Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial
Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial
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DOI：
10.1016/s0140-6736(19)32259-7
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发表时间：
2019-12-07
期刊：
影响因子：
168.9
通讯作者：
Ledermann, Jonathan A.
中科院分区：
文献类型：
--
作者：
Clamp, Andrew R.;James, Elizabeth C.;Ledermann, Jonathan A.
背景卡铂和紫杉醇每3周给药一次是上皮性卵巢癌的标准一线化疗。日本JGOG 3016试验显示，剂量密集的每周紫杉醇和每周3次卡铂治疗可显著改善无进展生存期和总生存期。在这项研究中，我们的目的是比较两种剂量密集的每周方案的有效性和安全性，以标准的3周化疗，主要是欧洲人口与上皮性卵巢癌。将新诊断的国际妇产科联盟IC-IV期上皮性卵巢癌妇女随机分配到第1组（卡铂AUC 5或AUC 6和175 mg/m2紫杉醇每3周一次）、第2组（卡铂AUC 5或AUC 6每3周一次和80 mg/m2紫杉醇每周一次）或第3组（卡铂AUC 2和80 mg/m2紫杉醇每周一次）。进入试验的所有女性均提供了书面知情同意书。该方案已获得研究所在国家的相应国家研究伦理委员会批准。患者在直接初次手术后或在新辅助化疗和随后计划的延迟初次手术前进入试验。试验的共同主要结局是无进展生存期和总生存期。数据分析是在意向性治疗的基础上进行的，并有把握度检测无进展生存期的风险比为0.75。主要比较是对照组（第1组）和每周一次的研究组（第2组和第3组）之间的比较。第1组中72%（365）、第2组中60%（305）和第3组中63%（322）完成了6个方案定义的治疗周期，尽管分别有90%（454）、89%（454）和85%（437）完成了6个含铂化疗周期。通过每周一次治疗实现紫杉醇剂量强化（第1组中位紫杉醇总剂量为1010 mg/m2;第2组为1233 mg/m2;第3组为1274 mg/m2）。截至2017年2月，1018例（65%）患者发生疾病进展。两种每周方案均未观察到无进展生存期显著延长（限制平均生存期：第1组24.4个月[97.5%CI 23.0-26.0]，第2组24.9个月[24.0-25.9]，第3组25.3个月[23.9-26.9];第1组的中位无进展生存期为17.7个月[IQR 10.6-未达到]，第2组为20.8个月[11.9-59.0]，第3组为21.0个月[12.0-54.0];第2组vs第1组的对数秩p=0.35;第3组与第1组p=0.51）。虽然3级或4级毒性反应随着每周治疗而增加，但这些反应主要是不复杂的。发热性中性粒细胞减少症和感觉神经病变的发病率是相似的groups.Interpretation每周剂量密集化疗可以成功地交付作为一线治疗上皮性卵巢癌，但并没有显着提高无进展生存率相比，标准的3周化疗，主要是欧洲人口。版权所有（C）2019作者。由爱思唯尔有限公司出版。这是一篇开放获取文章，使用CC BY-NC-ND 4.0许可证。
Background Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer.Methods In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m(2) paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m(2) paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m(2) paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0 .75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3).Findings Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m(2) in group 1; 1233 mg/m(2) in group 2; 1274 mg/m(2) in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24.4 months [97.5% CI 23.0-26.0] in group 1, 24.9 months [24.0-25.9] in group 2, 25.3 months [23.9-26.9] in group 3; median progression-free survival 17.7 months [IQR 10.6-not reached] in group 1, 20.8 months [11.9-59.0] in group 2, 21.0 months [12.0-54.0] in group 3; log-rank p=0.35 for group 2 vs group 1; group 3 vs 1 p=0.51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups.Interpretation Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.