系统评价招募难治性和复发性尤文肉瘤的 I/II 期试验：实际知识和未来方向以优化研究。
Systematic review of phase-I/II trials enrolling refractory and recurrent Ewing sarcoma: Actual knowledge and future directions to optimize the research.
机构信息
Department of Oncology for Child and Adolescent, Gustave Roussy Cancer Campus, Villejuif cedex, France.
Medical Oncology Department, Institut Bergonié, Bordeaux, France.
出版信息
Cancer Med. 2021 Mar;10(5):1589-1604. doi: 10.1002/cam4.3712. Epub 2021 Jan 15.
BACKGROUND
Optimal Phase-II design to evaluate new therapies in refractory/relapsed Ewing sarcomas (ES) remains imperfectly defined.
OBJECTIVES
Recurrent/refractory ES phase-I/II trials analysis to improve trials design.
METHODS
Comprehensive review of therapeutic trials registered on five databases (who.int/trialsearch, clinicaltrials.gov, clinicaltrialsregister.eu, e-cancer.fr, and umin.ac.jp) and/or published in PubMed/ASCO/ESMO websites, between 2005 and 2018, using the criterion: (Ewing sarcoma OR bone sarcoma OR sarcoma) AND (Phase-I or Phase-II).
RESULTS
The 146 trials identified (77 phase-I/II, 67 phase-II, and 2 phase-II/III) tested targeted (34%), chemo- (23%), immune therapies (19%), or combined therapies (24%). Twenty-three trials were ES specific and 48 had a specific ES stratum. Usually multicentric (88%), few trials were international (30%). Inclusion criteria cover the recurrent ES age range for only 12% of trials and allowed only accrual of measurable diseases (RECIST criteria). Single-arm design was the most frequent (88%) testing mainly single drugs (61%), only 5% were randomized. Primary efficacy outcome was response rate (RR=CR+PR; Complete+Partial response) (n = 116/146; 79%), rarely progression-free or overall survival (16% PFS and 3% OS). H0 and H1 hypotheses were variable (3%-25% and 20%-50%, respectively). The 62 published trials enrolled 827 ES patients. RR was poor (10%; 15 CR=1.7%, 68 PR=8.3%). Stable disease was the best response for 186 patients (25%). Median PFS/OS was of 1.9 (range 1.3-14.7) and 7.6 months (5-30), respectively. Eleven (18%) published trials were considered positive, with median RR/PFS/OS of 15% (7%-30%), 4.5 (1.3-10), and 16.6 months (6.9-30), respectively.
CONCLUSION
This review supports the need to develop the international randomized phase-II trials across all age ranges with PFS as primary endpoint.
背景
优化评估难治/复发性尤因肉瘤（ES）新疗法的 II 期设计仍不完善。
目的
分析复发/难治性 ES I/II 期试验以改进试验设计。
方法
综合评估了 2005 年至 2018 年间在五个数据库（who.int/trialsearch、clinicaltrials.gov、clinicaltrialsregister.eu、e-cancer.fr 和 umin.ac.jp）或 PubMed/ASCO/ESMO 网站上注册或发表的治疗试验，其纳入标准为：（尤文肉瘤或骨肉瘤或肉瘤）AND（I 期或 II 期）。
结果
共确定了 146 项试验（77 项 I/II 期、67 项 II 期和 2 项 II/III 期），这些试验分别测试了靶向治疗（34%）、化疗（23%）、免疫治疗（19%）或联合治疗（24%）。其中 23 项试验为 ES 特异性，48 项试验具有特定的 ES 分层。这些试验通常为多中心（88%），仅有 30%为国际试验。纳入标准仅涵盖 12%的试验中复发性 ES 的年龄范围，且仅允许测量可测量的疾病（RECIST 标准）。单臂设计是最常见的设计（88%），主要测试单一药物（61%），仅有 5%为随机设计。主要疗效终点为缓解率（RR=CR+PR；完全缓解+部分缓解）（n=116/146；79%），很少为无进展生存期或总生存期（16% PFS 和 3% OS）。H0 和 H1 假设各不相同（分别为 3%-25%和 20%-50%）。已发表的 62 项试验共纳入 827 例 ES 患者。RR 较差（10%；15 例 CR=1.7%，68 例 PR=8.3%）。186 例患者的最佳缓解为疾病稳定（25%）。中位 PFS/OS 分别为 1.9（范围为 1.3-14.7）和 7.6 个月（5-30）。11 项（18%）已发表的试验被认为是阳性的，其 RR/PFS/OS 中位数分别为 15%（7%-30%）、4.5（1.3-10）和 16.6 个月（6.9-30）。
结论
本综述支持在所有年龄范围内开展以 PFS 为主要终点的国际随机 II 期试验的必要性。
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