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Lancet Oncol:阿柏西普无助于前列腺癌的改善

2013-6-13 作者:Lancet Oncol   来源:医脉通 我要评论0
Tags: 前列腺癌  阿柏西普  

       6月3日,法国的一个研究小组发表了一份关于阿柏西普治疗转移性去势抵抗性前列腺癌的研究报告,该研究对比了阿柏西普与安慰剂联合多西他赛加强的松的三药方案一线救治转移性去势抵抗性前列腺癌的疗效。结果显示,加入阿柏西普的三药方案与加入安慰剂的三药方案疗效相当,这表明阿柏西普无助于此类前列腺癌患者总生存期的改善。
       多西他赛联合强的松已经成为治疗转移性去势抵抗性前列腺癌的标准一线化疗方案。阿柏西普(Aflibercept是一种重组人融合蛋白,能够结合VEGF的A亚型和B亚型,也能够与胎盘生长因子结合,从而抑制肿瘤血管的生成。该研究的目的是为了弄清楚阿柏西普联合多西他赛加强的松的治疗方案是否可以改善转移性去势抵抗性前列腺癌患者的总生存期。研究的对照为安慰剂加多西他赛联合强的松的治疗组。


 
       这项命名为VENICE的多中心参与、随机双盲、安慰剂对照的3期临床试验分别在31个国家的187个研究中心进行。参与试验的患者均被诊断为转移性去势抵抗性前列腺癌,并且器官功能良好,之前也未曾接受过化疗治疗。纳入的患者均接受了多西他赛(75 mg/m2,静脉给药,每3周一次)加强的松(5 mg,口服,每天2次),并按照1:1的比例被随机分配再次接受阿柏西普(6 mg/kg,静脉给药,每3周一次)或安慰剂治疗(静脉给药,每3周一次)。试验中的治疗分组是依据ECOG评分(0-1 vs 2)并利用中央交互式语音应答系统完成的。患者、研究人员以及相关其他人员都参与此试验,并严格按照试验要求进行。试验中使用到的药品阿柏西普及安慰剂均为相同来源的药品。
       研究的主要终点为利用意向治疗分析得出来的总生存期(OS),这也是对该试验的初步分析。
       在2007年8月17日至2010年2月11日之间,研究纳入的1224例患者被随机分配到两个治疗组,每个治疗组均为612例。结果显示,在平均随访了35个月(IQR 29-41)后,873例患者死亡。阿柏西普治疗组的中位生存期为22.1个月(95.6% CI 20.3-24.1),安慰剂治疗组的中位生存期为21.2个月(19.6-23.8)(分层HR,0.94,95.6%CI 0.82-1.08;P = 0.38)。


 
       阿柏西普治疗组对比安慰剂治疗组,出现的最频繁的3-4级不良反应包括胃肠功能紊乱(182 [30%] vs 48 [8.0%])、出血事件(32 [5.2%] vs ten [1.7%])、高血压(81 [13%] vs 20 [3.3%])、疲乏(97 [16%] vs 46 [7.7%])、感染(123 [20%] vs 60 [10%])、治疗相关的致死事件(21 [3.4%] vs 9 [1.5%])。
       研究结果表明,与多西他赛联合强的松的两药方案相比,阿柏西普加入的三药方案用于一线救治转移性去势抵抗性前列腺癌无助于患者总生存期的改善,并且毒性反应较大。因此,多西他赛联合强的松仍然可以作为一线治疗转移性去势抵抗性前列腺癌的标准化疗方案。
       该研究为赛诺菲和Regeneron制药公司的资助项目。
Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial.
BACKGROUND
Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone.
METHODS
VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m2 intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0-1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov, number NCT00519285 FINDINGS: Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29-41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3-24·1) in the aflibercept group and 21·2 months (19·6-23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82-1·08; p=0·38). We recorded a higher incidence of grade 3-4 gastrointestinal disorders (182 [30%] vs 48 [8·0%]), haemorrhagic events (32 [5·2%] vs ten [1·7%]), hypertension (81 [13%] vs 20 [3·3%]), fatigue (97 [16%] vs 46 [7·7%]), infections (123 [20%] vs 60 [10%]) and treatment-related fatal adverse events (21 [3·4%] vs nine [1·5%]) in the aflibercept group than in the placebo group.
INTERPRETATION
Aflibercept in combination with docetaxel and prednisone given as first-line chemotherapy for men with metastatic castrate-resistant prostate cancer resulted in no improvement in overall survival and added toxicity compared with placebo. Docetaxel plus prednisone remains the standard treatment for such men who need first-line chemotherapy.



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