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Adding bevacizumab to chemo prolongs life in advanced cervical cancer 晚期宫颈癌:化疗+贝伐珠单抗可延长生存  

2013-07-24 08:01:48|  分类: |  标签: |举报 |字号 订阅

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By: SUSAN LONDON, Oncology Practice

CHICAGO – Adding the antiangiogenic agent bevacizumab to chemotherapy improves overall survival in women who have advanced cervical cancer, according to findings of a randomized phase III trial of the Gynecologic Oncology Group.

In the trial – Gynecologic Oncology Group (GOG) protocol 240 – women who received bevacizumab (Avastin) in addition to chemotherapy lived about 4 months longer than their counterparts who received chemotherapy alone, lead investigator Dr. Krishnansu S. Tewari reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

The adverse effects seen were largely consistent with previous experience in other cancers with bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor.

"This study met its primary endpoint," said Dr. Tewari, a professor of obstetrics and gynecology at the University of California, Irvine. "Bevacizumab is the first molecularly targeted agent to improve overall survival in a gynecologic cancer."

"Moving forward, the incorporation of anti-VEGF therapy into primary treatment for locally advanced disease should be considered ..." he said. Also, "these data open up doors to study other classes of antiangiogenesis agents – both VEGF-dependent molecules as well as non–VEGF-dependent molecules."

Invited discussant Dr. Gottfried E. Konecny of the University of California, Los Angeles, commented, "Progression-free and overall survival improvements through bevacizumab in advanced cervical cancer as shown in the GOG 240 study are clinically meaningful. Adverse events and toxicities are manageable and, I believe, class specific."

In his opinion, as only about a fifth of the patients had metastatic disease, it is uncertain whether the drug benefits that population. And the data suggest bevacizumab may have less benefit in patients with adenocarcinoma tumors as compared with squamous tumors.

For future research, "most important is the identification and validation of response predictors," according to Dr. Konecny.

"Extending the global reach of antiangiogenic therapies for advanced cervical cancer is critical," he concluded, noting that the countries with highest incidence and mortality rates for this disease also have the lowest annual health care spending. "I think GOG 240 can be seen as a practice-changing study. But we urgently need to develop antiangiogenic treatment strategies that will benefit the global population."

The trial was open to women who had chemotherapy-naive, recurrent, persistent, or metastatic cervical cancer. They were randomized in dual factorial design according to chemotherapy doublet (cisplatin plus paclitaxel vs. topotecan plus paclitaxel) and receipt of bevacizumab (yes vs. no), which was provided by Roche/Genentech, manufacturer of the recombinant monoclonal antibody. Treatment was on an open-label basis, and crossover was not allowed.

Bevacizumab is approved by the Food and Drug Administration for selected indications in colorectal, renal, and lung cancer, and in glioblastoma.

An interim analysis concluded that the topotecan-paclitaxel regimen was not superior (or inferior) to the cisplatin-paclitaxel regimen that has been the standard in this setting, Dr. Tewari reported.

With longer follow-up, to a median of 20.8 months, women who received added bevacizumab had a longer median overall survival than did their counterparts who received chemotherapy alone (17.0 vs. 13.3 months; hazard ratio, 0.71; P = .0035).

Bevacizumab conferred a significant survival benefit when added to cisplatin-paclitaxel chemotherapy (HR, 0.68; P = .03) but not when added to topotecan-paclitaxel chemotherapy (HR, 0.74; P = .09).

"The effect of bevacizumab was sustained with multiple prognostic factors, including when the disease was in the previously irradiated pelvis," Dr. Tewari noted when reporting subgroup analyses.

Women who received added bevacizumab also had a longer median progression-free survival (8.2 vs. 5.9 months; HR, 0.67; P = .0002) and a higher response rate (48% vs. 36%, P = .008).

Adding bevacizumab led to significantly higher rates of grade 3/4 gastrointestinal fistula (3% vs. 0%), genitourinary fistula (2% vs. 0%), and thromboembolism (8% vs. 1%); grade 2 or higher hypertension (25% vs. 2%); and grade 4 or higher neutropenia (35% vs. 26%).

"We saw no new adverse events in this patient population, which includes patients who had been heavily irradiated," Dr. Tewari commented. There were four deaths each in the groups treated with and without bevacizumab.

Addition of bevacizumab did not compromise health-related quality of life as assessed with the FACT(Functional Assessment of Cancer Therapy) – Cervical Cancer Trial Outcome Index.

Dr. Tewari disclosed no relevant conflicts of interest. Dr. Konecny disclosed that he receives honoraria from Genentech and Sanofi, and research funding from Amgen and Pfizer.


芝加哥—— 美国妇科肿瘤学组(GOG)开展的一项Ⅲ期随机试验表明,在化疗的基础上加用贝伐珠单抗能改善晚期宫颈癌患者的总生存期。

作为这项试验(GOG试验方案编号240)的主要研究者,美国加州大学欧文分校的妇产科教授Krishnansu S. Tewari博士在美国临床肿瘤学会(ASCO)2013年会的全体会议上报告了试验结果。与仅接受化疗的患者相比,接受化疗加血管内皮生长因子(VEGF)抑制剂贝伐珠单抗(阿瓦斯汀)联合治疗者的总生存期延长了大约4个月。试验中观察到的不良反应与贝伐珠单抗用于其他类型癌症的既往经验大体一致。

这是一项在从未接受过化疗的复发性、持续性或转移性宫颈癌患者中开展的开放性试验。该试验采用的是双因子设计,根据二联化疗方案(顺铂加紫杉醇vs. 拓扑替康加紫杉醇)以及是否使用贝伐珠单抗(是vs.否)进行随机分组。试验所用贝伐珠单抗由其生产商罗氏/基因泰克公司提供。治疗过程中不允许交叉。



当中位随访期达到20.8个月时,与只接受化疗的患者相比,加用贝伐珠单抗者的中位总生存期显著延长(17.0 vs. 13.3 个月;危险比[HR],0.71;P=0.0035)。在顺铂加紫杉醇化疗的基础上加用贝伐珠单抗可以获得显著的生存效益(HR,0.68;P=0.03),但是在拓扑替康加紫杉醇化疗的基础上加用贝伐珠单抗获得的生存效益无统计学意义(HR,0.74;P=0.09)。


此外,加用了贝伐珠单抗的患者的中位无进展生存期也显著延长(8.2 vs. 5.9个月;HR,0.67;P=0.0002),应答率也更高(48% vs. 36%,P=0.008)。

安全性方面,加用贝伐珠单抗使得以下不良事件的发生率显著增加:3/4级消化道瘘(3% vs. 0%)、泌尿生殖道瘘(2% vs. 0%)和血栓栓塞(8% vs. 1%);≥2级高血压(25% vs. 2%),以及≥4级中性粒细胞减少(35% vs. 26%)。




特邀评论员、美国加州大学洛杉矶分校的Gottfried E. Konecny 博士评价道:“GOG 240试验表明,贝伐珠单抗能改善晚期宫颈癌患者的无进展生存期和总生存期,这是很有临床价值的。不良事件和毒性也都在可控范围内,在我看来都属于这类药物的常见反应。”

Konecny 博士认为,鉴于只有大约1/5的宫颈癌患者存在转移性疾病,因此尚不能确定贝伐珠单抗是否对于整个宫颈癌患者人群都有益。而且研究数据显示,与鳞状细胞癌相比,贝伐珠单抗用于腺癌肿瘤的效果可能要差一些。就未来研究而言,“最重要的是发现并验证治疗应答的预测因子。”

Konecny 博士总结道:“非常有必要扩大抗血管生成药物在全球晚期宫颈癌患者中的使用范围。”他指出,宫颈癌发病率和死亡率最高的国家每年的医疗卫生支出却最低。“我认为GOG 240可以看作是一项改变临床实践的重要研究。我们现在亟需制定出抗血管生成药物的治疗策略以惠及全球患者。”


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