Targeted Therapies for the Treatment of Metastatic Renal Cell Carcinoma: Clinical Evidence
Targeted Therapies for the Treatment of Metastatic Renal Cell Carcinoma: Clinical Evidence
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DOI：
10.1634/theoncologist.2011-s2-14
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发表时间：
2011-01-01
期刊：
影响因子：
5.8
通讯作者：
Hutson, Thomas E.
中科院分区：
文献类型：
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作者：
Hutson, Thomas E.
尽管转移性肾细胞癌（mRCC）患者的全身治疗一度仅限于细胞因子白细胞介素-2和干扰素（IFN）-α，但近年来，几种靶向治疗已可用于一线和二线治疗。这些药物包括索拉非尼、舒尼替尼、贝伐单抗（加IFN-α）、替西罗莫司、依维莫司，以及最近的帕唑帕尼。这一扩大的治疗选择清单来自分子生物学研究，该研究揭示了RCC中异常的信号转导活性，从而能够鉴定治疗的特定分子靶点。分子靶向治疗比细胞因子治疗具有更好的疗效和耐受性，并且许多是口服给药。考虑到所需长期随访的固有并发症、所需的大量人群以及交叉试验设计或感兴趣药物进展后后续治疗的影响引起的混淆，分子靶向药物实现的上级结局促使研究者重新考虑将总生存期作为临床试验的主要终点。在mRCC试验中，无进展生存期已成为流行的主要终点，并已成为批准几种靶向治疗的基础。除了鉴定新的药物外，目前的研究集中在评价与靶向药物的联合治疗。随着有关疾病和耐药性机制的更多信息的获得，将研究新的靶点，新的靶向药物和新的组合，以提供最大的疗效和最小的毒性。本文综述了支持靶向药物在mRCC治疗中获益的临床证据，讨论了其关键临床试验中使用的生存终点，并概述了未来的研究方向。肿瘤学家2011;16（增刊2）：14-22
Although systemic therapy for patients with metastatic renal cell carcinoma (mRCC) was once limited to the cytokines interleukin-2 and interferon (IFN)-alpha, in recent years several targeted therapies have become available for first- and second-line use. These include sorafenib, sunitinib, bevacizumab (plus IFN-alpha), temsirolimus, everolimus, and, most recently, pazopanib. This expanded list of treatment options arose from molecular biological research that revealed aberrant signal transduction activities in RCC, enabling the identification of specific molecular targets for therapy. Molecular-targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. The superior outcomes achieved with molecular-targeted agents are prompting investigators to reconsider overall survival as a primary endpoint in clinical trials, given the inherent complications of a required long duration of follow-up, a required large population, and confounding caused by crossover trial designs or effects of subsequent therapy after progression on the agent of interest. In mRCC trials, progression-free survival has become a popular primary endpoint and has served as the basis of approval for several targeted therapies. In addition to the identification of new agents, current research is focused on the evaluation of combination therapy with targeted agents. As more information regarding mechanisms of disease and drug resistance becomes available, new targets, new targeted agents, and new combinations will be studied with the goal of providing maximal efficacy with minimal toxicity. This article reviews the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions. The Oncologist 2011;16(suppl 2):14-22