Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial.
Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial.
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DOI：
10.1016/s1470-2045(15)00086-8
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发表时间：
2015-08
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通讯作者：
ICON7 trial investigators
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作者：
Oza AM;Cook AD;Pfisterer J;Embleton A;Ledermann JA;Pujade-Lauraine E;Kristensen G;Carey MS;Beale P;Cervantes A;Park-Simon TW;Rustin G;Joly F;Mirza MR;Plante M;Quinn M;Poveda A;Jayson GC;Stark D;Swart AM;Farrelly L;Kaplan R;Parmar MK;Perren TJ;ICON7 trial investigators
ICON 7试验先前报道，在标准化疗中加入贝伐单抗可改善卵巢癌女性的无进展生存期，对疾病进展高风险患者的影响最大。我们报告了试验的最终总生存率结果。ICON 7是一项在欧洲、加拿大、澳大利亚和新西兰11个国家的263个中心进行的国际、III期、开放标签、随机试验。符合条件的新诊断为卵巢癌的成年女性，（国际妇产科联合会[FIGO] I-IIa期，3级或透明细胞组织学）或更晚期疾病（FIGO IIb-IV期），东部肿瘤协作组体能状态评分为0-2，入选并随机分配至1：与标准化疗的比值1（6个3周周期的静脉内卡铂[AUC 5或6]和紫杉醇175 mg/m2体表面积）或相同的化疗方案加贝伐单抗7·5 mg/kg体重静脉给药，每3周一次，同时给药，并继续进行最多12个3周一次的维持治疗周期。采用最小化算法，按照FIGO分期、残留疾病、手术和化疗之间的间隔以及妇科癌症组间分组进行随机化。主要终点是无进展生存期;该研究还具有检测总生存期差异的能力。该试验已注册为国际标准随机对照试验，编号ISRCTN 91273375。在2006年12月18日至2009年2月16日期间，1528名妇女入选并随机分配接受化疗（n=764）或化疗加贝伐单抗（n=764）。2013年3月31日试验结束时的中位随访时间为48.9个月（IQR 26.6 - 56.2），此时有714例患者死亡（化疗组352例，贝伐单抗组362例）。我们的研究结果显示了非比例风险的证据，因此我们使用限制平均生存时间的差异作为效应的主要估计。没有记录到贝伐单抗的总生存期获益（标准化疗组的限制平均生存期为44.6个月[95% CI 43.2 - 45.9]，贝伐单抗组为45.5个月[44.2 - 46.7];对数秩p= 0.85）。在一项对502例预后不良的预先确定的亚组患者进行的探索性分析中，332例（66（标准化疗组174例，贝伐单抗组158例），在接受贝伐单抗联合化疗的妇女和仅接受化疗的妇女之间，总生存率有显著差异（标准化疗组的限制性平均生存时间为34.5个月[95% CI 32.0 - 37.0]，贝伐单抗组为39.3个月[37.0 - 41.7];对数秩p= 0.03）。然而，在非高危患者中，两个治疗组之间的限制性平均生存时间无显著差异（标准化疗组为49·7个月[95% CI 48·3-51·1]，贝伐珠单抗组为48·4个月[47·0-49·9]; p=0·20）。无进展生存期的最新分析显示治疗组间无差异。在扩展随访期间，报告了1起3级治疗相关事件（贝伐珠单抗治疗患者的胃肠道瘘）、3起2级治疗相关事件（心力衰竭、结节病和足部骨折，均发生在贝伐珠单抗治疗患者中）和1起1级治疗相关事件（阴道出血，发生在接受标准化疗的患者中）。贝伐珠单抗加用铂类药物化疗并没有增加研究人群的总体生存率。然而，在预后不良的患者中记录了总生存期获益，这与ICON 7和GOG-218的无进展生存期结果一致，并为贝伐珠单抗在卵巢癌治疗中的最佳使用提供了进一步的证据。国家健康研究所通过英国国家癌症研究网络、医学研究理事会和罗氏。
The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to standard chemotherapy, with the greatest effect in patients at high risk of disease progression. We report the final overall survival results of the trial. ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I–IIa, grade 3 or clear cell histology) or more advanced disease (FIGO stage IIb–IV), with an Eastern Cooperative Oncology Group performance status of 0–2, were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of intravenous carboplatin [AUC 5 or 6] and paclitaxel 175 mg/m2 of body surface area) or the same chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks, given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary endpoint was progression-free survival; the study was also powered to detect a difference in overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375. Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the end of the trial on March 31, 2013, was 48·9 months (IQR 26·6–56·2), at which point 714 patients had died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed evidence of non-proportional hazards, so we used the difference in restricted mean survival time as the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted mean survival time 44·6 months [95% CI 43·2–45·9] in the standard chemotherapy group vs 45·5 months [44·2–46·7] in the bevacizumab group; log-rank p=0·85). In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone (restricted mean survival time 34·5 months [95% CI 32·0–37·0] with standard chemotherapy vs 39·3 months [37·0–41·7] with bevacizumab; log-rank p=0·03). However, in non-high-risk patients, the restricted mean survival time did not differ significantly between the two treatment groups (49·7 months [95% CI 48·3–51·1]) in the standard chemotherapy group vs 48·4 months [47·0–49·9] in the bevacizumab group; p=0·20). An updated analysis of progression-free survival showed no difference between treatment groups. During extended follow-up, one further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with standard chemotherapy) were reported. Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer. The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche.