晚期非小细胞肺癌的靶向治疗研究进展

化学治疗晚期非小细胞肺癌疗效似已达到平台,分子靶向治疗是进-步提高疗效的新方法.靶向药物包括表皮生长因子受体抑制剂,抗血管生成药物等.EGFR抑制剂代表药物吉非替尼(Gefitinib)临床收益率低, 厄洛替尼(Erlotinib)作为第-个可延长生存期的EGFR酪氨酸激酶抑制剂,成为很有潜力的-线治疗晚期非小细胞肺癌的选择.贝伐单抗(Bevacizumab)作为第-个被美国FDA批准用于癌症治疗的抗血管生成药物,其与化疗联用在-线应用中显示出良好收益.以上药物与其他多种靶向药物的I临床研究进展-起,展示了靶向药物对于晚期非小细胞肺癌治疗的良好前景.     

阿帕替尼联合其他方法治疗肿瘤的研究进展

 血管新生在肿瘤的生长以及转移过程中发挥重要作用，其中血管内皮生长因子受体2（VEGFR2）是关键的调控因子。甲磺酸阿帕替尼是我国历经十年研制成功的一种小分子酪氨酸激酶抑制剂，可高特异性结合VEGFR2。目前阿帕替尼单药在临床已成功应用于晚期胃癌、非小细胞肺癌、乳腺癌等常见肿瘤的治疗。阿帕替尼与其他抗肿瘤疗法的联用往往可以达到增加药效、减少不良反应的效果。本文主要针对目前报道过的临床实验以及基础研究来简要说明阿帕替尼与其他药物联合治疗用于不同肿瘤的治疗效果以及作用机制。     

非小细胞肺癌抗血管生成治疗研究进展

非小细胞肺癌（non-small cell lung cancer,NSCLC）的增殖、浸润、转移都需要新生血管的支持,抗血管生成治疗已成为一种重要治疗手段。血管内皮生长因子（vascular endothelial growth factor,VEGF）作为关键的促血管生成因子,是目前NSCLC抗血管生成治疗药物的主要靶点。这些药物主要包括以VEGF或其受体VEGFR为靶点的单克隆抗体,及阻断VEGFR下游信号通路传导的小分子酪氨酸激酶抑制剂（VEGFR-TKI）两类。目前有两种抗血管生成单克隆抗体,贝伐单抗及雷莫卢单抗,被批准联合化疗一线或二线治疗原位进展或转移的NSCLC。多种VEGFR-TKI治疗NSCLC的临床试验均以失败告终,目前仅有安罗替尼在我国被批准用于NSCLC的三线治疗,而尼达尼布联合化疗在二线治疗中也显示了良好的生存获益。本篇综述我们将回顾总结抗血管生成药物单药或与其他抗肿瘤药物联用成功应用于NSCLC治疗的临床研究数据。     

VEGF和VEGFR通路抑制剂在晚期胃癌治疗中的疗效

抗新生血管形成是目前胃癌治疗的重要研究方向,血管内皮生长因子(VEGF)及血管内皮生长因子受体(VEGFR)抑制剂是主要的研究热点.目前治疗晚期胃癌的VEGF及VEGFR通路抑制剂包括贝伐珠单抗、雷莫芦单抗、阿帕替尼、瑞戈非尼、索拉非尼等,这些药物为晚期胃癌的治疗提供了更多可能性.     

晚期非小细胞肺癌抗血管生成药物的联合治疗模式

晚期非小细胞肺癌的治疗方案包括化疗、针对驱动基因的靶向治疗以及以免疫检查点抑制剂为代表的免疫治疗,疗效仍待进一步提高,而联合治疗是当前研究热点.抗血管生成药物在晚期非小细胞肺癌中应用广泛,不仅能通过抑制肿瘤新生血管来抑制肿瘤的生长和转移,还能使血管正常化,调节肿瘤微环境,从而与其他抗肿瘤治疗方式协同增效,共同抑制肿瘤生...     

VEGF 及其抑制剂 Axitinib 在非小细胞肺癌临床治疗中的应用

血管内皮生长因子（vascular endothelial growth factor,VEGF）是一种特异性极强的促血管生成因子,可促进新生血管及淋巴管的形成.在多种肿瘤（如肺癌、胃癌、结肠癌、肾癌等）中高表达,且与癌症的发生、发展及转移密切相关,为癌症的生化诊断及靶向治疗提供了研究方向.阿西替尼（Axitinib）是一种以酪氨酸激酶为靶向、抑制血管生成的新抗癌药.本文就VEGF及其抑制剂阿西替尼在非小细胞肺癌临床治疗中的应用进行简要综述.     

甲磺酸阿帕替尼的研究现状与进展

恶性肿瘤的发生、发展与其血管生成密切相关,其中血管内皮生长因子及其受体（VEGF/VEGFR）信号通路是诱导血管新生最重要的调控途径,也是多种抗肿瘤血管生成剂的关键靶点之一。甲磺酸阿帕替尼（艾坦）是一种新型小分子的酪氨酸激酶抑制剂,高度选择性地作用于VEGFR 2,强效抑制肿瘤血管生成,从而发挥抗肿瘤作用。阿帕替尼Ⅰ、Ⅱ、Ⅲ期注册临床试验结果表明,标准化疗失败的晚期胃癌患者应用阿帕替尼生存获益,且安全性较好。目前,阿帕替尼单药或者联合其他药物治疗肺癌、肝癌、胃癌、结直肠癌和乳腺癌等多种肿瘤的基础与临床研究正在积极开展。本文系统综述与阿帕替尼相关的基础和临床研究的现状与进展,为进一步的临床应用提供参考。     

甲磺酸阿帕替尼治疗晚期非小细胞肺癌的研究现状

甲磺酸阿帕替尼,一种小分子酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI),作用于血管内皮生长因子受体-2(vascular endothelial growth factor receptor-2,VEGFR-2),强效抑制内皮细胞新生血管生成。阿帕替尼是在中国获得批准的第一代口服抗血管生成药物,用于晚期胃癌标准化疗失败的后续治疗。目前阿帕替尼单药或者联合其他治疗在晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)中的临床研究正在积极开展,多数均显示一定生存获益。本文详细介绍近年阿帕替尼在晚期NSCLC中的研究现状,为后期临床应用提供参考。     

抗表皮生长因子受体和抗血管内皮生长因子药物在非小细胞肺癌治疗中的作用

采用以铂类药物为基础联合细胞毒性药物作为非小细胞肺癌(non-small-cell lung cancer,NSCLC)的标准化一线治疗的疗效已达到相应的平台.作用于特定通路的新型分子靶向药物逐渐成为治疗NSCLC的有效药物;某些药物的Ⅲ期试验已取得阳性结果.值得注意的是,有研究证实,采用抗血管内皮生长因子(vascular endothelial growth factor,VEGF)抗体贝伐珠单抗抑制VEGF通路,以及采用表皮生长因子受体(epidermal growth factor receptor,EGFR)的小分子酪氨酸激酶抑制剂厄洛替尼或单克隆抗体(西妥昔单抗)靶向作用于EGFR通路作为一线或二线治疗方案,均可延长晚期肺癌患者的生存期.可导致肿瘤细胞存活和增殖的信号处理过程不同,为靶向作用于多种信号通路为有效的抗癌治疗策略提供了依据.因此,分子靶向药物的合理联用可能达到更好的临床疗效,并可成为对标准化疗耐药或不能耐受标准化疗的患者的可替代的治疗选择.目前的挑战在于明确应探寻哪些分子实体,以及它们的最佳联合方案.本综述旨在探讨贝伐珠单抗联合厄洛替尼抑制血管生成和EGFR信号作为治疗NSCLC的有效的非化疗方案的潜在临床疗效.其它可阻滞EGFR和血管生成通路以及互补信号通路的新型药物的联合具有独特的作用机制和较轻的毒副作用,有可能为晚期NSCLC患者的个体化治疗选择提供更多的治疗方案.     

非小细胞肺癌抗血管生成治疗药物和策略

 非小细胞肺癌发生、发展及转移与血管生成密切相关,肺癌抗血管药物分为抗VEGF单抗、小分子抑制剂、肿瘤血管生成干扰剂、内皮细胞生成抑制剂等,多个临床试验研究显示抗血管生成药物较传统药物在疗效方面有生存优势,而抗血管生成药物与传统治疗方式的联合的治疗策略也在逐渐探索。     

晚期非小细胞肺癌抗血管生成治疗联合免疫检查点抑制剂的研究进展

近年来,转移性或局部晚期非小细胞肺癌的治疗取得了较大的进展,特别是在一线治疗或治疗后出现进展的患者。通过联合治疗提高疗效已成为该领域的主要研究方向,对于没有驱动基因突变或对靶向治疗无效的患者,这种探索尤为迫切。有证据表明促血管生成因子具有免疫抑制活性,这使得研究人员开始评估抗血管生成药物联合免疫检查点抑制剂治疗晚期非小细胞肺癌的潜在协同作用。本文就抗血管生成药物联合免疫检查点抑制剂治疗晚期非小细胞肺癌的理论基础及临床研究进行综述。     

晚期肺鳞癌靶向及免疫治疗进展

肺癌是目前世界上发病率和死亡率最高的恶性肿瘤。其中,肺鳞癌（squamous-cell lung cancer,SQCLC）为一种常见的病理类型。近年来,许多学者针对肺鳞癌的靶向药物与免疫制剂进行大量的科学研究及临床试验,EGFR单克隆抗体、VEGFR的单克隆抗体、免疫检查点抑制剂等多种药物已在临床试验中取得了一定成果。本文对晚期肺鳞癌的分子靶向治疗及免疫治疗进行系统性的阐述,通过分析其在提高患者生存率、改善生存质量等方面取得的实质性研究成果,探讨目前临床上晚期肺鳞癌的靶向及免疫治疗进展及未来发展方向。     

New angiogenic agents and non-small cell lung cancer: current results and future development

New blood vessel formation, known as angiogenesis, is a fundamental event in the process of tumor growth and metastatic dissemination. Due to its central role in tumor angiogenesis, the vascular endothelial growth factor (VEGF) and its receptor have been a major focus of basic research and drug development in the field of oncology, including the treatment of non-small cell lung cancer (NSCLC). Approaches targeting VEGF include monoclonal antibodies and vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). To date, bevacizumab, an anti-VEGF recombinant humanized monoclonal antibody, is the first targeted agent that, when combined with chemotherapy, reported superior efficacy versus chemotherapy alone in the treatment of advanced NSCLC. Several angiogenetic agents are being evaluated in clinical research and some of them, such as ZD6474, sorafenib and sunitinib, seem to be promising targeted agents for the treatment of NSCLC because of evidence of antitumor activity, an excellent toxicity profile and oral administration. The complexity of the signaling process leading to cancer cell proliferation and to the acquisition of a neoplastic phenotype supports the necessity to interfere at different stages to avoid an escape of potential resistance mechanisms. Targeting multiple pathways in tumor cells should be an effective strategy of treatment in NSCLC. Clinical trials of multiple targeted therapy may represent the second generation of studies in this setting.     

长春瑞滨节拍化疗在晚期非小细胞肺癌患者中的应用

传统化疗依靠常规剂量静脉给药,毒性较大,肿瘤易复发和耐药,而节拍化疗低剂量、频繁、短间歇给予细胞毒性药物的治疗方式在一定程度上减少了化疗不良反应,延缓了肿瘤的复发、耐药;节拍化疗通过抗血管生成、免疫调节、抑制肿瘤干细胞并诱导肿瘤细胞休眠抑制肿瘤生长。口服长春瑞滨节拍化疗在晚期非小细胞肺癌患者治疗中有多种应用方案,包括单药化疗、双药化疗、联合抗血管生成药、联合靶向治疗、联合放疗、联合免疫治疗等多种治疗方案。     

The potential of antiangiogenic therapy in non-small cell lung cancer.

The long-term prognosis for patients with advanced non-small cell lung cancer (NSCLC) remains poor despite the availability of several cytotoxic chemotherapy regimens. The use of targeted therapies, particularly those against the key mediator of angiogenesis vascular endothelial growth factor (VEGF), has the potential to improve outcomes for NSCLC patients. Bevacizumab, a recombinant humanized monoclonal anti-VEGF antibody, is the most clinically advanced antiangiogenic agent in NSCLC. In a phase III study, bevacizumab showed significantly improved overall and progression-free survival when used in combination with standard first-line chemotherapy in patients with advanced NSCLC. Bevacizumab was generally well tolerated in patients with NSCLC; however, tumor-related bleeding adverse events have been noted in some patients, predominantly those with squamous cell histology or centrally located tumors. Several small-molecule VEGF receptor tyrosine kinase inhibitors have also shown promise in phase I and II trials in NSCLC. This review summarizes the most important findings of angiogenesis inhibitors in NSCLC and discusses the potential for the use of these novel agents in different settings of NSCLC.     

Angiogenesis inhibitors in the treatment of non-small cell lung cancer

A therapeutic plateau seems to have been reached with the standard treatment of cytotoxic chemotherapy alone for advanced stage non-small cell lung cancer (NSCLC) and new treatment options are urgently needed. Recent insight into the molecular biology of cancer has identified angiogenesis as one of the key biological processes. The major player in tumor angiogenesis is the vascular endothelial growth factor (VEGF) pathway. VEGF is expressed in the majority of NSCLC and overexpression is associated with a poor prognosis. The VEGF pathway can be inhibited in two main ways: targeting VEGF directly or inhibiting the VEGF receptors. The development of angiogenesis inhibitors has shown great promise in the treatment of NSCLC. Bevacizumab, an anti-VEGF antibody, has been approved for the treatment of advanced NSCLC and other drugs are undergoing phase III investigation. However, a number of unresolved issues remain. In this review, we discuss the main angiogenesis inhibitors in development for the treatment of NSCLC focusing on the VEGF pathway.     

小分子抗血管生成药物在非小细胞肺癌中的研究进展

肺癌是世界上发病率最高的癌症之一,且尚无二线进展后的标准治疗方案,而肿瘤血管生成目前已被确定为恶性肿瘤的重要治疗靶点,小分子多靶点血管激酶抑制剂可通过抑制血管生成相关信号通路,抑制肿瘤血管的生成。目前已开展多项小分子抗血管生成药物治疗非小细胞肺癌的临床试验,且已有部分血管内皮生长因子受体酪氨酸激酶抑制剂(vascular endothelial growth factor receptor-tyrosine kinase inhibitors, VEGFR-TKIs)获批治疗晚期非小细胞肺癌,本文基于国内外多项小分子抗血管生成药物治疗非小细胞肺癌的发展现状,归纳了多个VEGFR-TKIs及成纤维细胞生长因子受体(fibroblast growth factor receptor, FGFR)-TKI单药或联合[包括分别与化疗、表皮生长因子受体(epidermal growth factor receptor, EGFR)-TKIs、免疫治疗、放疗等联合)]治疗非小细胞肺癌的疗效与安全性研究,同时探讨了VEGFR-TKIs可能存在的耐药机制及疗效预测指标等,并对未来抗血管治疗非小细胞肺癌的发展趋势以及存在的潜在问题进行展望,同时为肺癌后续的精准治疗及个体化治疗提供新的思路。     

老年晚期非小细胞肺癌的靶向治疗

老年肺癌发病及死亡呈上升趋势,但老年患者整体接受积极治疗的人数却明显少于非老年患者。随着分子靶向治疗药物,如人表皮生长因子受体酪氨酸激酶抑制剂、新生血管抑制剂、抗肿瘤单克隆抗体及多靶点药物的出现,老年晚期非小细胞肺癌患者的总生存时间得到显著延长,生活质量得到明显改善。靶向治疗已成为最有希望且能显著改善老年患者预后的治疗方法。     

Toxicities of antiangiogenic therapy in non-small-cell lung cancer

The addition of antiangiogenic agents has improved overall survival in a wide variety of tumor types, including non-small-cell lung cancer (NSCLC). Antibodies to the vascular endothelial growth factor (VEGF) were the first targeted agent to yield a significant improvement in overall survival when combined with first-line chemotherapy for metastatic NSCLC. Anti-VEGF antibodies and tyrosine kinase inhibitors blocking VEGF receptor (VEGFR) activity are also being investigated in pretreated NSCLC. Initial experience with anti-VEGF antibodies suggested a mild adverse event profile. However, it has become clear with additional experience that antiangiogenic agents are associated with a distinct array of toxicities, such as hemorrhage, hypertension, thromboembolic events, and proteinuria. Furthermore, an increase in chemotherapy-associated toxicities such as neutropenia has been observed with the addition of anti-VEGF antibodies. Multitargeted small-molecule inhibitors that block activity of the VEGFR tyrosine kinase are associated with fatigue and other toxicities in addition to the aforementioned class-effect toxicities, possibly because of their inhibition of multiple signaling pathways. Currently, only patients without predominant squamous cell histology are eligible to receive bevacizumab. Trials are ongoing to address the feasibility of bevacizumab in patients who were excluded from the phase III pivotal trial. Additionally, further investigation is necessary to determine risk factors for hemorrhage with antiangiogenic agents.