚期肾癌的优选药物.方法:选取海口市人民医院肿瘤科60例晚期肾癌患者,以数字表法随机分为试验组和对照组,每组30例.实验组给予阿昔替尼,对照组给予索拉非尼治疗,比较两组患者的DCR、ORR、PFS、OS及不良反应的差异.结果:两组患者均能完成试验并进行结果评价.试验组和对照组的DCR分别为83.33％和80.00％、ORR分别为20.00％和20.00％,差异均无统计学意义(P＞0.05);试验组和对照组的中位PFS分别为12.8个月和10.1个月,差异有统计学意义(P＜0.05);中位OS分别为22.2个月和22.8个月,差异无统计学意义(P＞0.05).两组患者不良反应发生率相近,差异无统计学意义(P＞0.05),主要表现在高血压、全身反应、手足皮肤综合征、消化道反应、肝功能损害,未见严重不良反应.结论:分子靶向药物阿昔替尼较索拉非尼一线治疗晚期肾癌更能延长患者中位PFS,两药治疗后患者的DCR、ORR、OS及不良反应相似,阿昔替尼可以作为一线治疗晚期肾癌的优选.     

进展期胃癌分子靶向治疗

进展期胃癌化疗效果不佳。分子靶向治疗是近年来进展期胃癌综合治疗的新手段。目前这些策略主要包括针对表皮生长因子受体（EGFR）通道的靶向治疗、针对血管内皮生长因子通道的靶向治疗、口服小分子靶向药物等。近期有关HER2、EGFR、VEGF、mTOR信号通路的靶向药物曲妥珠单抗、西妥昔单抗、贝伐单抗、阿帕替尼、索拉非尼、舒尼替尼、拉帕替尼、RAD001（everolimus）等综合治疗进展期胃癌的报道结果令人鼓舞。     

食管癌靶向治疗研究进展

2012年报告显示食管癌发病率在全球恶性肿瘤中居第5位,死亡率居第4位,与往年数据统计相比,其发病率及死亡率均呈上升趋势。目前对食管癌的治疗已进入多学科综合治疗时代,其中分子靶向治疗也成为研究热点,表现为靶向药物呈现多样化,由单一靶点走向多靶点化,应用于大量Ⅱ~Ⅲ期临床研究中。现今,在食管癌治疗中研究较多的靶向药物主要包括西妥昔单抗、厄罗替尼、曲妥珠单抗、贝伐单抗等。本文通过总结近几年国内外文献资料,对食管癌分子靶向治疗做一综述。     

肺癌靶向治疗研究:以文献计量学和可视化分析描述的热点与趋势

目的:通过文献计量学分析方法,阐述并分析肺癌靶向治疗的研究热点与趋势。方法:文章检索了万方数据库、Web of Science、SooPAT(中国专利)数据库近10年来国内外肺癌靶向治疗的相关文献,以文献计量学方法,分析并归类了肺癌靶向治疗的研究热点与时效变迁的趋势。结果:在万方数据库3 744篇肺癌靶向治疗的中文文章中,发现作用于表皮生长因子受体基因突变位点的分子靶向药物-吉非替尼治疗非小细胞肺癌的研究是中国学者近10年的主要研究热点;在近10年Web of Science数据库中检索到的810篇英文文章及参考文献显示,西妥昔单抗、贝伐单抗、纳武单抗、吉非替尼、厄洛替尼和环唑替尼为这10年肺癌治疗领域靶向治疗的热点药物,而多种靶向药物的联合治疗、晚期非小细胞肺癌的靶向治疗效果和肺癌靶向治疗后的脑转移也成为近5年该领域的国际关注热点;中国肺癌靶向治疗领域的254项有权专利的分析显示,申报了专利的主要药物包括酸敏感的吉非替尼-氟硼二吡咯衍生物、顺铂抗肺癌主动靶向隐形类脂质体等。结论:文章采用文献计量学的量化分析技术,呈现出近10年肺癌靶向治疗已成为该领域专业研究者持续关注的热点,而如何选择正确的靶向药物或药物组合方案来解决肺癌治疗中的耐药性问题,同时最大程度地减少患者的不良反应,以延长患者的生存率,应是未来集中研究的方向。     

舒尼替尼治疗肾细胞癌的新进展

肾细胞癌（ｒｅｎａｌｃｅｌｌｃａｒｃｉｎｏｍａ,ＲＣＣ）是最常见的肾脏肿瘤,其发病率呈逐年上升趋势,近年来随着ＲＣＣ增殖分子机制研究的深入和新的分子靶向药物不断问世,ＲＣＣ患者的生存率及生活质量均得到显著提高,ＲＣＣ的治疗进入了分子靶向时代。更重要是的,多靶点药物舒尼替尼已经取代传统的ＩＦＮ被列为转移性ＲＣＣ的一线标准治疗药物,联合分子靶向治疗与免疫治疗将是未来的发展方向。本文就舒尼替尼治疗ＲＣＣ的研究现状及进展作一综述。     

索拉非尼治疗肝细胞癌进展后的二线治疗

原发性肝癌是临床最常见的恶性肿瘤之一,其病理分型绝大多数属于肝细胞癌（HCC）。索拉非尼是第一个亦是目前唯一一个被多个国家批准用于治疗HCC的分子靶向药物,但其疗效有限,多数患者口服一段时间后会出现耐药而病情进展,对于这些患者目前尚缺乏标准的二线治疗方案,本文就索拉非尼治疗HCC耐药后的最新二线治疗研究进展作一综述。     

Systemic Treatment of Patients with Advanced,Unresectable Hepatocellular Carcinoma: Emergence of Therapies

To date, sorafenib, a multiple tyrosine kinase inhibitor, is the only systemic agent approved by the FDA in the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Several other tyrosine kinase-inhibiting agents have been investigated in the first-line setting, either alone (sunitinib, brivanib, linifanib, and lenvatinib) or in combination with sorafenib (erlotinib and doxorubicin) in phase 3 trials. However, none of these studies demonstrated an improvement in survival over sorafenib. Many agents have also been tested in patients with HCC whose disease has progressed on sorafenib, but regorafenib is the only one to have demonstrated efficacy in this setting in a randomized, phase 3 trial. There were no clear survival benefits shown with everolimus, brivanib, or ramucirumab as second-line therapy. Nivolumab has also shown promising efficacy in patients with HCC who progressed on sorafenib, which was recently granted approval by the FDA, although larger confirmative trials may be considered. The treatment landscape for patients with advanced unresectable hepatocellular tumors has remained fairly static for the past 10 years, with multiple failed trials yield little change in the way these patients might be treated. However, recent findings for regorafenib, lenvatinib, and nivolumab have led to the most significant changes in the treatment paradigm in years.     

Drug Treatment for Advanced Hepatocellular Carcinoma: First-Line and Beyond

Hepatocellular carcinoma (HCC) has high mortality. The option of systemic therapy has increased significantly over the past five years. Sorafenib was the first multikinase inhibitor, introduced in 2007, as a treatment option for HCC, and it was the only effective systemic treatment for more than ten years. It was not until 2017 that several breakthroughs were made in the development of systemic strategies. Lenvatinib, another multikinase inhibitor, stood out successfully after sorafenib, and has been applied to clinical use in the first-line setting. Other multikinase inhibitors such as regorafenib, ramucirumab and cabozantinib, were approved in quick succession as second-line therapies. Concurrently, immune checkpoint inhibitors (ICIs) have readily become established treatments for many solid tumors, including HCC. The most studied ICIs to date, target programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These ICIs have demonstrated efficacy in treating advanced HCC. More recently, combination of bevacizumab and atezolizumab (ICI targeting PD-L1) was approved as the gold-standard first-line therapy. Combination of ICIs with nivolumab and ipilimumab was also approved in the second-line setting for those who failed sorafenib. At the moment, numerous clinical trials in advanced HCC are underway, which will bring continuous change to the management, and increase the survival, for patients with advanced HCC. Our review article: (1) summarizes United States Food and Drug Administration (US FDA) approved systemic therapies in advanced HCC, (2) reports the evidence of currently approved treatments, (3) discusses potential drugs/drug combinations being currently tested in phase III clinical trials, and (4) proposes possible future directions in drug development for advanced HCC.     

肝细胞肝癌的免疫治疗基础和临床研究进展

原发性肝癌，特别是肝细胞肝癌，严重威胁我国人民的生命和健康。由于肝癌起病隐匿，首次诊断时只有不到30%的患者适合接受根治性治疗，系统抗肿瘤治疗在中晚期肝癌的治疗过程中发挥重要作用。近年来肝癌的免疫治疗飞速发展，越来越多的免疫治疗药物成为肝癌一线、二线治疗选择，较好地控制肝癌的进展，延长患者的生存时间。本文就近年来肝癌免疫治疗进展行简要综述。     

Second-line therapy for advanced non-small-cell lung cancer

Over the past three decades, progress has been made in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). Current recommendations include combination chemotherapy with or without targeted therapy. Despite these advances, the majority of patients relapse after initial treatment. Many of these patients are eligible for second-line therapy, which has prompted significant clinical research in this area. In 1999, docetaxel became the first drug approved by the US Food and Drug Administration for the treatment of patients with advanced NSCLC in the second-line setting. In 2004, two additional agents, pemetrexed and erlotinib, also received approval, giving patients three options for second-line treatment. Many promising new drugs and drug combinations are currently under investigation.     

Technology insight: Image-guided therapies for hepatocellular carcinoma--intra-arterial and ablative techniques

Locoregional techniques have become the mainstay of therapy for patients with unresectable hepatocellular carcinoma (HCC). Such image-guided interventions include catheter-based approaches (transarterial chemoembolization and yttrium-90 radiotherapy) and locoregional ablative techniques, either chemical (percutaneous ethanol injection), or thermal (radiofrequency ablation, laser ablation, microwave ablation and cryoablation). These therapies are mainly utilized for palliation, but have also been used with curative intent. In selected cases, percutaneous interventional treatments have shown good results (5-year survival 40-50%), but, even when chosen as first-line treatment, have not been able to achieve the response rates and outcomes achieved by surgical options (resection or transplantation). New promising image-guided therapies are continuously emerging, as we attempt to improve tumor targeting, minimize hepatic toxicity and ultimately improve quality of life and survival of patients with HCC. With new technologies in imaging and drug delivery becoming available, it is likely that, in the future, patients with HCC will be best treated by a multidisciplinary team approach, utilizing a combination of techniques to improve patient survival. This review outlines the current status of the most commonly used image-guided locoregional interventions in the treatment of patients with HCC, and describes recent research and advances related to image-guided interventions for liver cancer.     

The association of clinical outcome to first-line VEGF-targeted therapy with clinical outcome to second-line VEGF-targeted therapy in metastatic renal cell carcinoma patients

There are many active drugs to treat metastatic renal cell carcinoma (mRCC) patients who progress through their first-line vascular endothelial growth factor (VEGF) inhibitor. Many clinicians choose a second-line VEGF inhibitor based on the type of response to first-line VEGF inhibitor, without data supporting this practice. This study was conducted to determine the association of response to second-line VEGF inhibitor with response to first-line VEGF inhibitor. All mRCC patients in participating centers of the International mRCC Database Consortium who were treated from January 2004 through June 2011 with a second-line VEGF inhibitor after failure of a different first-line VEGF inhibitor were retrospectively identified. The primary outcome is objective response rate (ORR) and the secondary outcome is progression-free survival (PFS) in each line of therapy. Of 1,602 total database patients, 464 patients received a first- and second-line VEGF inhibitor. The ORR to first-line therapy was 22 %, and the ORR to second-line therapy was 11 %. The ORR to second-line therapy was not different among patients achieving partial response versus stable disease versus progressive disease to first-line therapy (14 % vs. 10 % vs. 11 %, respectively; chi-squared trend test p?=?0.17). The median PFS on first-line VEGF-targeted therapy was 7.5 months (95 % CI, 6.6–8.1), and the median PFS on second-line VEGF inhibitor was 3.9 months (95 % CI, 3.6–4.5). There was no correlation between first-line and second-line PFS (Pearson correlation coefficient 0.025; p?=?0.59). The clinical response to a second-line VEGF inhibitor is not dependent on response to the first-line VEGF-inhibitor. Further studies are needed to define clinical parameters that predict response to second-line therapy to optimize the sequence of VEGF-targeted therapy in metastatic RCC patients.     

Second-line systemic therapy for the treatment of metastatic renal cell cancer

The discovery of molecular mechanisms driving the progression of renal cell carcinoma (RCC) has led to the development of drugs that target RCC at the molecular level. Inhibition of VEGF-targeting pathways is successful as a front-line treatment in patients with metastatic RCC. In addition, bevacizumab/IFN-α, sunitinib and pazopanib are recommended for first-line use in good- or intermediate-risk patients, whereas temsirolimus is approved for poor-risk patients. Second-line options are valuable as these patients eventually progress. The present review addresses which drug is best in this second-line setting. Options for sequential therapy include tyrosine kinase inhibitor (TKI)-mTOR inhibitor or TKI-TKI sequences. We also address the question of whether sequential therapy with TKIs or the combination of VEGF followed by mTOR inhibition is the best choice for specific patients, and which sequence of TKIs is most beneficial.     

Second-line systemic therapy for the treatment of metastatic renal cell cancer

The discovery of molecular mechanisms driving the progression of renal cell carcinoma (RCC) has led to the development of drugs that target RCC at the molecular level. Inhibition of VEGF-targeting pathways is successful as a front-line treatment in patients with metastatic RCC. In addition, bevacizumab/IFN-α, sunitinib and pazopanib are recommended for first-line use in good- or intermediate-risk patients, whereas temsirolimus is approved for poor-risk patients. Second-line options are valuable as these patients eventually progress. The present review addresses which drug is best in this second-line setting. Options for sequential therapy include tyrosine kinase inhibitor (TKI)–mTOR inhibitor or TKI–TKI sequences. We also address the question of whether sequential therapy with TKIs or the combination of VEGF followed by mTOR inhibition is the best choice for specific patients, and which sequence of TKIs is most beneficial.