背景：目前尚不清楚局部晚期食管腺癌和食管胃交界部(AEG)的最佳联合治疗方法。是否进行新辅助治疗是关键问题，特别是 CROSS(卡铂/紫杉醇，41.4Gy 放疗)优于最佳围手术期化疗方案，包括改良的 MAGIC(表阿霉素、顺铂(奥沙利铂)、5-FU(卡培他滨))和更晚的 FLOT(多西紫杉醇、5-FU、亚叶酸钙、奥沙利铂)。Neo-AEGIS 是解决这个问题的第一个随机对照试验。

Background: The optimum combination curative approach to locally advanced adenocarcinoma of the esophagus and esophago-gastric junction (AEG) is unknown. A key question is whether neoadjuvant multimodal therapy, specifically CROSS (carboplatin/paclitaxel, 41.4Gy radiation therapy), is superior to optimum peri-operative chemotherapeutic regimens including modified MAGIC (epirubicin, cisplatin (oxaliplatin), 5-FU (capecitabine)) and more latterly FLOT (docetaxel, 5-FU, leucovorin, oxaliplatin). Neo-AEGIS was designed as the first randomised controlled trial to address this question.

方法：有 cT2-3N0-3M0AEG 的 377 例患者被随机分配到 24 个地点(爱尔兰、英国、丹麦、法国、瑞典)进行交叉或围手术期化疗(ECF/ECX/EOF/EOX Pre 2018，FLOT OPTION 2019/20)。主要结果是总体存活。初始功率计算基于 10%的交叉优势。这在第一次无效性分析(70 个事件)后被修改为 5%的非劣势边际。次要终点包括毒性、病理反应和术后并发症，根据食道并发症共识小组(ECCG)的定义和 Clavien-Dindo 严重程度分级。

Methods: 377 patients with cT2-3N0-3M0 AEG were randomly assigned to CROSS or peri-operative chemotherapy (ECF/ECX/EOF/EOX pre-2018, FLOT option 2019/20) at 24 sites (Ireland, UK, Denmark, France, Sweden). The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. This was modified after the first futility analysis (70 events) to a non-inferiority margin of 5%. Secondary end points included toxicity, pathologic measures of response, and postoperative complications as per the Esophageal Complications Consensus Group (ECCG) definitions and Clavien-Dindo severity grade.

结果：在 362 例可评估的患者中，178 例交叉，184 例 MAG-IC/FLOT (157/27)，90%为男性，中位年龄 64 岁(35-83 岁)，84%为 cT3，58%为 cN1。在中位(范围)24.5(1-92)个月的随访中，第二次无效性分析(占计划事件的 60%)时，143 例死亡，70 例交叉和 73 例 MAG-IC/FLOT，估计 3 年生存率分别为 56%(95%可信区间 47，64)和 57%(95%可信区间 48，65)，[(HR 1.02(95% 可信区间，0.74-1.42)。基于这一数据证明有效，DSMB 建议在 2020 年 12 月结束招募。

Results: Of 362 evaluable patients, 178 CROSS, 184 MAGIC/FLOT (157/27), 90% were male, median (range) age 64 (35-83), 84% were cT3, and 58% cN1. At a median (range) follow up of 24.5 (1-92) months, at the second futility analysis (60% of planned events), there were 143 deaths, 70 CROSS and 73 MAGIC/FLOT arm, with 3-year estimated survival probability of 56% (95% CI 47,64) and 57% (95% CI 48,65), respectively [(HR 1.02 (95%CI. 0.74-1.42))]. Based on the absence of futility evidenced in this data the DSMB recommended closure of recruitment in December 2020.

结论：这项随机对照试验没有证据表明围手术期化疗比多模式治疗差得令人无法接受，尽管交叉组局部肿瘤反应的代理标记物更多。肿瘤学和手术结果与现代最佳基准一致。这些数据表明，在现代实践中，决策并不逊色，支持均衡。

Conclusions: This RCT reveals no evidence that peri-operative chemotherapy is unacceptably inferior to multimodal therapy, notwithstanding greater proxy markers of local tumour response in the CROSS arm. Oncologic and operative outcomes were consistent with optimum modern benchmarks. These data strongly suggest non-inferiority and support equipoise in decision making in modern practice.