分子靶向药物舒尼替尼治疗肾细胞癌

肾细胞癌(RCC)具有高转移性、易复发且对放、化疗不敏感三大特征,免疫治疗仅对少数患者有效.随着RCC分子生物学研究的进展,临床转移性RCC的靶向治疗不断取得新突破.分子靶向药物舒尼替尼(sunitinib)治疗RCC疗效确切,但其诸多不良反应和并发症仍需引起足够重视.     

肾细胞癌辅助治疗研究进展

肾细胞癌(renal cell carcinoma,RCC)是泌尿外科常见的恶性肿瘤之一.早期RCC的治疗以根治性切除为主,但仍有约20％的患者最终发生远处转移.对于具有转移、复发高风险的患者以及已失去根治性手术机会的患者来说,通过辅助治疗来提高总的生存率,延长无进展生存期,提高生活质量是十分有意义的.虽然RCC对放化疗不敏感,但免疫治疗以及各种新的靶向治疗药物和方法给RCC的治疗带来了更多的选择和希望.文中就RCC辅助治疗研究进展进行综述.     

受体酪氨酸激酶抑制剂对于晚期肾透明细胞癌的靶向治疗作用

晚期肾透明细胞癌（renal clear-cell carcinoma）的预后不良，而且临床缺乏有效的治疗手段。随着人们对其分子生物学更加深刻的认识和分子靶向药物如受体酪氨酸激酶抑制剂（tyrosine kinase inhibitor，TKI）的出现，使晚期肾透明细胞癌临床治疗取得明显的进展。     

转移性肾细胞癌靶向药物的临床应用进展

肾细胞癌(RCC)是泌尿系第二大常见的恶性肿瘤,其发病率和死亡率呈逐年升高趋势。2005年12月美国食品和药物管理局(FDA)批准索拉非尼作为治疗转移性肾细胞癌(mRCC)的首个靶向治疗药物,其后陆续有临床随机试验表明舒尼替尼、替西罗莫司、帕唑帕尼、贝伐珠单抗、依维莫司、阿昔替尼、卡博替尼、纳武单抗和乐伐替尼等靶向药物也可提高m RCC患者的总生存期和耐受性。本文主要对FDA批准用于治疗mRCC的靶向治疗药物的最新进展进行综述。     

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。     

晚期肾癌免疫治疗新进展

肾细胞癌（RCC）是泌尿系统常见的恶性肿瘤,早期可行手术根治性切除,晚期对放化疗均不敏感。随着肿瘤生物治疗的研究,晚期RCC的免疫治疗取得了许多实质性的进展。本文综述近年晚期RCC免疫治疗的临床研究进展。     

Sunitinib在治疗转移性肾细胞癌中的作用

背景:现有的转移性肾细胞癌(RCC)的治疗方法非常有限,所以急需寻找新的有效的治疗方法。Sunitinibmalate为口服多靶点酪氨酸激酶抑制剂,并且在一项对细胞因子难治性转移性RCC患者的初期研究中已经显示有效果。目的:证实sunitinib作为患有转移性透明细胞(clear-cell,该恶性肿瘤中的主要细胞类型)RCC患者二线治疗药物的抗肿瘤功效。方法:此研究为一项公开标签、单一试验组、多中心的临床试验。在2004年2月～10月之间招募患者,并随访至疾病进展、发生严重的毒性作用或者受试者要求退出试验为止。试验收录了106例先前经过细胞活素疗法治疗后…     

分子靶向治疗新药在临床转移性肾癌治疗中的应用

肾细胞癌(RCC)对化疗、放疗以及激素治疗均不敏感。细胞因子治疗是其主要方法,但有效率低且毒副作用明显,尤其转移性肾癌(mRCC)患者很少能从中获益。近些年,随着肿瘤分子生物学的不断发展,分子靶向治疗成为mRCC治疗新策略。本文重点针对血管内皮生长因子通路和雷帕霉素靶蛋白通路综述几种新型分子靶向治疗药物的临床应用。     

肾癌靶向治疗现状

分子靶向治疗对肾透明细胞癌的疗效优于传统的免疫治疗,而对其他类型的肾癌亦有一定的疗效,为晚期肾癌患者带来了新的希望。本文对已经批准上市以及正在进行研究的肾癌靶向治疗药物作一综述。     

肾细胞癌常见亚型的CT分析

目的：探讨肾细胞癌（renal cel carcinoma,RCC）主要亚型的CT表现,提高术前诊断率,从而确定合适的治疗方案。方法：回顾性分析本院2014年1月-2016年4月份30例经手术及病理证实的并且临床资料完整的病例,术前均行CT平扫、皮髓质交界期、实质期及MPR重建扫描。将皮髓质交界期强化程度与肾皮质相仿定义为明显强化,明显低于肾皮质定义为轻度强化,介于两者之间为中等度强化。结果：透明细胞癌（clear cel RCC）23例,平扫时囊变5例,出血6例,钙化5例,增强后明显强化呈快进快出表现13例,轻度强化3例;嫌色细胞癌（chromophobe RCC）3例,平扫时钙化1例,增强后均呈中度不均匀强化;乳头状细胞癌（papilary RCC）4例,平扫时病灶内均有坏死,增强后呈轻度强化。透明细胞癌皮髓质交界期强化程度明显强于嫌色细胞癌及乳头状肾癌,嫌色细胞癌及乳头状肾癌呈轻中度延迟强化,透明细胞癌出血、坏死、囊变及钙化多见,乳头状肾癌容易坏死。结论：肾癌不同亚型的CT表现有一定的特征性,仔细分析病灶的特征及强化方式有助于做出正确的术前诊断。     

晚期非小细胞肺癌治疗的新趋势

当今肺癌研究的热点是以与肿瘤发生、发展相关的驱动基因为靶点,研发新的药物,进行有针对性的个体化分子靶向治疗,从而改善患者预后。靶向药物、新型化疗药物、抗血管新生药物以及治疗性疫苗等各种治疗手段在晚期非小细胞肺癌(NSCLC)患者的治疗中均取得了显著的进展。其中表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)对于EGFR突变阳性NSCLC患者无论在一线、维持还是二线治疗中疗效均得到肯定;替吉奥胶囊有望成为晚期NSCLC一线、二线治疗新的选择;克唑替尼是棘皮动物微管结合蛋白4与间变淋巴瘤激酶融合基因(EML4-ALK)阳性患者治疗的新标准;抗血管新生药物在NSCLC的治疗疗效得到了进一步证实;EGF疫苗在晚期NSCLC治疗中的结果值得期待。这些成果将会改变目前晚期NSCLC的治疗策略,而基于患者临床特点及分子分型的个体化治疗将成为晚期非小细胞肺癌治疗的新趋势。     

Targeted-therapy in advanced renal cell carcinoma

Surgery has been the mainstay of renal cell carcinoma (RCC) treatment for resectable tumours. In stages I-III disease, nephrectomy is the standard of care and may be curative. Historically, patients presenting with stage IV disease may achieve improved survival with debulking nephrectomy, which is commonly performed prior to systemic therapy. The response rate of immunotherapy is low, with a smaller percentage exhibiting complete remission upon treatment. Therefore, new therapeutic approaches against metastatic RCC are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC have been identified, and molecular targeted therapy has developed. Clear cell RCC commonly features mutation or inactivation of the von Hippel- Lindau (VHL) gene and resultant over-expression of vascular endothelial growth factor (VEGF). The first drug to validate VEGF as a target in the treatment of clear cell RCC was the monoclonal antibody bevacizumab. Sunitinib is now a standard first-line therapy for advanced disease and sorafenib is among the second-line treatment options. Mammalian target of rapamycin (mTOR) is a second validated therapeutic target as the mTOR inhibitor temsirolimus has been shown to prolong survival in first-line treatment of poor prognosis RCC of all histologies. Everolimus is an oral mTOR inhibitor and has been shown to prolong progression-free survival (PFS) when used in second-line treatment. This review describes recent advances in molecular targeted therapy for metastatic RCC, focusing on chemical structure and mechanism of action of VEGFR and mTOR inhibitors.     

Everolimus suppresses invasion and migration of renal cell carcinoma by inhibiting FAK activity and reversing epithelial to mesenchymal transition in vitro and in vivo

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and the major cause of mortality in urological cancer. Most patients with RCC are asymptomatic until the disease is advanced and unresectable. In this situation, systemic therapy with immunotherapy or molecularly targeted therapy agents play an important role in therapeutic strategy. Everolimus (EVE), an m‐TOR inhibitor, has the potential to inhibit tumor progression at multiple levels and is indicated for the treatment of advanced RCC in patients whose disease has metastasis. In this study, we provide molecular evidence associated with the antimetastatic effect of everolimus by demonstrating the suppression of lung metastasis of 786‐O cells in mouse model. This effect was associated with reduced protein expressions of p‐FAK (Tyr 925), p‐Src (Tyr416), Vimentin, and RhoA and also with increased the E‐cadherin protein expression. In summary, these findings provide new insights into the molecular mechanisms involved in the antimetastatic effect of everolimus and are thus valuable in the treatment of metastatic RCC.     

Growing opportunities for adjuvant therapy of renal cell carcinoma: targeted drugs and vaccines

The management of advanced renal cell carcinoma (RCC) is undergoing a revolution, with the introduction of new agents and surgical paradigms. Thoughtful integration of diagnostic, surgical and medical approaches to the patient is paramount for disease control. Methods of risk stratifying kidney cancers are reviewed, as well as mechanisms of action of newer drugs approved in advanced metastatic kidney cancer. These drugs present opportunities for application to patients in an earlier stage of disease, and adjuvant RCC trials designs are discussed. Improvements have been made in the understanding of the molecular and genetic basis of RCC, both for causative and prognostic markers, with models addressing prediction of tumor behavior and therapeutic targets. Practice patterns have shifted from cytokine therapies to targeted molecular approaches, particularly emphasizing the VEGF pathway, related intracellular kinases and the mammalian target of rapamycin. Autologous vaccine adjuvant studies are maturing. In conclusion, elucidation of specific genes, proteins and aberrant molecular pathways associated with kidney cancer are ongoing. These new agents may lead to opportunities to improvement of disease-free survival through therapy in the adjuvant setting.     

晚期非小细胞肺癌表皮生长因子受体-酪酸激酶抑制剂靶向治疗进展

随着分子生物学研究的深入,靶向治疗特别是表皮生长因子-酪氨酸激酶抑制剂(EGFR-TKI)为肺癌治疗开辟了蹊径。EGFR-TKI无论作为一线还是二、三线治疗或维持治疗对晚期非小细胞肺癌(NSCLC)均有效。本文概述EGFR-TKI在晚期NSCLC治疗中的应用进展。     

Emerging drugs for renal cell carcinoma

Importance of the field: The treatment of metastatic renal cell carcinoma (RCC) has evolved significantly over the past 5 years and targeted therapy has become the standard of care. However, complete and lasting responses to these drugs are still uncommon. Currently, novel agents are being tested in clinical trials.

Areas covered in this review: We discuss approved targeted agents in RCC and emphasize on emerging therapies. We searched the US National Library of Medicine (PubMed) using the terms ‘renal cell carcinoma’, ‘targeted therapy’ and ‘novel agents’, from 1990 to the present. We also searched for abstracts from the meetings of the American Society of Clinical Oncology and Genitourinary Cancers Symposium from 2007 to the present.

What the reader will gain: This paper provides understanding of the approved treatments for advanced RCC as well as the novel agents and their targeted biological pathways.

Take home message: Despite dynamic and recent advances in the management of metastatic RCC much about the molecular biology of this tumor has yet to be delineated. Even more so, strategies of sequential treatment, combination of targeted drugs, mechanisms of resistance, optimal dosages and scheduling remain areas of potential development interest.     

Present and future therapeutic options for locally advanced and metastatic renal cell carcinoma

Introduction: Locally advanced or metastatic renal cell carcinoma (RCC) is notoriously chemo- and radioresistant, leaving immunotherapy as the only treatment option. In recent years, targeted therapies have offered significant increases in progression-free survival (PFS). Despite this, the majority of patients soon develops resistant disease and finally succumbs. The need to implement treatment strategies that improve overall survival while having an acceptable safety profile is imperative.

Areas covered: This review provides information on the efficacy of recently studied treatment strategies for advanced RCC. These include sequential and combination therapy of established drugs as well as data on agents in early clinical development. The Medline and ASCO database were searched for clinical trials on medical therapy of advanced RCC from 2004 until May 2010. Data on targeted therapies, including tyrosine kinase inhibitors, vascular endothelial growth factor inhibitors, mammalian target of rapamycin inhibitors, and antiepidermal growth factor receptor agents are summarized.

Expert opinion: Improvements in response rates and PFS in patients with advanced RCC have been observed with new treatment strategies. The benefit in overall survival is less clear and needs further evaluation. Toxicity represents a concern especially in combination regiments.     

Targeted therapy and hand–foot skin reaction in advanced renal cell carcinoma

Importance of the field: Targeted therapy has significantly prolonged the survival of patients with advanced renal cell carcinoma (RCC). As first-line treatment, sunitinib, temsirolimus and bevacizumab plus IFN-α are demonstrated to prolong progression-free survival and/or overall survival. As second-line treatment, sorafenib was active mainly for patients in whom cytokine therapy failed. Recently, second-line treatment with everolimus has been shown to benefit patients progressing through tyrosine kinase inhibitors. Meanwhile, FDA has just approved pazopanib for the treatment of patients with advanced RCC. Various toxicities were associated with these agents. These toxicities were generally well tolerated. However, a high frequency of severe skin and bone marrow toxicities has been reported in Asian countries.

Areas covered in this review: We have reviewed the literature of current targeted therapeutic agents and hand–foot skin reaction (HFSR) in advanced RCC available in MEDLINE and meeting reports of ASCO, ECCO-ESMO and the 2009 Genitourinary Cancers Symposium.

What the reader will gain: Readers will know of the efficacy and safety, including HFSR, of current targeted therapy.

Take home message: Careful monitoring and appropriate management of the toxicities, especially HFSR, are needed.     

Emerging molecular targeted therapies in the treatment of head and neck cancer

Current development of molecular targeted therapies in oncology is particularly active. The aim of this study is to review recent advances in the field of molecular targeted therapies for head and neck squamous cell carcinoma (HNSCC). As EGFR signaling pathway and angiogenesis play a key role in the growth of HNSCC, EGFR with its downstream effectors and molecular factors implicated in the angiogenesis process, such as VEGF and its receptors, represent the main targets of the new therapeutic agents now in development. Today, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of HNSCC in patients with locally advanced tumors, in association with radiotherapy, and in patients with recurrent or metastatic diseases. Future progress is expected with the integration of cetuximab into induction chemotherapeutic regimens or in association with concurrent chemoradiotherapy for locally advanced tumors and with the development and evaluation of other molecular targeted therapies such as antiangiogenic drugs. As these innovative molecules start to be used in clinical practice, the identification of predictive markers for efficacy and toxicity becomes a crucial issue.