背景:国际上,尤文肉瘤的单一标准化疗治疗方法尚不明确.因为不同的化疗方案在欧洲和美国是新诊断的尤因肉瘤的标准,在没有新的代理人进行调查的情况下,我们旨在比较这两种策略。
方法:EUROEWING2012是欧洲研究者发起的,开放标签,随机化,在10个国家进行的对照3期试验。我们纳入了2-49岁的患者,任何经组织学和基因证实的骨或软组织尤因肉瘤,或类似尤因的肉瘤.最初的资格标准排除肺外转移性疾病患者,但这在9月份的协议(3.0版)中进行了修改,2016年。患者被随机分配(1:1)接受欧洲长春新碱治疗方案,异环磷酰胺,阿霉素,和依托泊苷诱导,使用长春新碱进行巩固,放线菌素D,用异环磷酰胺或环磷酰胺,或白消安和美法仑(第1组);或美国的长春新碱治疗方案,阿霉素,环磷酰胺,异环磷酰胺,和依托泊苷诱导,再加上异环磷酰胺和依托泊苷,使用长春新碱和环磷酰胺进行巩固,或者长春新碱,放线菌素D,和异环磷酰胺,白消安和美法仑(第2组)。所有药物均静脉给药。主要结局指标是无事件生存率。我们使用贝叶斯方法进行设计,分析,和结果的解释。在安全性分析中考虑接受至少一个剂量的研究治疗的患者。该试验已在EudraCT注册,2012-002107-17和ISRCTN,54540667。
结果:在2014年3月21日至2019年5月1日之间,640名患者进入EE2012,每组320名(50%)随机分配。存活患者的中位随访时间为47个月(范围0-84)。第1组3年无事件生存率为61%,第2组为67%(调整后的风险比[HR]0·71[95%可信区间0·55-0·92有利于第1组)。真实HR小于1·0的概率大于0·99。作为3-5级治疗毒性的发热性中性粒细胞减少症发生在第1组的234(74%)患者和第2组的183(58%)患者中。与第2组(n=138[43%])相比,第1组(n=205[64%])更多的患者需要至少一次血小板输注。相反,第2组(n=286[89%])需要输血的患者多于第1组(n=277[87%]).
结论:长春新碱的剂量密集化疗,阿霉素,环磷酰胺,异环磷酰胺,依托泊苷更有效,毒性较小,新诊断的尤因肉瘤的所有阶段的持续时间都比长春新碱短,异环磷酰胺,阿霉素,和依托泊苷诱导,现在应该是尤文肉瘤的治疗标准。
背景:欧盟第七框架研究计划,技术开发,和示范;法国国家协调中心,莱昂·贝拉德中心;SFCE;Liguecontrelecancer;英国癌症研究中心。
Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies.
EURO EWING 2012 was a European investigator-initiated, open-label, randomised, controlled phase 3
trial done in 10 countries. We included patients aged 2-49 years, with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in the protocol (version 3.0) in September, 2016. Patients were randomly assigned (1:1) to either the European regimen of vincristine, ifosfamide, doxorubicin, and etoposide induction, and consolidation using vincristine, actinomycin D, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1); or the US regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide induction, plus ifosfamide and etoposide, and consolidation using vincristine and cyclophosphamide, or vincristine, actinomycin D, and ifosfamide, with busulfan and melphalan (group 2). All drugs were administered intravenously. The primary outcome measure was event-free survival. We used a Bayesian approach for the design, analysis, and interpretation of the results. Patients who received at least one dose of
study treatment were considered in the safety analysis. The
trial was registered with EudraCT, 2012-002107-17, and ISRCTN, 54540667.
Between March 21, 2014, and May 1, 2019, 640 patients were entered into EE2012, 320 (50%) randomly allocated to each group. Median follow-up of surviving patients was 47 months (range 0-84). Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55-0·92 in favour of group 1). The probability that the true HR was less than 1·0 was greater than 0·99. Febrile neutropenia as a grade 3-5 treatment toxicity occurred in 234 (74%) patients in group 1 and in 183 (58%) patients in group 2. More patients in group 1 (n=205 [64%]) required at least one platelet transfusion compared with those in group 2 (n=138 [43%]). Conversely, more patients required blood transfusions in group 2 (n=286 [89%]) than in group 1 (n=277 [87%]).
Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction and should now be the standard of care for Ewing sarcoma.
The European Union\'s Seventh Framework Programme for Research, Technological Development, and Demonstration; The National Coordinating Centre in France, Centre Léon Bérard; SFCE; Ligue contre le cancer; Cancer Research UK.