Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis
Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis
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DOI：
10.1016/s1470-2045(09)70112-3
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发表时间：
2009-06-01
期刊：
影响因子：
51.1
通讯作者：
Wu, Shenhong
中科院分区：
文献类型：
--
作者：
Hapani, Sanjaykumar;Chu, David;Wu, Shenhong
背景 胃肠穿孔是与贝伐单抗相关的严重不良事件，贝伐单抗是当前癌症治疗中广泛使用的血管内皮生长因子 (VEGF) 抑制剂。美国食品和药物管理局发布的黑框警告强调了这种关联，建议胃肠道穿孔患者永久停用贝伐珠单抗。然而，随机对照试验尚未确定贝伐珠单抗与胃肠道穿孔之间存在显着关联。我们对已发表的随机对照试验进行了系统回顾和荟萃分析，以评估与贝伐珠单抗治疗相关的胃肠道穿孔的总体风险。方法我们在 PubMed 和 Web of Science 中检索了 1966 年 1 月至 2008 年 7 月期间发表的文章。此外，还检索了 2000 年 1 月至 2008 年 7 月期间举行的美国临床肿瘤学会会议上发表的摘要，以确定相关的临床试验。符合条件的研究包括前瞻性随机对照试验，其中将贝伐单抗与标准抗肿瘤治疗组合的对照进行比较。根据纳入研究的异质性，使用固定效应或随机效应模型计算总结发病率、相对风险和 95% CI。我们的分析纳入了来自 17 项随机对照试验的 12294 名患有各种实体瘤的患者。接受贝伐珠单抗治疗的患者胃肠道穿孔发生率为0.9%（95% Cl 0.7-1.2），死亡率为21.7%（11.5-37.0）。与接受对照药物治疗的患者相比，接受贝伐单抗治疗的患者胃肠道穿孔的风险显着增加，相对风险为2.14（95% Cl 1.19-3.85；p=0.011）。风险因贝伐单抗剂量和肿瘤类型而异。每周接受 5 mg/kg 和 2.5 mg/kg 贝伐珠单抗治疗的患者的相对风险分别为 2.67 (95% CI 1.14-6.26) 和 1.61 (0.76-3.38)。在结直肠癌（相对风险 3.10，95% CI 1.26-7.63）和肾细胞癌（相对风险 5.67，0.66-48.42）患者中观察到较高的风险。 解释 与对照组相比，在癌症治疗中添加贝伐单抗显着增加了胃肠道穿孔的风险。风险可能因贝伐单抗剂量和肿瘤类型而异。建议进一步研究贝伐珠单抗在选定的胃肠道穿孔康复患者中的使用情况。
Background Gastrointestinal perforation is a serious adverse event associated with bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF) widely used in current cancer treatment. The association is highlighted by a black-box warning issued by the US Food and Drug Administration, recommending that bevacizumab be permanently discontinued in patients with gastrointestinal perforation. However, no significant association has yet been established between bevacizumab and gastrointestinal perforation in randomised controlled trials. We did a systematic review and meta-analysis of published randomised controlled trials to assess the overall risk of gastrointestinal perforation associated with bevacizumab treatment.Methods We searched PubMed and Web of Science for articles published between January, 1966, and July, 2008. Additionally, abstracts presented at American Society of Clinical Oncology conferences held between January, 2000, and July, 2008, were searched to identify relevant clinical trials. Eligible studies included prospective randomised controlled trials in which bevacizumab was compared with controls in combination with standard anti-neoplastic therapy. Summary incidence rates, relative risks, and 95% CIs were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies.Findings 12294 patients with a variety of solid tumours from 17 randomised controlled trials were included in our analysis. The incidence of gastrointestinal perforation was 0.9% (95% Cl 0.7-1.2) among patients receiving bevacizumab, with a mortality of 21.7% (11.5-37.0). Patients treated with bevacizumab had a significantly increased risk of gastrointestinal perforation compared with patients treated with control medication, with a relative risk of 2.14 (95% Cl 1.19-3.85; p=0.011). Risk varied with bevacizumab dose and tumour type. Relative risks for patients receiving bevacizumab at 5 and 2.5 mg/kg per week were 2.67 (95% CI 1.14-6.26) and 1.61 (0.76-3.38), respectively. Higher risks were observed in patients with colorectal carcinoma (relative risk 3.10, 95% CI 1.26-7.63) and renal cell cancer (relative risk 5.67, 0.66-48.42).Interpretation The addition of bevacizumab to cancer therapy significantly increased the risk of gastrointestinal perforation compared with controls. The risk may vary with bevacizumab dose and tumour type. Further studies are recommended to investigate the use of bevacizumab in selected patients who have recovered from gastrointestinal perforation.