Genitourinary Malignancies Program, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111, USA.
Semin Oncol. 2009 Dec;36 Suppl 3:S26-36. doi: 10.1053/j.seminoncol.2009.10.013.
Clinical trials have validated the importance of mammalian target of rapamycin (mTOR) as a therapeutic target in patients with advanced renal cell carcinoma (RCC). The TORC1 complex controls translation of key proteins involved in cell proliferation and regulates the expression and stability of hypoxia-inducible factor (HIF)-1alpha. Temsirolimus, the first mTOR inhibitor approved for treatment of advanced RCC, has demonstrated significantly longer overall survival (hazard ratio for death, 0.73; 95% confidence interval, 0.58-0.92, P = .008) and progression-free survival (P <.001) compared with interferon alfa (IFN) for patients with poor prognostic features. Median progression-free survival durations were 3.8 and 1.9 months, respectively, for patients treated with temsirolimus or IFN, and median overall survivals were 10.9 and 7.3 months, respectively. Exploratory analyses indicate that temsirolimus benefits those patients with metastatic RCC and multiple adverse prognostic factors regardless of tumor histology or nephrectomy status. Most adverse events that occur in patients receiving temsirolimus can be managed medically (eg, hyperglycemia, hyperlipidemia) or addressed by supportive measures (eg, stomatitis, rash). Although development of symptomatic pneumonitis is rare, monitoring is recommended. Temsirolimus is now considered an important first-line treatment option for patients with advanced RCC and multiple factors predictive of short survival. Current trials are investigating the use of temsirolimus in sequence or in combination with other targeted agents to further improve outcomes.
临床试验已经验证了哺乳动物雷帕霉素靶蛋白（mTOR）作为晚期肾细胞癌（RCC）患者治疗靶点的重要性。TORC1 复合物控制参与细胞增殖的关键蛋白的翻译，并调节缺氧诱导因子（HIF）-1α的表达和稳定性。替西罗莫司是首个被批准用于治疗晚期 RCC 的 mTOR 抑制剂，与干扰素 alfa（IFN）相比，它显著延长了具有不良预后特征的患者的总生存期（死亡风险比，0.73；95%置信区间，0.58-0.92，P =.008）和无进展生存期（P <.001）。分别接受替西罗莫司或 IFN 治疗的患者中位无进展生存期分别为 3.8 个月和 1.9 个月，中位总生存期分别为 10.9 个月和 7.3 个月。探索性分析表明，替西罗莫司有益于那些具有转移性 RCC 和多种不良预后因素的患者，无论肿瘤组织学或肾切除术状态如何。接受替西罗莫司治疗的患者发生的大多数不良事件可以通过药物治疗（如高血糖、高血脂）或支持性措施（如口炎、皮疹）来管理。尽管症状性肺炎的发生很少见，但建议进行监测。替西罗莫司现在被认为是具有多种因素预测生存期短的晚期 RCC 患者的重要一线治疗选择。目前的试验正在研究替西罗莫司的序贯或联合其他靶向药物的使用，以进一步改善结果。
