索拉非尼治疗晚期肾癌的现状

随着临床对肾癌发病机制研究的不断深入,其细胞学、分子生物学领域的不断进展,其细胞信号转导路中的一些关键分子已经成为治疗的靶点,不断有新的分子靶向治疗药物问世,索拉非尼是2005年被美国FDA批准用于晚期肾癌治疗的靶向药物,美国国家综合癌症网络制定的2008年版《肾癌诊治指南》中推荐索拉非尼作为部分患者的一线治疗或者所有患者的二线治疗用药。现就索拉非尼在肾癌晚期的治疗现状、机制及应用前景作一简介。     

肾癌靶向治疗临床研究现状

美国国家综合癌症网络制定的2008年版《肾癌诊治指南》中推荐将舒尼替尼可作为晚期肾癌的一线或二线治疗用药；推荐将索拉非尼可作为部分患者的一线治疗或者所有患者的二线治疗用药；推荐将temsirolimus用于转移性肾癌危险因素评分高危患者一线和二线治疗用药；推荐将贝伐单抗联合IFN-α作为晚期肾癌的一线或二线治疗用药。     

第一个被批准用于临床的多靶点的靶向抗癌新药——索拉非尼

索拉非尼临床研究进展 2005年12月美国FDA首先批准索拉非尼作为不能手术切除的晚期肾细胞癌（RCC）的一线治疗药物上市;2007年10月欧洲药品评价局（EMEA）批准索拉非尼用于治疗肝细胞癌（HCC）、2007年11月美国FDA批准索拉非尼作为未能手术切除的肝细胞癌的治疗药物上市。此外,目前世界各地还有近50项应用索拉非尼治疗其他多种癌症的各类临床试验正在进行中。     

NCCN更新肾癌和卵巢癌的指南

美国国家综合癌症网络（NCCN）已经对2006年2月版的NCCN肾癌指导原则的肾癌处理指南进行了更新。更新内容包括对晚期疾病推荐用有意义的结构重建治疗，根据组织学来确定治疗方法，sorafenib和sunitinib现在被纳入可供选择的一线和二线治疗药物中。     

医药快讯

新药快递 治疗晚期肾癌新药Pazopanib获准上市 美国食品药品监督管理局(FDA)于2009年10月19日批准葛兰素史克公司研发的新药Pazopanib(通用名：Votrient)在美国上市,用于晚期肾细胞癌患者的治疗.Pazopanib是自2005年以来第六个获得FDA批准的肾癌治疗药.     

2011年版中国《肾细胞癌诊治指南》药物治疗原则解读

肾癌组织病理学分类复杂多样,但从临床药物治疗上分为透明细胞癌和非透明细胞癌两大类型。在我国目前对于转移性肾癌患者,药物治疗推荐分子靶向药物——索拉非尼为一线方案,其他分子靶向药物的推荐有待于中国的临床试验结果;细胞因子IFN-α或IL-2治疗对透明细胞癌类型肾癌也为一线推荐方案,而化疗可作为转移性非透明细胞类型肾癌的选择方案。伴有肾癌骨转移患者,推荐应用双膦酸盐药物,以减少骨相关事件的发生。局限性及局部浸润性肾癌患者术后尚无标准的可推荐的辅助治疗方案。     

Temsirolimus

肾细胞癌占全部肾肿瘤的85%.美国癌症协会估计2007年将有新诊断肾癌患者51190例,其中40%在诊断时已经是晚期或进展期.美国FDA已于2007年5月批准rorisel(Temsirolimus)上市,用于治疗晚期肾细胞癌(RCC).该药是惟一上市的特异性抑制mTOR激酶的药物,是第一个治疗肾癌的靶向治疗药物,也是目前第一剂用于治疗癌症的注射剂.     

世界药物新闻(六十二)

1　美国批准 Gleevec作为一线用药美国已批准诺华公司的抗癌药物 Gleevec(译注 :亦称Glivec) (通用名 :伊马替尼 ,imatinib)用作治疗早期慢性髓细胞样白血病 ( chronic myeloid leukaemia,CML)的一线药物 ,这是该药的新适应证。美国 FDA于 8月份优先审查了该药治疗早期 CML(慢性期 )适应证。Gleevec现已成为晚期 CML ,即加速期和未成熟细胞危象期的一线治疗药物 ,并可用于 α-干扰素治疗失败后的早期CML 治疗。公司说 ,Gleevec作为治疗早期 CML 的一线药物 ,在瑞士首先上市 ,该药的这一适应证在欧洲的其他国家即将获准上市。美国 …     

对索拉非尼运用在晚期肾癌患者治疗中的效果及不良反应观察

目的分析索拉非尼运用在晚期肾癌患者治疗中的效果及不良反应观察。方法选择我院2012年9月至2014年9月收治的晚期肾癌患者95例作为本研究对象,均给予患者索拉非尼药物治疗,观察患者治疗效果、不良反应发生情况、总体中位的生存时间、中位无进展的生存总时间。结果经过治疗后,患者治疗总有效率达91.58%,常见的不良反应包括腹泻、疲劳、手足表面皮肤反应等。结论将索拉非尼运用在晚期肾癌患者治疗中,能够有效提升患者整体治疗效果,且安全性较高,值得在临床大力推广使用。     

世界制药企业新药研发动态

美国Cephalon公司的Nuvigil获准用于治疗嗜睡症；盐酸雷洛昔芬可用于治疗或预防骨质疏松症及降低乳腺癌的风险；FDA批准Cymbalta作为重性抑郁障碍患者的维持治疗药物；阿斯利康公司产品Nexium在欧洲获得批准用于治疗儿童胃食管反流病；Avastin在欧洲被批准作为晚期肾癌的一线治疗药物     

Sorafenib for the treatment of renal cancer

INTRODUCTION: Sorafenib was the first oral antiangiogenic multikinase inhibitor (Raf kinases, VEGF receptors 1 - 3, PDGF-beta, Flt-3, c-kit) for advanced renal cell carcinoma (RCC) to be approved. Since 2005, a total of six drugs have been approved for the treatment of RCC. AREAS COVERED: The preclinical and clinical development of sorafenib that led to its approval for advanced RCC is reviewed in this paper. Its safety, tolerability and efficacy are summarized and compared with other approved treatment options for RCC. Preliminary data on sequential treatment strategies and combination trials with other targeted drugs are also discussed. EXPERT OPINION: The efficacy and good tolerability of sorafenib in patients with RCC has already been confirmed by numerous studies. The drug proved to be suitable for patients of any age, with respect to efficacy and safety. Sequential use of sorafenib and other targeted drugs is characterized by only limited cross-resistance and many studies seem to indicate more clinical benefits and longer overall progression-free survival when sorafenib is administered as a first-line therapy. However, the optimal sequential therapy remains to be determined within prospective trials, such as the SWITCH study. In addition, we need predictive biomarkers to preselect the patients with the best chances of benefiting from sorafenib, in the context of personalized medicine.     

Sorafenib-induced hand-foot syndrome in a patient of renal cell carcinoma

Sorafenib, a multikinase inhibitor, is approved for treatment of renal cell cancer and hepatocellular cancer. Hand-foot syndrome (HFD) is a condition where erythema, scaling, and bullous lesion affect the hand and feet. In this case, a post-nephrectomy renal carcinoma patient prescribed sorafenib developed HFD 1 week after the drug usage. All laboratory parameters were within normal limits. The dose of sorafenib was reduced and topical corticosteroids, antihistamines, and emollients were prescribed. The reaction reduced after 2 weeks of therapy, only to reappear again when the second cycle of sorafenib-targeted therapy was started. The case was diagnosed as sorafenib-induced HFD.KEY WORDS: Hand-foot syndrome, renal cell carcinoma, sorafenib     

索拉非尼治疗急性髓系白血病的研究进展

作为一种新型多激酶抑制剂,索拉非尼(sorafenib)已被美国FDA批准用于治疗肾细胞癌、肝细胞癌和分化甲状腺癌。而近年来的研究显示通过抑制FMS样酪氨酸激酶-3的活性,该药可发挥一定的抗白血病作用,特别是FMS样酪氨酸激酶-3近膜区的内部串联重复序列(FMS-like tyrosine kinase-3-internal tandem duplication,FLT3-ITD)突变阳性的急性髓系白血病。笔者通过查阅国内外相关文献,对其在治疗急性髓系白血病的药理作用、药物代谢动力学、临床疗效和安全性等方面的研究进展作一综述。     

肾细胞癌新辅助靶向治疗的不良反应及其防治

肾细胞癌靶向药物主要有索拉菲尼、舒尼替尼、帕唑帕尼、贝伐珠单抗(联合IFN-α)、替西罗莫司、依维莫司及最近批准的阿西替尼,肾癌术前新辅助治疗和术后辅助治疗极大改善了进展期或转移性肾癌患者的预后。与此同时,靶向治疗药物也会引起手足皮肤反应、高血压、乏力、消化道反应等药物相关性不良反应。因此临床中及时发现并采取有效干预措施,对改善患者生活质量和提高靶向治疗效果尤为重要。     

Sorafenib in non-small cell lung cancer

Introduction: Conventional chemotherapy has reached a plateau of effectiveness for the treatment of non-small cell lung cancer (NSCLC). Patients with EGFR mutation or ALK translocations will benefit significantly from agents targeting these pathways, however, only 20% of western NSCLC patients have these mutations. Anti-VEGF antibody bevacizumab was approved for advanced NSCLC, but the clinical benefits are modest and all patients eventually develop resistance. Multi-targeted tyrosine kinase inhibitors (TKI) may offer more efficient inhibition of angiogenesis by blocking overlapping pathways and they may also have direct anti-tumor effects. Sorafenib is approved in the treatment of renal cell carcinoma and hepatocellular carcinoma and is now under investigation in the treatment of NSCLC. Areas covered: This review summarizes recent studies evaluating sorafenib in the treatment of NSCLC. Expert opinion: Sorafenib has shown anti-tumor activity in NSCLC. However, because NSCLC is complex and molecularly heterogeneous, it is very likely that only a subset of NSCLC patients will benefit from sorafenib, and so it is imperative to discover biomarkers to select patients who will probably benefit from sorafenib. Combination with other agents targeting parallel and compensatory pathways, such as EGFR inhibitors, may offer broader coverage and better disease control.     

Stimulatory effects of the multi-kinase inhibitor sorafenib on human bladder cancer cells

BACKGROUND AND PURPOSE

Sorafenib is an inhibitor of several intracellular signalling kinases with anti-proliferative, anti-angiogenic and pro-apoptotic effects in tumour cells. Sorafenib is used in the therapy of advanced renal cell carcinoma, and several phase II clinical trials are being carried out in patients with urothelial carcinomas.

EXPERIMENTAL APPROACH

Using a panel of human bladder cancer cell lines (RT4, T24, J82), we characterized systematically the effects of sorafenib on intracellular signalling, migration, proliferation and apoptosis.

KEY RESULTS

We demonstrated that at low concentrations (<1 µM), sorafenib is capable of significantly stimulating migration and proliferation of the bladder cancer cells. We hypothesize that these stimulatory effects on tumour cell functions might be explained by an activation of the Ras/ERK-1/2 signal transduction pathway. In addition, the comparison of different bladder cancer cell lines not only revealed a different biology (e.g. cell migration), but also a differential susceptibility to the anti-apoptotic effects of sorafenib. Finally, we confirmed in different bladder cancer cell lines the known inhibitory actions of sorafenib in pharmacological concentrations (≥3 µM) on ERK-1/2 phosphorylation, migration and proliferation, as well as the pro-apoptotic effects of the compound.

CONCLUSIONS AND IMPLICATIONS

Taken together, these findings suggest that although sorafenib has the potential to be used in the treatment of urothelial carcinoma, this compound might also activate bladder cancer cells at low concentrations. This should be relevant for dosing regiments to optimize the treatment with this promising anti-tumour drug.     

Sorafenib: activity and clinical application in patients with hepatocellular carcinoma

INTRODUCTION: Sorafenib is a novel oral bis-aryl urea compound that has proven survival benefit in patients with advanced hepatocellular carcinoma (HCC), for which several therapies are currently available with unsatisfactory results. Sorafenib is the first compound to demonstrate a significant effect on survival in HCC. AREAS COVERED: Our experience in the clinical application of sorafenib is reviewed in conjunction with relevant publications in the literature. Based on ex vivo and in vivo experiments, we conclude that sorafenib plays an important role in blocking tumor cell proliferation, inducing apoptosis, and reversing multidrug resistance. Antitumor activities were observed in multiple tumor types in ongoing randomized Phase III studies. Toxicity was observed as tolerable. On 16 November 2007, sorafenib was approved by the United States Food and Drug Administration for the treatment of unresectable HCC, based on the results of an international, multicenter, randomized, double-blind, placebo-controlled trial in patients with unresectable, biopsy-proven HCC. EXPERT OPINION: With the approval of sorafenib being given the significance of a milestone, systemic treatment of HCC is no longer regarded as ineffective. The tyrosine kinase inhibitor, sorafenib, gives us new hope for successful cancer therapy.     

常规及加量剂量的索拉非尼治疗转移性肾癌17例疗效观察

目的：探讨抑制血管生成的分子靶向药物酪氨酸激酶抑制剂索拉菲尼常规剂量及加量后治疗晚期肾透明细胞癌的疗效。方法：我科从2007年3月～2011年11月接受索拉菲尼治疗的17例晚期肾癌患者（mRCC）,观察常规剂量治疗转移性肾癌的疗效,及常规剂量多吉美治疗第一次进展的病人,加量至600mg,bid应用后患者的无疾病进展时间,再次进展后再次加量至800mg,bid后的无疾病进展时间,并观察其不良反应。结果：该组患者常规剂量多吉美治疗的中位疾病进展时间（TTP）10个月,加量至600mg,bid后中位疾病进展时间（TTP）为10个月,中位生存期25个月。结论：索拉菲尼对转移性肾癌具有明显的治疗效果,常规剂量进展的病人,加量应用后大部分患者仍获得较长的无疾病进展时间,提示加量治疗后可能仍有效,且安全性较高。     

Recent advances in the research and development of RAF kinase inhibitors

The RAS-RAF-MEK-ERK signaling pathway (ERK pathway) plays a key role in tumorigenesis and cancer progression. Mutations of RAS or B-RAF lead to a constitutive activation of the ERK pathway, which ultimately results in increased cell division, and cell survival. This review article focuses on the recent literature related to ERK pathway inhibitors, with a particular emphasis on RAF kinase inhibitors. Preclinical and clinical data for the RAF kinase inhibitor sorafenib (BAY 43-9006 tosylate), that was recently approved in the US for the treatment of advanced renal cell carcinoma, are also outlined.     

索拉非尼治疗转移性肾细胞癌的疗效及安全性研究

目的 评价索拉非尼治疗转移性肾癌的疗效及安全性.方法 转移性肾癌40例患者,均给予甲基磺酸索拉非尼片治疗,初始剂量为800 mg/d,2次/d,连续给药21 d,停药7d,观察疗效和不良反应,以及免疫组织化学检测结果.结果 40例患者中未见完全缓解（CR）和部分缓解（PR）;疾病稳定（SD） 32例（80.0％）和疾病进展（PD）8例（20.0％）;消化系统不良反应发生28例（70.0％）;间隙连接蛋白32（ Cx32）在局限性肾癌中表达阳性率为30.5％,明显低于转移性肾癌组织的1.2％（x2=8.123,P＜0.01）,Cx32表达与临床分期呈负相关（r=-0.419,P＜0.05）;肾癌组织中血管内皮生长因子（VEGF）蛋白表达的阳性率75.5％,明显高于正常肾组织的18.5％ （x2 =8.723,P＜0.01）;VEGF在局限性肾癌阳性表达率72.0％与转移性肾癌的89.1％差异无统计学意义（x2=1.978,P＞0.05）.结论 索拉非尼对晚期肾癌病情控制有较好的效果,是治疗转移性肾癌的新选择.