Improved survival with bevacizumab in advanced cervical cancer.
Improved survival with bevacizumab in advanced cervical cancer.
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DOI：
10.1056/nejmoa1309748
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发表时间：
2014-02-20
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影响因子：
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通讯作者：
Monk BJ
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作者：
Tewari KS;Sill MW;Long HJ 3rd;Penson RT;Huang H;Ramondetta LM;Landrum LM;Oaknin A;Reid TJ;Leitao MM;Michael HE;Monk BJ
血管内皮生长因子（VEGF）促进血管生成，是宫颈癌疾病进展的中介。贝伐单抗是一种人源化抗vegf单克隆抗体，在既往治疗的复发性疾病中具有单药活性。大多数复发性宫颈癌患者以前接受过顺铂放射治疗，这降低了复发时顺铂的有效性。我们评估了贝伐单抗和非铂联合化疗在复发性、持续性或转移性宫颈癌患者中的有效性。采用2 × 2因子设计，我们随机分配了452例患者，以每公斤体重15 mg的剂量接受贝伐单抗治疗或不接受化疗。化疗包括顺铂的剂量为每平方米体表面积50毫克，加上紫杉醇的剂量为每平方米135或175毫克，或拓扑替康的剂量为每平方米0.75毫克，在第1天至第3天加上紫杉醇的剂量为每平方米175毫克。每21天重复一个周期，直到疾病进展、出现不可接受的毒性作用或完全缓解。主要终点为总生存期；死亡风险比降低30%被认为具有重要的临床意义。各组在年龄、组织学表现、运动状态、以前使用或未使用放射线致敏铂剂以及疾病状况方面平衡良好。拓扑替康-紫杉醇并不优于顺铂-紫杉醇（死亡风险比为1.20）。结合两种化疗方案的数据，贝伐单抗加入化疗与总生存期增加（17.0个月vs 13.3个月；死亡风险比为0.71；98%可信区间为0.54 ~ 0.95；单侧检验P = 0.004）和更高的缓解率（48% vs 36%, P = 0.008）相关。与单独化疗相比，贝伐单抗与2级或以上高血压（25% vs. 2%）、3级或以上血栓栓塞事件（8% vs. 1%）和3级或以上胃肠道瘘（3% vs. 0%）的发生率增加相关。复发性、持续性或转移性宫颈癌患者在联合化疗中加入贝伐单抗可使中位总生存期延长3.7个月。（由美国国家癌症研究所资助；gog240 ClinicalTrials.gov编号，NCT00803062。）
Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan–paclitaxel was not superior to cisplatin–paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P = 0.004 in a one-sided test) and higher response rates (48% vs. 36%, P = 0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.)