背景：目前尚不清楚局部晚期食管腺癌和食管胃交界部(AEG)的最佳聯合治療方法。是否進行新輔助治療是關鍵問題，特別是 CROSS(卡鉑/紫杉醇，41.4Gy 放療)優於最佳圍手術期化療方案，包括改良的 MAGIC(表阿黴素、順鉑(奧沙利鉑)、5-FU(卡培他濱))和更晚的 FLOT(多西紫杉醇、5-FU、亞葉酸鈣、奧沙利鉑)。Neo-AEGIS 是解決這個問題的第一個隨機對照試驗。
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 例患者被隨機分配到 24 個地點(愛爾蘭、英國、丹麥、法國、瑞典)進行交叉或圍手術期化療(ECF/ECX/EOF/EOX Pre 2018，FLOT OPTION 2019/20)。主要結果是總體存活。初始功率計算基於 10%的交叉優勢。這在第一次無效性分析(70 個事件)後被修改為 5%的非劣勢邊際。次要終點包括毒性、病理反應和術後並發症，根據食道並發症共識小組(ECCG)的定義和 Clavien-Dindo 嚴重程度分級。
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.
結果：在 362 例可評估的患者中，178 例交叉，184 例 MAG-IC/FLOT (157/27)，90%為男性，中位年齡 64 歲(35-83 歲)，84%為 cT3，58%為 cN1。在中位(範圍)24.5(1-92)個月的隨訪中，第二次無效性分析(占計劃事件的 60%)時，143 例死亡，70 例交叉和 73 例 MAG-IC/FLOT，估計 3 年生存率分別為 56%(95%可信區間 47，64)和 57%(95%可信區間 48，65)，[(HR 1.02(95% 可信區間，0.74-1.42)。基於這一數據證明有效，DSMB 建議在 2020 年 12 月結束招募。
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.
Arm A (Magic/FLOT) |
Arm B CROSS |
|
R0 (negative margins) |
82% |
95% |
ypN0 |
44.5% |
60.1% |
Tumor regression grade 1 & 2 |
12.1% |
41.7% |
Pathologic complete response |
5% |
16% |
Neutropenia (Gr 3/4) |
14.1% |
2.8% |
Neutropenic sepsis |
2.7% |
0.6% |
Postoperative in-hospital deaths |
3% |
3% |
Postoperative Pneumonia/ARDS |
20%/0.6% |
16%/4.3% |
Anastomotic Leak |
12% |
11.7% |
Clavien-Dindo > III |
23.6% |
22% |
結論：這項隨機對照試驗沒有證據表明圍手術期化療比多模式治療差得令人無法接受，盡管交叉組局部腫瘤反應的代理標記物更多。腫瘤學和手術結果與現代最佳基準一致。這些數據表明，在現代實踐中，決策並不遜色，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.
