FCP(SA), FRCPC, The Ottawa Hospital Cancer Centre, 501 Smyth Rd, Ottawa ON K1H 8L6, Canada.
J Clin Oncol. 2010 Jan 1;28(1):49-55. doi: 10.1200/JCO.2009.22.9427. Epub 2009 Nov 16.
PURPOSE This phase II/III double-blind study assessed efficacy and safety of cediranib with standard chemotherapy as initial therapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Paclitaxel (200 mg/m(2)) and carboplatin (area under the serum concentration-time curve 6) were given every 3 weeks, with daily oral cediranib or placebo at 30 mg (first 45 patients received 45 mg). Progression-free survival (PFS) was the primary outcome of the phase II interim analysis; phase III would proceed if the hazard ratio (HR) for PFS < or = 0.77 and toxicity were acceptable. Results A total of 296 patients were enrolled, 251 to the 30-mg cohort. The phase II interim analysis demonstrated a significantly higher response rate (RR) for cediranib than for placebo, HR of 0.77 for PFS, no excess hemoptysis, and a similar number of deaths in each arm. The study was halted to review imbalances in assigned causes of death. In the primary phase II analysis (30-mg cohort), the adjusted HR for PFS was 0.77 (95% CI, 0.56 to 1.08) with a higher RR for cediranib than for placebo (38% v 16%; P < .0001). Cediranib patients had more hypertension, hypothyroidism, hand-foot syndrome, and GI toxicity. Hypoalbuminemia, age > or = 65 years, and female sex predicted increased toxicity. Survival update (N = 296) 10 months after study unblinding favored cediranib over placebo (median of 10.5 months v 10.1 months; HR, 0.78; 95% CI, 0.57 to 1.06; P = .11). Causes of death in the cediranib 30-mg cohort were NSCLC (81%), protocol toxicity +/- NSCLC (13%), and other (6%); for the placebo group, they were 98%, 0%, and 2%, respectively. CONCLUSION The addition of cediranib to carboplatin/paclitaxel results in improved response and PFS, but does not appear tolerable at a 30-mg dose. Consequently, the National Cancer Institute of Canada Clinical Trials Group and the Australasian Lung Cancer Trials Group initiated a randomized, double-blind, placebo-controlled trial of cediranib 20 mg with carboplatin and paclitaxel in advanced NSCLC.
目的 这项 II/III 期双盲研究评估了西地尼布联合标准化疗作为晚期非小细胞肺癌（NSCLC）初始治疗的疗效和安全性。
患者和方法 每 3 周给予紫杉醇（200mg/m²）和卡铂（血清浓度-时间曲线下面积 6），同时每日口服西地尼布或安慰剂 30mg（前 45 例患者接受 45mg）。无进展生存期（PFS）是 II 期中期分析的主要结局；如果 PFS 的风险比（HR）≤0.77 且毒性可接受，则进行 III 期研究。
结果 共纳入 296 例患者，其中 251 例入组 30mg 队列。II 期中期分析显示，西地尼布组的缓解率（RR）显著高于安慰剂组，PFS 的 HR 为 0.77，无过度咯血，且各治疗组的死亡例数相似。研究因分配死因的不平衡而暂停，以进行审查。在主要的 II 期分析（30mg 队列）中，PFS 的调整 HR 为 0.77（95%CI，0.56 至 1.08），西地尼布组的 RR 高于安慰剂组（38%比 16%；P<0.0001）。西地尼布组患者高血压、甲状腺功能减退、手足综合征和胃肠道毒性更多见。低白蛋白血症、年龄≥65 岁和女性提示毒性增加。研究揭盲后 10 个月的生存更新（N=296）结果显示，西地尼布组的生存优于安慰剂组（中位 10.5 个月比 10.1 个月；HR，0.78；95%CI，0.57 至 1.06；P=0.11）。西地尼布 30mg 组的死亡原因为 NSCLC（81%）、方案毒性±NSCLC（13%）和其他（6%）；安慰剂组的死亡原因为 NSCLC（98%）、0%和 2%。
结论 西地尼布联合卡铂/紫杉醇治疗可改善缓解率和 PFS，但在 30mg 剂量下似乎不能耐受。因此，加拿大国家癌症研究所临床试验组和澳大利亚肺癌临床试验组启动了一项随机、双盲、安慰剂对照的西地尼布 20mg 联合卡铂和紫杉醇治疗晚期 NSCLC 的研究。
