Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial.
Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial.
复制标题
在一线上皮性卵巢癌、输卵管癌或原发性腹膜癌治疗（ICON8）中，每周剂量密集化疗：一项开放标签、随机、对照的3期试验的总生存期结果。
DOI：
10.1016/s1470-2045(22)00283-2
复制
发表时间：
2022-07
期刊：
影响因子：
51.1
通讯作者：
Ledermann, Jonathan A.
中科院分区：
文献类型：
--
作者：
Clamp, Andrew R.;James, Elizabeth C.;McNeish, Iain A.;Dean, Andrew;Kim, Jae-Won;O'Donnell, Dearbhaile M.;Gallardo-Rincon, Dolores;Blagden, Sarah;Brenton, James;Perren, Tim J.;Sundar, Sudha;Lord, Rosemary;Dark, Graham;Hall, Marcia;Banerjee, Susana;Glasspool, Rosalind M.;Hanna, C. Louise;Williams, Sarah;Scatchard, Kate M.;Nam, Helena;Essapen, Sharadah;Parkinson, Christine;McAvan, Lucy;Swart, Ann Marie;Popoola, Babasola;Schiavone, Francesca;Badrock, Jonathan;Fananapazir, Fuad;Cook, Adrian D.;Parmar, Mahesh;Kaplan, Richard;Ledermann, Jonathan A.
卵巢上皮癌的标准一线化疗是卡铂和紫杉醇，每3周一次。JGOG 3016试验报告了剂量密集的每周一次紫杉醇和3周一次（即每3周一次）卡铂的无进展生存期和总生存期显著改善。然而，在先前报告的ICON 8的无进展生存期结果中未观察到这种获益。在这里，我们介绍了ICON 8的总生存期和更新的无进展生存期分析的最终共同主要结局。在这项开放标签、随机、对照、III期试验（ICON 8）中，年龄≥ 18岁的新诊断为IC-IV期上皮性卵巢癌、原发性腹膜癌或输卵管癌的女性（这里统称为卵巢癌，根据国际妇产科联合会[FIGO] 1988标准定义），东部肿瘤协作组体能状态为0- 2名患者来自英国、澳大利亚和新西兰、墨西哥、韩国和爱尔兰的117家设有肿瘤科的医院。患者可以在立即初次手术（IPS）后或计划在化疗期间延迟初次手术（DPS）后进入试验，也可以没有计划的手术。使用伦敦大学学院医学研究理事会临床试验单位的随机化线，按照妇科癌症组间组、FIGO疾病分期、手术结局和时间进行分层，将参与者随机分配（1：1：1）至3周一次的卡铂曲线下面积（AUC）5或AUC 6和3周一次的紫杉醇175 mg/m2（对照组;第1组），卡铂AUC 5或AUC 6每周3次和紫杉醇80 mg/m2每周1次（第2组），或卡铂AUC 2每周1次和紫杉醇80 mg/m2每周1次（第3组），全部通过静脉输注给药，共6个21天的周期。共同主要结局为无进展生存期和总生存期，并在意向治疗人群中对第2组和第1组以及第3组和第1组进行比较。在所有开始至少一个化疗周期的患者中评估安全性。该试验在ClinicalTrials.gov（NCT 01654146）和ISRCTN注册中心（ISRCTN 10356387）注册，并已停止累积。在2011年6月6日至2014年11月28日期间，1566例患者被随机分配至第1组（n=522）、第2组（n=523）或第3组（n=521）。中位年龄为62岁（IQR 54-68），1566例患者中有1073例（69%）患有高级别浆液性癌，1119例（71%）患有IIIC-IV期疾病，745例（48%）患有IPS。截至数据截止（2020年3月31日），中位随访69个月（IQR 61-75），在两种比较中均未观察到总生存期的显著差异：中位总生存期为47·4个月（95% CI 43.1 - 54.8）组1，54.8个月第2组46·6-61·6个月，（49.2 - 59.6）（第2组vs第1组：风险比0.87 [97.5%CI 0.73 - 1.05];第3组vs第1组：0.91 [0.76 - 1.09]）。两组比较无进展生存期无显著差异，存在非比例风险（p= 0.037），平均生存期为23.9个月（97.5% CI 22.1 - 25.6），第2组为25.3个月（23.6 - 27.1），第3组为24.8个月（23.0 - 26.5）。最常见的3-4级不良事件是中性粒细胞计数减少（第1组511例患者中有78例[15%]，第2组514例患者中有183例[36%]，第3组513例患者中有154例[30%]），白色血细胞计数降低（第1组22例[4%]，第2组80例[16%]，第3组71例[14%]）和贫血（第1组26例[5%]，第2组66例[13%]，第3组24例[5%]）。没有报告新的严重不良事件。报告了7例治疗相关死亡（第1组2例，第2组4例，第3组1例）。在我们的队列中，主要是欧洲女性上皮性卵巢癌患者，我们发现，与标准的3周化疗相比，一线每周剂量密集化疗并不能改善总生存期或无进展生存期，不应作为该患者组标准多模式一线治疗的一部分。英国癌症研究中心、医学研究理事会、爱尔兰健康研究委员会、爱尔兰癌症协会和澳大利亚癌症协会。
Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly (ie, once every 3 weeks) carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8. Here, we present the final coprimary outcomes of overall survival and updated progression-free survival analyses of ICON8. In this open-label, randomised, controlled, phase 3 trial (ICON8), women aged 18 years or older with newly diagnosed stage IC–IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (here collectively termed ovarian cancer, as defined by International Federation of Gynecology and Obstetrics [FIGO] 1988 criteria) and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited from 117 hospitals with oncology departments in the UK, Australia and New Zealand, Mexico, South Korea, and Ireland. Patients could enter the trial after immediate primary surgery (IPS) or with planned delayed primary surgery (DPS) during chemotherapy, or could have no planned surgery. Participants were randomly assigned (1:1:1), using the Medical Research Council Clinical Trials Unit at University College London randomisation line with stratification by Gynecologic Cancer Intergroup group, FIGO disease stage, and outcome and timing of surgery, to either 3-weekly carboplatin area under the curve (AUC)5 or AUC6 and 3-weekly paclitaxel 175 mg/m2 (control; group 1), 3-weekly carboplatin AUC5 or AUC6 and weekly paclitaxel 80 mg/m2 (group 2), or weekly carboplatin AUC2 and weekly paclitaxel 80 mg/m2 (group 3), all administered via intravenous infusion for a total of six 21-day cycles. Coprimary outcomes were progression-free survival and overall survival, with comparisons done between group 2 and group 1, and group 3 and group 1, in the intention-to-treat population. Safety was assessed in all patients who started at least one chemotherapy cycle. The trial is registered on ClinicalTrials.gov, NCT01654146, and ISRCTN registry, ISRCTN10356387, and is closed to accrual. Between June 6, 2011, and Nov 28, 2014, 1566 patients were randomly assigned to group 1 (n=522), group 2 (n=523), or group 3 (n=521). The median age was 62 years (IQR 54–68), 1073 (69%) of 1566 patients had high-grade serous carcinoma, 1119 (71%) had stage IIIC–IV disease, and 745 (48%) had IPS. As of data cutoff (March 31, 2020), with a median follow-up of 69 months (IQR 61–75), no significant difference in overall survival was observed in either comparison: median overall survival of 47·4 months (95% CI 43·1–54·8) in group 1, 54·8 months (46·6–61·6) in group 2, and 53·4 months (49·2–59·6) in group 3 (group 2 vs group 1: hazard ratio 0·87 [97·5% CI 0·73–1·05]; group 3 vs group 1: 0·91 [0·76–1·09]). No significant difference was observed for progression-free survival in either comparison and evidence of non-proportional hazards was seen (p=0·037), with restricted mean survival time of 23·9 months (97·5% CI 22·1–25·6) in group 1, 25·3 months (23·6–27·1) in group 2, and 24·8 months (23·0–26·5) in group 3. The most common grade 3–4 adverse events were reduced neutrophil count (78 [15%] of 511 patients in group 1, 183 [36%] of 514 in group 2, and 154 [30%] of 513 in group 3), reduced white blood cell count (22 [4%] in group 1, 80 [16%] in group 2, and 71 [14%] in group 3), and anaemia (26 [5%] in group 1, 66 [13%] in group 2, and 24 [5%] in group 3). No new serious adverse events were reported. Seven treatment-related deaths were reported (two in group 1, four in group 2, and one in group 3). In our cohort of predominantly European women with epithelial ovarian cancer, we found that first-line weekly dose-dense chemotherapy did not improve overall or progression-free survival compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality front-line therapy in this patient group. Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.