University of Ioannina, Ioannina, Greece,
J Cancer Res Clin Oncol. 2013 Nov;139(11):1917-26. doi: 10.1007/s00432-013-1510-5. Epub 2013 Sep 14.
Patients with metastatic renal cell carcinoma (mRCC) and a good performance status typically receive an anti-vascular endothelial growth factor receptor (VEGFR) TKI (sunitinib or pazopanib) as initial therapy. Upon disease progression or intolerance, there are four orally administered agents approved in the second-line setting (including cytokine-refractory). However, head-to-head comparative trial data are limited. In this study, an indirect statistical comparison of safety and efficacy was undertaken between axitinib, sorafenib, pazopanib and everolimus in second-line therapy mRCC.
A systematic review of major databases was conducted from January 2005 to June 2013 for randomized controlled trials (RCTs) evaluating at least one of the four agents in second-line mRCC. Bayesian mixed treatment comparison models were fitted to assess relative effectiveness on multiple endpoints such as objective response rates, dose-limiting grade III/IV toxicities, treatment discontinuations and progression-free survival (PFS).
Four RCTs met the inclusion criteria. All four agents seem able to induce tumor shrinkage and to provide patients with a clinically meaningful PFS benefit. Axitinib was superior to pazopanib [hazard ratio (HR) 0.64; 95 % credible interval (95 % Crl) 0.42-0.96] and sorafenib (HR 0.70; 95 % Crl 0.57-0.87) in terms of PFS. However, axitinib was associated with an elevated risk of fatigue and to a lesser extent stomatitis.
Keeping in mind the caveats associated with cross-trial statistical comparisons, axitinib provides superior PFS relative to pazopanib and sorafenib. Everolimus, an mammalian target of rapamycin inhibitor, is mechanistically distinct from the other agents and remains a useful option for patient's post-anti-VEGFR TKI failure.
转移性肾细胞癌（mRCC）患者一般身体状况良好，通常接受抗血管内皮生长因子受体（VEGFR）TKI（舒尼替尼或帕唑帕尼）作为初始治疗。疾病进展或不耐受时，二线治疗有四种口服药物获批（包括细胞因子难治性）。然而，头对头比较试验数据有限。本研究采用间接统计比较阿昔替尼、索拉非尼、帕唑帕尼和依维莫司在二线 mRCC 治疗中的安全性和疗效。
对 2005 年 1 月至 2013 年 6 月期间主要数据库进行系统性综述，检索评估四种药物中至少一种药物在二线 mRCC 中的随机对照试验（RCT）。采用贝叶斯混合治疗比较模型评估多个终点（如客观缓解率、剂量限制的 III/IV 级毒性、治疗中止和无进展生存期（PFS））的相对有效性。
四项 RCT 符合纳入标准。所有四种药物似乎都能诱导肿瘤缩小，并为患者提供有临床意义的 PFS 获益。阿昔替尼在 PFS 方面优于帕唑帕尼[风险比（HR）0.64；95 %可信区间（95 % Crl）0.42-0.96]和索拉非尼（HR 0.70；95 % Crl 0.57-0.87）。然而，阿昔替尼与疲劳风险升高相关，且程度较轻的为口腔炎。
考虑到跨试验统计比较的注意事项，阿昔替尼与帕唑帕尼和索拉非尼相比提供了更好的 PFS。依维莫司是一种哺乳动物雷帕霉素靶蛋白抑制剂，与其他药物在机制上不同，仍然是抗 VEGFR TKI 治疗失败后患者的一个有用选择。
