转移性肾细胞癌分子靶向治疗研究进展

肾细胞癌是泌尿系统肿瘤中常见的恶性肿瘤,发病率约5～10/10万。转移性肾细胞癌在以细胞因子为基础的治疗失败后,尚无明确的二线治疗措施。随着对乏氧诱导因子（hypoxia-inducible factor,HIF）相关蛋白的研究,转移性肾细胞癌分子靶向治疗研究成为热点。本文综述较有前景的靶向药物,包括Bevacizumab（贝伐单抗）、Sorafenib（索拉非尼）、Sunitinib（舒尼替尼）、AG-013736、Vatalanib（PTK787）、Thalidomide（沙利度胺）及Temsirolimus（CCI-779）。     

肾细胞癌靶向治疗的临床研究进展

肾细胞癌（RCC ）是难治的恶性肿瘤之一,对放化疗不敏感,免疫治疗方式有效率一直徘徊于10% ～15% 。随着对肿瘤分子机制的深入以及多种分子靶向药物的深入研究,靶向治疗取得了重大进展。肾癌的发病机制与VHL 、Ras、PTEN等抑癌基因的突变有关,可诱导其下游的蛋白激酶受体表达异常。而蛋白激酶抑制剂可以通过干扰细胞内信号传导通路及改变肿瘤细胞微环境而影响肿瘤细胞的存活和增殖,是当前研发最集中的靶向治疗药物之一。近年来,多项靶向药物临床试验的可喜结果为转移性肾细胞癌（mRCC）治疗带来了新希望。本文就2009年NCCN 肿瘤治疗指南中介绍的舒尼替尼、索拉非尼、Temsirolimus、贝伐单抗等四种药物在肾细胞癌靶向治疗方面的临床研究最新进展展开综述。      

索拉菲尼与舒尼替尼对转移性肾细胞癌患者的近远期疗效及预后影响因素分析

目的探讨索拉菲尼与舒尼替尼对转移性肾细胞癌患者的近远期疗效及其预后影响因素。方法选取2015年1月至2018年1月间榆林市第一医院收治的79例转移性肾细胞癌患者,根据治疗方法不同分为舒尼替尼组(39例)和索拉非尼组(40例)。索拉非尼组患者口服索拉非尼,舒尼替尼组患者口服舒尼替尼,比较两组患者的中位无进展生存时间、总生存时间、疾病控制率及不良反应发生情况,分析转移性肾细胞癌患者无进展生存时间及总生存时间的影响因素。结果索拉非尼组患者中位无进展生存时间为12个月,总生存时间为24个月;舒尼替尼组患者中位无进展生存时间为12个月,总生存时间为23个月。两组比较,差异均无统计学意义(P> 0. 05)。索拉非尼组患者疾病控制率为62. 5%(25/40),低于舒尼替尼组患者的84. 6%(33/39),差异有统计学意义(P <0. 05)。索拉非尼组患者腹泻发生率高于舒尼替尼组,血小板下降低于舒尼替尼组,差异均有统计学意义(均P <0. 05)。两组患者手足综合征、乏力、高血压、皮疹、中性粒细胞下降、肝功能异常、贫血和脱发发生情况比较,差异无统计学意义(P> 0. 05)。单因素及Cox回归分析结果表明,Fuhrman和IMDC分级是转移性肾细胞癌患者无进展生存时间和总生存时间的独立影响因素,差异均有统计学意义(均P <0. 05)。结论与索拉非尼相比,舒尼替尼对转移性肾癌的疾病控制率更好,两种药物不良反应分布不同,但均可控制。Fuhrman和IMDC分级是影响转移性肾癌预后的独立影响因素。     

晚期肾细胞癌的舒尼替尼新辅助治疗进展

舒尼替尼治疗晚期肾细胞癌的疗效已获得多项Ⅲ期临床试验的支持,并在美国国家癌症综合网(National Comprehensive Cancer Network,NCCN)2010年肾癌治疗指南中被推荐为晚期肾细胞癌的一线治疗药物.晚期肾细胞癌往往无手术指征,舒尼替尼治疗能够明显改善患者的预后,但作为新辅助治疗手段,尚缺少高质量的循证医学证据,国内外的临床研究仍较罕见.为此,本研究对晚期肾细胞癌的舒尼替尼新辅助治疗进展进行初步综述.     

舒尼替尼一线治疗转移性肾细胞癌临床疗效分析

目的:观察舒尼替尼一线治疗转移性肾细胞癌疗效及安全性。 方法:2010年4月-2012年4月我科收治转移性肾细胞癌患者31例,采用舒尼替尼行靶向治疗（50mg,pd,4/2方案）。服药期间进行不良事件管理及随访,每间隔2周期行疗效评价,随访截止至2013年8月,Kaplan-Meier分析总体生存期及无进展生存期。结果:随访8-35个月,平均22.3个月,可评价31例,PR 9例(29.0%),SD 14例(45.2%),PD 8例（25.8%）,疾病控制率为74.2%,客观反应率为29%。中位无进展生存期12个月（95%CI:9.2-14.8个月）,中位总生存期21个月(95%CI:17.9-24.1个月)。不良事件多为Ⅰ/Ⅱ级,Ⅲ/Ⅳ级少见,常见的为腹泻、乏力、高血压及造血系统毒性等。41.9%的患者需调整给药剂量或暂时停药,不良事件经管理后可缓解。结论:舒尼替尼治疗转移性肾细胞癌疗效好,安全性较高,是转移性肾细胞癌较好的治疗选择之一。     

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。     

头颈部癌的靶向治疗进展

近十年中,靶向治疗逐渐成为头颈部综合治疗策略中重要的组成部分.靶向药物包括各种单克隆抗体、小分子化合物以及反义寡核苷酸等.西妥昔单抗是目前唯一获得批准用于头颈部癌治疗的靶向药物,其他靶向药物如吉非替尼、拉帕替尼等在头颈部癌的Ⅰ～Ⅲ期临床试验中亦获得令人鼓舞的结果.     

替西罗莫司治疗转移性肾细胞癌初探

目的探讨替西罗莫司治疗转移性肾细胞癌的效果。方法 2008年6月4日至2008年12月18日共入组12例转移性肾细胞癌患者,接受替西罗莫司单药治疗,25mg,静脉滴注30～50分钟,每周1次,直至肿瘤进展或出现不可耐受的毒副作用。结果 12例患者中,按MSKCC评分中高危占75%(9/12),其中10例为多程治疗失败。最佳疗效:PR 2例(16.7%),另有6(50%)例患者出现不同程度的肿瘤缩小,PD 2例(16.7%)。临床受益率(CR+PR+SD≥24周)为41.7%(5/12)。中位PFS为8.4个月,中位OS 16.4个月。4例索拉非尼失败的患者的PFS分别为9个月、15个月、2.2个月和18.8个月。主要不良反应包括:皮疹、瘙痒、指甲改变、发热、口腔溃疡、高血糖、胆固醇和甘油三酯升高等。1例患者发生了V度间质性肺炎。结论替西罗莫司治疗转移性肾癌有效,对索拉非尼或舒尼替尼失败的患者的疗效值得进一步研究。代谢异常和间质性肺炎是需要重视的不良反应。     

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.     

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。      

Signaling inhibitors in metastatic renal cell carcinoma

Renal cell carcinoma has made considerable progress in the past years, and new emerging strategies are coming almost every year since 2005. Development of targeted therapies in renal cell cancer is largely due to the fact that Von Hippel Lindau gene is often mutated in sporadic renal cell cancer. Von Hippel Lindau protein abnormalities lead to accumulation of hypoxia inducible factor-alpha, and activation of a series of gene, including vascular endothelial growth factor, and thus induce angiogenesis. Results from many recent studies with new agents, blocking the vascular endothelial growth factor pathway or the mammalian target of rapamycin pathway, have been recently reported and offer new strategic options for the patients with metastatic renal cell carcinoma. Sunitinib, sorafenib, and combination of bevacizumab and interferon improves progression free survival in either first or second line treatment of renal cell cancer and have been approved. Temsirolimus, a mammalian target of rapamycin inhibitor regulating hypoxia inducible factor-alpha, improves survival in renal cancer with poor risk features. Finally, everolimus improves progression free survival in patients who fail tyrosine kinase inhibitors. Overall, treatment of metastatic renal cell carcinoma is currently moving from the cytokine era to the targeted agent era. However, many questions still remain on the efficacy of combination treatments and on the best way to get complete remission, which is probably the best way to lead to cure of metastatic renal cell cancer in the future.     

Optimizing recent advances in metastatic renal cell carcinoma

The past few years have seen dramatic advances in the treatment of metastatic renal cell carcinoma (RCC). Dissection of the molecular pathways that regulate proliferation, apoptosis, and angiogenesis has led to the development of targeted therapies such as the receptor tyrosine kinase inhibitors sunitinib and sorafenib, the anti-vascular endothelial growth factor antibody bevacizumab, and a class of rapamycin analogues including everolimus and temsirolimus. Each of these agents has demonstrated clinical efficacy in patients with metastatic RCC. The challenge before us is to expand on these successes by identifying which patients will best respond to these targeted therapies, optimizing the proper combination or sequence of available therapies, developing agents with improved side effect profiles, and identifying novel therapeutic targets to expand our armamentarium in the treatment of RCC.     

立体定向体部放疗联合靶向药物治疗转移性肾癌的研究进展

立体定向体部放疗(Stereotactic body radiotherapy, SBRT)是近年来放疗取得的一个突破性进展,具有分次剂量高、生物学效应高、分割次数少等优势,可显著提高肾癌的放疗敏感性。分子靶向治疗显著延长了部分患者的无进展生存期和总生存期,但在大多数情况下产生全身用药的耐药性仍不可避免。近年来,SBRT联合靶向药物治疗转移性肾癌初步显示了有效性和安全性,有可能成为一种更有效的治疗方案。本文针对SBRT联合靶向药物治疗转移性肾癌研究进展进行综述。     

Combination drug regimens for metastatic clear cell renal cell carcinoma

Renal cell carcinomas (RCC) make up about 90% of kidney cancers, of which 80% are of the clear cell subtype. About 20% of patients are already metastatic at the time of diagnosis. Initial treatment is often cytoreductive nephrectomy, but systemic therapy is required for advanced RCC. Single agent targeted therapies are moderately toxic and only somewhat effective, leading to development of immunotherapies and combination therapies. This review identifies limitations of monotherapies for metastatic renal cell carcinoma, discusses recent advances in combination therapies, and highlights therapeutic options under development. The goal behind combining various modalities of systemic therapy is to potentiate a synergistic antitumor effect. However, combining targeted therapies may cause increased toxicity. The initial attempts to create therapeutic combinations based on inhibition of the vascular endothelial growth factor or mammalian target of rapamycin pathways were largely unsuccessful in achieving a profile of increased synergy without increased toxicity. To date, five combination therapies have been approved by the U.S. Food and Drug Administration, with the most recently approved therapies being a combination of checkpoint inhibition plus targeted therapy. Several other combination therapies are under development, including some in the phase 3 stage. The new wave of combination therapies for metastatic RCC has the potential to increase response rates and improve survival outcomes while maintaining tolerable side effect profiles.     

Renal cell cancer

Metastatic renal cell cancer has traditionally been treated with interferon and interleukin-2. An improved understanding of the biology of renal cancer has engendered novel targeted therapeutic agents that have altered the natural history of this disease. The vascular endothelial growth factor and its related receptor and the mammalian target of rapamycin signal transduction pathway in particular have been utilized as therapeutic targets. Sunitinib malate, sorafenib tosylate, temsirolimus, and bevacizumab/interferon alfa have improved clinical outcomes in randomized trials. Other antiangiogenic agents have also demonstrated activity in early studies. Given the availability of multiple treatment options, several questions emerge as to how to integrate these new therapies into the management of metastatic renal cell cancer. Recently reported and planned clinical trials will help clarify the role of these agents. The future of therapy for renal cancer appears promising owing to the efficacy of these novel agents.     

Cytoreductive nephrectomy in metastatic renal cell carcinoma

Metastatic renal cell carcinoma is associated with a poor prognosis and a median survival time of only 6–12 months. However, the emergence of immunotherapies has rekindled interest in cytoreductive nephrectomy as a therapeutic option. Phase III randomized trials have demonstrated that cytoreductive nephrectomy significantly improves overall survival in selected patients with metastatic renal cell carcinoma treated with interferon immunotherapy. While cytokine-based immunotherapy may be considered the standard systemic therapy, clinical studies are ongoing to develop molecular biomarkers and new therapies with improved efficacy and tolerability. With further advances in our understanding of the pathogenesis, behavior and molecular biology of renal cell carcinoma, cytoreductive nephrectomy, in combination with molecular targeted therapies, may become the new standard of care for patients with metastatic renal cell carcinoma.     

Cytoreductive nephrectomy in metastatic renal cell carcinoma

Metastatic renal cell carcinoma is associated with a poor prognosis and a median survival time of only 6-12 months. However, the emergence of immunotherapies has rekindled interest in cytoreductive nephrectomy as a therapeutic option. Phase III randomized trials have demonstrated that cytoreductive nephrectomy significantly improves overall survival in selected patients with metastatic renal cell carcinoma treated with interferon immunotherapy. While cytokine-based immunotherapy may be considered the standard systemic therapy, clinical studies are ongoing to develop molecular biomarkers and new therapies with improved efficacy and tolerability. With further advances in our understanding of the pathogenesis, behavior and molecular biology of renal cell carcinoma, cytoreductive nephrectomy, in combination with molecular targeted therapies, may become the new standard of care for patients with metastatic renal cell carcinoma.     

Circulating Biomarkers in Advanced Renal Cell Carcinoma: Clinical Applications

Advances in understanding the biology of renal cell carcinoma (RCC) have resulted in treatment strategies based on molecularly targeted agents that have substantially improved the outcomes of patients with metastatic RCC. Agents targeting the vascular endothelial growth factor pathway and the mammalian target of rapamycin have shown efficacy in randomized clinical trials and received international approval for treating RCC. Multiple candidate biomarkers of the biologic activity of such targeted therapies as well as markers of treatment response and patients’ prognosis are being evaluated to improve drug development and to identify patients who may obtain the greatest benefit from the various treatment options. This review summarizes recent developments in identifying circulating biomarkers of targeted therapies for metastatic RCC, including soluble proteins and circulating cells.     

转移性肾癌的靶向治疗

转移性肾癌是一种对于传统化、放疗较不敏感的不可治愈性疾病。虽然免疫治疗对部分患者具一定疗效，但疗效通常并不持久，且治疗可能导致严重的毒副作用。随着近年来对肾癌生物学及分子发病机制的加深理解，针对使用多种靶向治疗药物治疗肾癌的研究取得了可喜的成果。无论针对初治或以往治疗失败的患者，靶向治疗均显示出高于传统治疗的优越性。此外，治疗的耐受性非常良好，并不影响患者的生存质量。本综述将依据最新的临床证据，着重围绕目前主要的治疗进展加以分别阐述，同时简单概括相关的治疗靶点信息，力求使读者在基础和临床两方面对转移性肾癌的靶向治疗获得较为深刻的认识。