Systematic Review of the Risk of Adverse Outcomes Associated with Vascular Endothelial Growth Factor Inhibitors for the Treatment of Cancer

BackgroundAnti-angiogenic therapy targeted at vascular endothelial growth factor (VEGF) is now used to treat several types of cancer. We did a systematic review of randomized controlled trials (RCTs) to summarize the adverse effects of vascular endothelial growth factor inhibitors (VEGFi), focusing on those with vascular pathogenesis.Methods and FindingsWe searched MEDLINE, EMBASE and Cochrane Library until April 19, 2012 to identify parallel RCTs comparing a VEGFi with a control among adults with any cancer. We pooled the risk of mortality, vascular events (myocardial infarction, stroke, heart failure, and thromboembolism), hypertension and new proteinuria using random-effects models and calculated unadjusted relative risk (RR). We also did meta-regression and assessed publication bias. We retrieved 83 comparisons from 72 studies (n = 38,078) on 11 different VEGFi from 7901 identified citations. The risk of mortality was significantly lower among VEGFi recipients than controls (pooled RR 0.96, 95% confidence interval [CI] 0.94 to 0.98, I2 = 0%, tau2 = 0; risk difference 2%). Compared to controls, VEGFi recipients had significantly higher risk of myocardial infarction (MI) (RR 3.54, 95% CI 1.61 to 7.80, I2 = 0%, tau2 = 0), arterial thrombotic events (RR 1.80, 95% CI 1.24 to 2.59, I2 = 0%, tau2 = 0); hypertension (RR 3.46, 95% CI 2.89 to 4.15, I2 = 58%, tau2 = 0.16), and new proteinuria (RR 2.51, 95% CI 1.60 to 3.94, I2 = 87%, tau2 = 0.65). The absolute risk difference was 0.8% for MI, 1% for arterial thrombotic events, 15% for hypertension and 12% for new proteinuria. Meta-regression did not suggest any statistically significant modifiers of the association between VEGFi treatment and any of the vascular events. Limitations include heterogeneity across the trials.ConclusionsVEGFi increases the risk of MI, hypertension, arterial thromboembolism and proteinuria. The absolute magnitude of the excess risk appears clinically relevant, as the number needed to harm ranges from 7 to 125. These adverse events must be weighed against the lower mortality associated with VEGFi treatment.

以血管内皮生长因子（vascular endothelial growth factor, VEGF）为靶点的抗血管生成疗法目前已应用于多种癌症的临床治疗。本研究针对随机对照试验（randomized controlled trial, RCT）开展系统综述，旨在汇总血管内皮生长因子抑制剂（vascular endothelial growth factor inhibitor, VEGFi）的不良反应，重点关注存在血管病理机制的相关不良事件。
研究方法与结果 本研究检索了MEDLINE、EMBASE及Cochrane图书馆截至2012年4月19日的公开文献，筛选纳入成人各类癌症患者、对比血管内皮生长因子抑制剂与对照治疗方案的平行组随机对照试验。采用随机效应模型合并分析全因死亡风险、血管事件（包括心肌梗死、卒中、心力衰竭及血栓栓塞事件）、高血压及新发蛋白尿的发生风险，并计算未校正相对风险（relative risk, RR）。同时开展Meta回归分析并评估发表偏倚。本研究从7901条初始检索结果中，筛选得到72项符合纳入标准的研究，共包含83个治疗对比组，涉及38078名受试者及11种不同的血管内皮生长因子抑制剂。
结果显示，与对照组相比，接受血管内皮生长因子抑制剂治疗的患者全因死亡风险显著降低（合并相对风险RR=0.96，95%置信区间[CI]：0.94~0.98，I²=0%，tau²=0；风险差为2%）。与对照组相比，血管内皮生长因子抑制剂治疗组患者的心肌梗死（myocardial infarction, MI）风险显著升高（RR=3.54，95%CI：1.61~7.80，I²=0%，tau²=0）、动脉血栓事件风险升高（RR=1.80，95%CI：1.24~2.59，I²=0%，tau²=0）、高血压风险升高（RR=3.46，95%CI：2.89~4.15，I²=58%，tau²=0.16）、新发蛋白尿风险升高（RR=2.51，95%CI：1.60~3.94，I²=87%，tau²=0.65）。上述事件的绝对风险差分别为：心肌梗死0.8%、动脉血栓事件1%、高血压15%、新发蛋白尿12%。Meta回归分析未发现血管内皮生长因子抑制剂治疗与各类血管事件之间的关联存在具有统计学意义的调节因素。本研究的局限性在于各试验间存在研究异质性。
结论 血管内皮生长因子抑制剂会升高心肌梗死、高血压、动脉血栓栓塞及蛋白尿的发生风险。这类额外风险的绝对临床量级具有明确的临床相关性，每例不良事件所需的暴露治疗人数（number needed to harm, NNH）为7~125。临床实践中需权衡此类不良反应与血管内皮生长因子抑制剂治疗带来的死亡风险降低获益。