FACP, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo 251, São Paulo, Brazil.
J Clin Oncol. 2012 Oct 10;30(29):3596-603. doi: 10.1200/JCO.2012.42.6031. Epub 2012 Sep 10.
Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signaling with activity against all three VEGF receptors. HORIZON II [Cediranib (AZD2171, RECENTIN) in Addition to Chemotherapy Versus Placebo Plus Chemotherapy in Patients With Untreated Metastatic Colorectal Cancer] assessed infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (FOLFOX/CAPOX) with or without cediranib in patients with previously untreated metastatic colorectal cancer (mCRC).
Eligible patients were initially randomly assigned 1:1:1 to receive cediranib (20 or 30 mg per day) or placebo plus FOLFOX/CAPOX. In an early analysis of this and two other cediranib studies (HORIZON I [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Previously Treated Metastatic Colorectal Cancer] and HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer]), the 20-mg dose met the predefined criteria for continuation. Subsequent patients were randomly assigned 2:1 to the cediranib 20 mg or placebo arms. Progression-free survival (PFS) and overall survival (OS) were coprimary end points.
In all, 860 patients received cediranib 20 mg (n = 502) or placebo (n = 358). The addition of cediranib to FOLFOX/CAPOX resulted in PFS prolongation (hazard ratio [HR], 0.84; 95% CI, 0.73 to 0.98; P = .0121; median PFS, 8.6 months for cediranib v 8.3 months for placebo) but had no impact on OS (HR, 0.94; 95% CI, 0.79 to 1.12; P = .5707; median OS, 19.7 months for cediranib v 18.9 months for placebo). There were no significant differences in the secondary end points of objective response rate, duration of response, or liver resection rate. Median chemotherapy dose-intensity was decreased by approximately 10% in patients treated with cediranib. Adverse events (AEs) associated with cediranib were manageable. CONCLUSION Addition of cediranib 20 mg to FOLFOX/CAPOX resulted in a modest PFS prolongation, but no significant difference in OS. The cediranib AE profile was consistent with those from previous studies. Because of the lack of improvement in OS, cediranib plus an oxaliplatin-based regimen cannot be recommended as a treatment for patients with mCRC.
西地尼布是一种强效的血管内皮生长因子（VEGF）信号抑制剂，对所有三种 VEGF 受体均有活性。HORIZON II [西地尼布（AZD2171，RECENTIN）联合化疗与安慰剂联合化疗治疗未经治疗的转移性结直肠癌]评估了氟尿嘧啶、亚叶酸钙和奥沙利铂/卡培他滨与奥沙利铂（FOLFOX/CAPOX）联合或不联合西地尼布治疗未经治疗的转移性结直肠癌（mCRC）患者。
符合条件的患者最初按 1:1:1 的比例随机分配接受西地尼布（每天 20 或 30mg）或安慰剂加 FOLFOX/CAPOX。在这项研究和另外两项西地尼布研究（HORIZON I [西地尼布加 FOLFOX6 与贝伐珠单抗加 FOLFOX6 治疗既往治疗转移性结直肠癌]和 HORIZON III [西地尼布加 FOLFOX6 与贝伐珠单抗加 FOLFOX6 治疗未经治疗的转移性结直肠癌]）的早期分析中，20mg 剂量符合继续治疗的预设标准。随后的患者按 2:1 的比例随机分配至西地尼布 20mg 或安慰剂组。无进展生存期（PFS）和总生存期（OS）是共同的主要终点。
共有 860 名患者接受了西地尼布 20mg（n=502）或安慰剂（n=358）治疗。西地尼布联合 FOLFOX/CAPOX可延长 PFS（风险比[HR]，0.84；95%CI，0.73 至 0.98；P=0.0121；中位 PFS，西地尼布组 8.6 个月，安慰剂组 8.3 个月），但对 OS 无影响（HR，0.94；95%CI，0.79 至 1.12；P=0.5707；中位 OS，西地尼布组 19.7 个月，安慰剂组 18.9 个月）。客观缓解率、缓解持续时间或肝切除术率等次要终点无显著差异。接受西地尼布治疗的患者化疗剂量强度平均降低约 10%。与西地尼布相关的不良事件（AE）是可管理的。结论：西地尼布 20mg 联合 FOLFOX/CAPOX 可适度延长 PFS，但 OS 无显著差异。西地尼布的 AE 谱与之前的研究一致。由于 OS 无改善，西地尼布联合奥沙利铂为基础的方案不能作为 mCRC 患者的治疗推荐。
