Phase III Trial Assessing Bevacizumab in Stages II and III Carcinoma of the Colon: Results of NSABP Protocol C-08
Phase III Trial Assessing Bevacizumab in Stages II and III Carcinoma of the Colon: Results of NSABP Protocol C-08
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DOI：
10.1200/jco.2010.30.0855
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发表时间：
2011-01-01
影响因子：
45.3
通讯作者：
Wolmark, Norman
中科院分区：
文献类型：
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作者：
Allegra, Carmen J.;Yothers, Greg;Wolmark, Norman
目的：国家乳腺和肠道手术辅助治疗计划C-08试验旨在研究贝伐单抗加用改良FOLFOX 6的安全性和有效性（mFOLFOX 6;即输注/推注氟尿嘧啶，亚叶酸，方法患者接受mFOLFOX 6每2周一次，持续26周，单独或修改为FOLFOX 6+贝伐单抗（5 mg/kg，每2周一次，持续52周[即实验组]）。主要终点是无病生存期（DFS）。结果在2,672例分析患者中，人口统计学因素在治疗中得到了很好的平衡。中位随访时间为35.6个月，在mFOLFOX 6中添加贝伐珠单抗并未导致DFS总体显著增加（风险比[HR]，0.89; 95% CI，0.76 - 1.04; P= 0.15）。试验组和对照组总体人群3年DFS的点估计值分别为77.4%和75.5%。对于II期和III期疾病患者，这些相同的估计值分别为87.4%和84.7%，II期和74.2%和72.4%，分别为III期。探索性分析发现，贝伐珠单抗对DFS的影响在15个月里程碑之前和之后是不同的（时间-治疗相互作用P值< .0001）。贝伐单抗在界标前有很强的效果（HR，0.61; 95%CI，0.48至0.78; P <0.001），但界标后无显著效果（HR，1.22; 95%CI，0.98至1.52; P = 0.076）。然而，在实验组中观察到贝伐单抗暴露期间的显著但短暂的效应，我们假设这一观察结果反映了贝伐单抗暴露期间的生物学效应。由于DFS缺乏改善，因此不建议将贝伐珠单抗用于结肠癌患者的辅助治疗。
PurposeThe National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and efficacy of adding bevacizumab to modified FOLFOX6 (mFOLFOX6; ie, infusional/bolus fluorouracil, leucovorin, and oxaliplatin) for the adjuvant treatment of patients with stages II to III colon cancer.MethodsPatients received mFOLFOX6 every 2 weeks for 26 weeks alone or modified as FOLFOX6 + bevacizumab (5 mg/kg every 2 weeks for 52 weeks [ie, experimental group]). The primary end point was disease-free survival (DFS).ResultsAmong 2,672 analyzed patients, demographic factors were well balanced by treatment. With a median follow-up of 35.6 months, the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS (hazard ratio [HR], 0.89; 95% CI, 0.76 to 1.04; P= .15). The point estimates for 3-year DFS for the overall population were 77.4% and 75.5% for the experimental and control arms, respectively. For patients with stages II and III diseases, these same estimates were 87.4% and 84.7%, respectively, for stage II and 74.2% and 72.4%, respectively, for stage III. Exploratory analyses found that the effect of bevacizumab on DFS was different before and after a 15-month landmark (time-by-treatment interaction P value < .0001). Bevacizumab had a strong effect before the landmark (HR, 0.61; 95% CI, 0.48 to 0.78; P < .001) but no significant effect after (HR, 1.22; 95% CI, 0.98 to 1.52; P = .076).ConclusionBevacizumab for 1 year with mFOLFOX6 does not significantly prolong DFS in stages II and III colon cancer. However, a significant but transient effect during bevacizumab exposure was observed in the experimental arm. We postulate that this observation reflects a biologic effect during bevacizumab exposure. Given the lack of improvement in DFS, the use of bevacizumab cannot be recommended for use in the adjuvant treatment of patients with colon cancer.