Yang James C, Haworth Leah, Sherry Richard M, Hwu Patrick, Schwartzentruber Douglas J, Topalian Suzanne L, Steinberg Seth M, Chen Helen X, Rosenberg Steven A
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md 20892, USA.
N Engl J Med. 2003 Jul 31;349(5):427-34. doi: 10.1056/NEJMoa021491.
Mutations in the tumor-suppressor gene VHL cause oversecretion of vascular endothelial growth factor by clear-cell renal carcinomas. We conducted a clinical trial to evaluate bevacizumab, a neutralizing antibody against vascular endothelial growth factor, in patients with metastatic renal-cell carcinoma.
A randomized, double-blind, phase 2 trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks; the time to progression of disease and the response rate were primary end points. Crossover from placebo to antibody treatment was allowed, and survival was a secondary end point.
Minimal toxic effects were seen, with hypertension and asymptomatic proteinuria predominating. The trial was stopped after the interim analysis met the criteria for early stopping. With 116 patients randomly assigned to treatment groups (40 to placebo, 37 to low-dose antibody, and 39 to high-dose antibody), there was a significant prolongation of the time to progression of disease in the high-dose--antibody group as compared with the placebo group (hazard ratio, 2.55; P<0.001). There was a small difference, of borderline significance, between the time to progression of disease in the low-dose--antibody group and that in the placebo group (hazard ratio, 1.26; P=0.053). The probability of being progression-free for patients given high-dose antibody, low-dose--antibody, and placebo was 64 percent, 39 percent, and 20 percent, respectively, at four months and 30 percent, 14 percent, and 5 percent at eight months. At the last analysis, there were no significant differences in overall survival between groups (P>0.20 for all comparisons).
Bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer.
肿瘤抑制基因VHL的突变会导致透明细胞肾细胞癌过度分泌血管内皮生长因子。我们开展了一项临床试验，以评估抗血管内皮生长因子的中和抗体贝伐单抗对转移性肾细胞癌患者的疗效。
进行了一项随机、双盲、2期试验，比较安慰剂与每两周一次、剂量为每千克体重3毫克和10毫克的贝伐单抗；疾病进展时间和缓解率为主要终点。允许从安慰剂交叉至抗体治疗，生存率为次要终点。
观察到的毒性作用极小，主要为高血压和无症状蛋白尿。中期分析达到提前终止标准后，试验停止。116例患者被随机分配至治疗组（40例接受安慰剂，37例接受低剂量抗体，39例接受高剂量抗体），与安慰剂组相比，高剂量抗体组的疾病进展时间显著延长（风险比为2.55；P<0.001）。低剂量抗体组与安慰剂组的疾病进展时间存在微小差异，接近显著水平（风险比为1.26；P=0.053）。接受高剂量抗体、低剂量抗体和安慰剂治疗的患者在4个月时无进展的概率分别为64%、39%和20%，在8个月时分别为30%、14%和5%。在最后一次分析中，各组之间的总生存率无显著差异（所有比较的P>0.20）。
贝伐单抗可显著延长转移性肾细胞癌患者的疾病进展时间。
