贝伐珠单抗加化疗可延长转移性宫颈癌患者生存

GOG(妇科肿瘤组)240研究的中期分析结果显示，对于化疗初治的顽固性、复发性或转移性宫颈癌患者，与单纯化疗相比，采用化疗加贝伐珠单抗可使生存期延长约4个月。

基于上述结果，试验数据安全性监测委员会宣布，GOG 240研究(紫杉醇与顺铂或拓扑替康加或不加贝伐珠单抗治疗ⅣB期、复发性或顽固性宫颈癌患者)已达到主要终点——接受含贝伐珠单抗(阿瓦斯汀)方案治疗的患者的总生存期显著延长。截至中期分析时，已有271例患者死亡。

GOG研究负责人、加州大学Irvine医疗中心的Krishnansu S. Tewari博士指出：“这一临床试验结果相当重要，因为它可能会改变临床实践，并且提供了改善复发性宫颈癌患者结局的机会，而以往这类患者的治疗选择非常有限。” 据估计，2013年美国将会有超过1.2万名女性被诊断为宫颈癌，将会有超过4千名女性死于该病。

这项试验旨在回答2个问题：拓扑替康联合紫杉醇是否优于顺铂联合紫杉醇？这两种方案加用贝伐珠单抗是否能进一步改善总生存？研究者从美国和西班牙招募了452例标准治疗无法治愈的晚期、复发性或顽固性宫颈癌。受试者被随机分为4个治疗组：顺铂50 mg/m²+紫杉醇135~175 mg/m²，加或不加贝伐珠单抗15 mg/kg；拓扑替康0.75 mg/m²第1~3天+紫杉醇175 mg/m²第1天，加或不加贝伐珠单抗15 mg/kg。每21天为1个治疗周期，持续治疗至出现疾病进展、无法耐受的毒性或完全应答。共有225例患者接受含贝伐珠单抗方案治疗，其余227例接受标准方案治疗。

2012年开展的一项分析显示，拓扑替康+紫杉醇方案并不优于标准的顺铂+紫杉醇方案。受试者被告知了这一结果。

在最近报告的这次分析中，使用了贝伐珠单抗的患者的死亡率比未使用该药者降低了29%，差异有统计学显著性[危险比(HR)，0.71]。两类患者的中位生存期分别为17个月和13个月，应答率分别为48%和26%。

但使用贝伐珠单抗的患者更易发生3级和4级副作用，包括出血(5% vs. 1%)、血栓形成/栓塞(9% vs. 2%)和胃肠瘘(9% vs. 2%)。

相关评论：确实会改变实践，但毒性仍令人担忧

尽管该研究的数据尚未完全公开，但中期结果已足以改变临床实践。

自从发现顺铂加放疗可改善生存之后，10年来宫颈癌领域一直没有大的进展。而如今我们掌握了不仅能显著改善生存，而且可在临床意义上带来改变的治疗手段。基于该研究的结果，我相信这种治疗方法将成为标准。现有数据已足以支持这一方案的实施。

仔细选择患者将是采用包含贝伐珠单抗方案时至关重要的一环，原因在于有较高比例的患者可能发生严重毒性。我不会对已经存在呼吸问题、血栓或瘘的患者采用这种方案。但对于没有这些问题、功能状态良好的一般患者，我认为收益大于风险。贝伐珠单抗的确增加了延长生存的机会。

不仅如此，本项试验采用了大剂量贝伐珠单抗。在肺癌和卵巢癌中，这一剂量的一半就已被证实有效。我不知道减少剂量是否对这类患者仍然有效，假如仍然有效，减少剂量是否能减轻毒性。我认为这一想法值得一试，因为贝伐珠单抗相当昂贵，用量减半将可节省大笔费用。

评论专家Maurie Markman博士是美国癌症治疗中心肿瘤内科全国主任。他过去曾担任基因泰克的顾问，但目前与该公司无利益关系。他未参加GOG研究。

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By: MICHELE G. SULLIVAN, Oncology Practice

Adding bevacizumab to chemotherapy extended survival by about 4 months beyond the survival achieved with chemotherapy alone in chemotherapy-naïve patients with persistent, recurrent, or metastatic cervical cancer.

The findings seen at the interim analysis of the GOG(Gynecology Oncology Group) 240 study (Paclitaxel and Cisplatin or Topotecan With or Without Bevacizumab for Treating Patients With Stage IV-B, Recurrent, or Persistent Cervical Cancer) prompted the trial’s data safety monitoring committee to announce the study had reached its primary endpoint – a statistically significant increase in overall survival for patients given the regimen that included bevacizumab (Avastin). The interim analysis took place after 271 patients had died.

"The findings in this clinical trial are important because they are likely to change clinical practice and provide an opportunity to improve outcome in patients with recurrent cervical cancer who have previously had very limited treatment options," GOG study chair Dr. Krishnansu S. Tewari and also of University of California, Irvine Medical Center, Orange, said in a statement announcing the trial results.

The trial was designed to answer two questions: Whether topotecan in combination with paclitaxel was superior to cisplatin and paclitaxel in combination, and whether the addition of bevacizumab to either regimen improved overall survival.

The study comprised 452 patients in the United States and Spain with advanced, recurrent, or persistent cervical cancer that was not curable with standard treatment. The trial participants were randomized to four treatment arms: cisplatin 50 mg/m2 plus paclitaxel 135-175 mg/m2, with and without bevacizumab 15 mg/kg; and topotecan 0.75 mg/m2 d1-3 plus paclitaxel 175 mg/ m2 d1, with and without bevacizumab 15 mg/kg. The treatment cycles were repeated every 21 days until there was disease progression, unacceptable toxicity, or a complete response. In all, 225 received the bevacizumab-containing regimens and 227 received the standard regimens.

In an analysis conducted in 2012, it was determined that topotecan plus paclitaxel was not superior to the standard therapy of cisplatin plus paclitaxel and investigators, and patients were notified of the finding.

In the more recent analysis, those who received bevacizumab were 29% less likely to die than were those who did not get the drug – a significant difference (hazard ratio, 0.71). The median survival was 17 months vs. 13 months. The response rates were 48% for the bevacizumab regimens and 26% for the standard regimens.

Patients who received bevacizumab also experienced more grade 3 and 4 side effects, including bleeding (5% vs. 1%), thrombosis/embolism (9% vs. 2%), and gastrointestinal fistula (9% vs. 2%).

More than 12,000 women will be diagnosed with cervical cancer in the United States in 2013 and more than 4,000 women will die of the disease, according to estimates.

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Practice changer, but toxicities a concern

Although the full data have yet to be made public, the interim results alone are enough to change clinical practice.

There have been no real advances in cervical cancer since it was seen that cisplatin with radiation improves survival, and that was more than a decade ago. What we have now is evidence not just of a statistically significant difference in survival, but a clinically meaningful difference as well. Based on these results, I believe that this treatment approach will become the standard of care. These data are adequate for implementing this protocol now.

Careful patient selection will be critical when implementing bevicizumab regimens, as there was a high proportion of potentially serious toxicities. I would not use this regimen for patients who already have breathing problems, blood clots or fistulas. But for the average patient without these issues, who has good functional status, I would think the benefits far outweigh the risks. Bevicizumab does appear to add a very meaningful opportunity to achieve extended survival.

Further, a high dosage of bevacizumab was used in this trial. In lung and ovarian cancer, half this dose has been shown to be effective. I don’t know if cutting the dose would be effective in these patients, or, if it was, if that would reduce some of the toxicity. But I think this option could be explored, as bevicizumab is quite expensive, being able to halve the dose would translate into a real cost savings.

I hope third-party payers will quickly be made aware of these data, and that they will agree to pay for this regimen based on these very important results.

Dr. Maurie Markman is national director of medical oncology at the Cancer Treatment Centers of America. Dr. Markman has, in the past, served on an advisory board for Genentech but is not currently associated with the company. He was not involved with the GOG study.