抗肿瘤血管生成靶向药物的不良反应、发生机制及处理

通过抑制新生血管以达到控制肿瘤是目前抗肿瘤治疗的重要研究方向,抗肿瘤血管生成靶向药物在临床肿瘤治疗中已广泛应用,包括贝伐单抗、重组人血管内皮抑素以及多靶点激酶抑制剂索拉非尼、舒尼替尼等,药物不良反应包括高血压、心脏毒性、血栓形成、出血、蛋白尿、胃肠道穿孔、伤口愈合不良以及索拉非尼和舒尼替尼较常见的疲乏、腹泻、手足综合征等,多数不良反应为1及或2级,患者耐受性及依从性较好.     

抗肿瘤血管生成靶向药物的不良反应、发生机制及处理

通过抑制新生血管以达到控制肿瘤是目前抗肿瘤治疗的重要研究方向,抗肿瘤血管生成靶向药物在临床肿瘤治疗中已广泛应用,包括贝伐单抗、重组人血管内皮抑素以及多靶点激酶抑制剂索拉非尼、舒尼替尼等,药物不良反应包括高血压、心脏毒性、血栓形成、出血、蛋白尿、胃肠道穿孔、伤口愈合不良以及索拉非尼和舒尼替尼较常见的疲乏、腹泻、手足综合征等,多数不良反应为1及或2级,患者耐受性及依从性较好.     

抗血管形成靶向药物的研究进展

肿瘤的生长和转移离不开肿瘤新生血管,这使得抗血管形成治疗成为肿瘤治疗的重要途径之一。血管内皮生长因子及其受体是抗肿瘤治疗的重要靶点之一。本文主要介绍了近年来抗血管形成治疗的一些最新药物研究成果——包括针对血管内皮生长因子的单克隆抗体——贝伐;针对血管内皮生长因子受体的酪氨酸激酶抑制剂——舒尼替尼、索拉非尼等;以及血管内皮生长因子受体的单克隆抗体IMC-1C11等。     

小分子抗血管生成药物在乳腺癌中的研究进展

乳腺癌是全世界发病率最高的肿瘤,为女性肿瘤第二大致死病因,内科治疗方法包括化疗、靶向药物治疗及内分泌治疗.化疗联合靶向治疗是恶性肿瘤辅助和晚期治疗的主要手段.血管生成在肿瘤局部进展和转移方面占据重要的地位,成为了一个潜在的治疗靶点.本文主要探讨索拉非尼、舒尼替尼及阿帕替尼这三种小分子酪氨酸激酶类抗血管生成药物在乳腺癌中的研究进展.     

抗血管生成药物在乳腺癌治疗中的现状和思考

 抗血管生成药物已成为肿瘤治疗的重要手段和研究热点。该类药物如贝伐单抗、舒尼替尼、索拉非尼、拉帕替尼等也被临床用于治疗乳腺癌，显示出一定疗效，同时也带来了一些问题和思考。     

转移性肾细胞癌的靶向治疗研究进展

转移性肾细胞癌靶向治疗的药物包括VHL-低氧缺乏因子-血管内皮生长因子(VHL-HIF-VEGF)途径靶向药物舒尼替尼、索拉非尼、贝伐单抗、阿西替尼等和哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂西罗莫司脂化物、依维莫司等.这些靶向药物在转移性肾细胞癌的治疗中取得了良好的效果,但是其不良反应需要引起足够的重视.在患者治疗方案上的选择以及对非透明肾细胞癌的治疗效果方面还需要进一步的研究.     

多靶点酪氨酸激酶抑制剂舒尼替尼的研究进展

舒尼替尼（Sunitinib、SU011248、Sutent）是一种多靶点的生物靶向抗肿瘤药物，能同时抑制多条信号传导通路，具有抗肿瘤和抗血管生成作用。舒尼替尼在肾细胞癌（renal cell carcinoma，RCC）和胃肠间质瘤（gastrointestinal stromaltumor，GIST）的临床前和临床研究中均显示出了确切的抗肿瘤效应。2006年1月美国食品和药品管理局（FDA）正式批准了舒尼替尼用于治疗上述两种肿瘤。此外，舒尼替尼在其他实体瘤的研究中也显示出了一定的作用。本文主要就舒尼替尼的研究进展进行综述。     

舒尼替尼与索拉非尼交替应用治疗肾癌1例并文献复习

目的:探讨舒尼替尼与索拉非尼交替应用治疗转移性肾癌的疗效。方法:报道舒尼替尼与索拉非尼交替应用治疗转移性肾癌1例并结合文献讨论。结果:该患者一线舒尼替尼治疗疾病进展时间（TTP）为6个月。二线索拉非尼治疗TTP为5个月。二线治疗失败后改变舒尼替尼给药方式（37.5mg 每日1次,连续口服）继续治疗,三线TTP为8个月。结论:患者一线应用舒尼替尼和二线应用索拉非尼的治疗疗效与文献报道相符。二线治疗失败后改变舒尼替尼给药方式继续治疗仍获得较好的疗效。     

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。     

舒尼替尼与索拉非尼一线治疗晚期肾细胞癌的对比研究

目的 评价分子靶向药物舒尼替尼与索拉非尼一线治疗晚期肾细胞癌的疗效与安全性.方法 42例晚期肾细胞癌患者根据治疗方法分为舒尼替尼组20例(50 mg,1次/d,口服4周,停药2周,6周为1周期)和索拉非尼组22例(400 mg,2次/d,口服,直至疾病进展,6周为1周期).每2周期评价疗效.结果 42例患者均可评价疗效,舒尼替尼组、索拉非尼组疾病缓解率(RR)分别为30.0％(6/20)、22.7％ (5/22),疾病控制率(DCR)分别为90.0％ (18/20)、77.3％ (17/22),中位无进展生存期(PFS)分别为10.8、6.2个月,中位总生存时间(0S)分别为25.6、18.6个月.两组比较,近期疗效RR(x2=0.287,P=0.592)和DCR(x2=1.222,P=0.269)差异无统计学意义;远期疗效PFS(x2=6.041,P=0.014)及OS(x2=11.245,P=0.001)差异有统计学意义.舒尼替尼组常见的不良反应为腹泻、乏力、口腔黏膜炎、恶心、呕吐等,多见Ⅰ～Ⅱ度,可耐受.索拉非尼组手足综合征发生率(59.1％)明显高于舒尼替尼组(25.0％),差异有统计学意义(x2=4.972,P=0.026).结论 舒尼替尼治疗晚期肾细胞癌疗效较好,不良反应小于索拉非尼,值得临床进一步推广应用.     

Antiangiogenic agents in combination with chemotherapy in patients with advanced non-small cell lung cancer

Most patients with non-small cell lung cancer (NSCLC) present with advanced disease requiring systemic chemotherapy. Treatment with the antiangiogenic agent bevacizumab in combination with standard platinum-based doublet chemotherapy has been shown to improve outcomes in patients with advanced NSCLC. Several multitargeted antiangiogenic tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, and axitinib) are also being evaluated in combination with standard chemotherapy. Here we review current clinical data with combination therapy involving antiangiogenic agents and cytotoxic chemotherapy in patients with advanced NSCLC.     

Can we develop effective combination antiangiogenic therapy for patients with hepatocellular carcinoma?

Antiangiogenic therapy has shown promise in the treatment of patients with hepatocellular carcinoma (HCC). Bevacizumab, sorafenib, and sunitinib showed efficacy in patients with HCC; and sorafenib is approved by the FDA for treatment of this cancer. In practice, the clinical benefit of these agents has been heterogeneous; and in patients who do respond, the benefit is modest and/or short-lived. Recent advances in the molecular understanding of tumor angiogenesis along with the rapid development of targeted drug discovery have made it possible to explore novel combination therapy for HCC. We review the clinical trial results, discuss possible molecular mechanisms of resistance, and suggest novel combinations with antiangiogenic therapy.     

Improvement of antiangiogenic cancer therapy by understanding the mechanisms of angiogenic factor interplay and drug resistance

Several antiangiogenic agents, including bevacizumab, sunitinib, and sorafenib, which mainly target the VEGF signaling system, have been approved for the treatment of human cancers. These drugs have been paired with conventional chemotherapeutic agents to treat different types of cancers, including colorectal and lung cancers; however, the patient response rate and resultant increase in overall survival time have been rather modest. The current antiangiogenic regimen is far from optimal. Improvements of therapeutic efficacy and minimization of adverse effects and drug resistance are urgent tasks that are most likely to be resolved by understanding the molecular mechanisms underlying tumor angiogenesis. The aim of this article is to discuss these clinically related issues, to highlight several recent examples of the complex interplays between tumor-produced angiogenic factors, and to propose a new paradigm for improvement of therapeutic intervention of tumor angiogenesis.     

Targeting angiogenesis in metastatic breast cancer

Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC.     

Combination therapy for renal cell cancer: what are possible options?

Antiangiogenic therapy has shown promise in the treatment of patients with renal cell carcinoma (RCC). Two classes of antiangiogenic drugs, the anti-vascular endothelial growth factor antibody bevacizumab and the tyrosine kinase inhibitors sorafenib, sunitinib and pazopanib, have shown efficacy in patients with RCC and are approved by the US Food and Drug Administration for treatment of this cancer. In practice, the clinical benefit of antiangiogenic drugs in RCC has been heterogeneous, and in patients who do respond, benefits are modest and/or short-lived. To improve efficacy, combination targeted therapy has been attempted, but with either very limited additional efficacy or nontolerable toxicities. Recent advances in the molecular understanding of tumor angiogenesis and mechanism of resistance, along with the rapid development of targeted drug discovery, have made it possible to further explore novel combination therapy for RCC.     

Dermatologic side effects induced by new angiogenesis inhibitors

While new anticancer angiogenesis inhibitors present a well-tolerated safety profile, they are not without adverse events. The signaling pathways and/or receptors inhibited by these new drugs are often physiologically expressed in the skin and/or hair follicle and cutaneous toxicity is on the forefront. This article reviews the main dermatologic adverse events induced by these targeted anticancer therapies with a partial or exclusive antiangiogenic activity: sorafenib, sunitinib, pazopanib, vandetanib, everolimus, temsirolimus or bevacizumab.     

Antiangiogenic therapy for ovarian cancer

PURPOSE OF REVIEW: To highlight the current antiangiogenic compounds being evaluated as single agents or in association with chemotherapy in the treatment of ovarian cancer, as well as the rationale for their development. RECENT FINDINGS: Several proangiogenic factors may be potential targets for antiangiogenic therapy in ovarian cancer. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been evaluated as a single agent in two phase II clinical trials and in combination with chemotherapy in three phase II studies, with promising results. This agent is also being evaluated in association with chemotherapy in two phase III clinical trials, both in the treatment and in the maintenance settings. Heparanase inhibitors and inhibitors of platelet-derived growth factor signalling remain as potential agents to be investigated in phase II trials. The development of biomarkers to define appropriate dosing regimens and predict which patients may benefit from antiangiogenic therapies is of great importance. SUMMARY: Data from preclinical and clinical studies reported in the last 2 years demonstrate the importance of several proangiogenic factors in the prognosis of ovarian cancer, suggesting possible new targets for antiangiogenic therapy. The agents that are currently being investigated in phase II and III clinical trials include bevacizumab, erlotinib, sunitinib, sorafenib and vascular endothelial growth factor Trap, and the results of these trials will have significant implications in the future management of ovarian cancer.