英国曼彻斯特皇家儿童医院Bernadette Brennan团队比较了两种化疗方案治疗新诊断尤文肉瘤的疗效与安全性。相关论文于2022年10月29日发表在《柳叶刀》杂志上。

在国际上，尤文肉瘤的单一标准化疗方案尚未确定。由于欧洲和美国对新诊断尤文肉瘤采用不同的标准化疗方案，且缺乏新药物进行研究，该研究旨在比较这两种化疗策略的效果。

EURO EWING 2012是一项由欧洲研究者发起、开放标签、随机、对照的3期临床试验，在10个国家进行。研究组招募2-49岁的患者，他们患有任何经组织学和遗传学证实的骨或软组织尤文肉瘤或尤文样肉瘤。资格标准最初排除了肺外转移性疾病患者，但在2016年9月的方案（3.0版）中对此进行了修订。

将患者随机（1:1）分为两组，分别接受长春新碱、异环磷酰胺、阿霉素和依托泊苷诱导的欧洲方案，并使用长春新碱、放线菌素D、异环磷酰胺或环磷酰胺或丁磺胺和美法仑进行强化（第1组）；或长春新碱、阿霉素、环磷酰胺、异环磷酰胺和依托泊苷诱导的美国方案，加上异环磷酰胺和依托泊苷，并使用长春新碱和环磷酰胺，或长春新碱、放线菌素D和异环磷酰胺与白消安和美法仑合并进行巩固（第2组）。所有药物均静脉注射。主要结局指标是无事件生存率。研究组使用贝叶斯方法设计、分析和解释结果。在安全性分析中考虑接受至少一剂研究治疗的患者。

2014年3月21日至2019年5月1日，640名患者入组EE2012，将其随机分配，每组320名（50%）。存活患者的中位随访时间为47个月。第1组的3年无事件生存率为61%，第2组为67%（校正后的危险比[HR]为0.71）。真实HR小于1.0的概率大于0.99。

第1组中有234例（74%）患者出现热性中性粒细胞减少症，为3-5级治疗毒性，第2组中有183例（58%）患者。第1组患者中有205例（64%）需要至少输一次血小板，第2组患者中有138例（43%）。相反，第2组需要输血的患者（286例[89%]）比第1组（277例[87%]）多。

研究结果表明，长春新碱、阿霉素、环磷酰胺、异环磷酰胺和依托泊苷的剂量强化化疗对新诊断的尤文肉瘤的所有分期都比长春新碱、异环磷酰胺、阿霉素和依托泊苷诱导更有效、毒性更小、持续时间更短，现在应该成为治疗尤文肉瘤的标准。

附：英文原文

Title: Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial

Author: Bernadette Brennan, Laura Kirton, Perrine Marec-Bérard, Nathalie Gaspar, Valerie Laurence, Javier Martín-Broto, Ana Sastre, Hans Gelderblom, Cormac Owens, Nicola Fenwick, Sandra Strauss, Veronica Moroz, Jeremy Whelan, Keith Wheatley

Issue&Volume: 2022/10/29

Abstract:

Background

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.

Methods

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.

Findings

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%]).

Interpretation

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.

DOI: 10.1016/S0140-6736(22)01790-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01790-1/fulltext