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Perioperative chemotherapy and neoadjuvant multimodality therapy appear equally effective

Presented by
Prof. John Reynolds, Trinity St James Cancer Institute, Ireland
ASCO 2021
Phase 3, Neo-AEGIS
First results of the phase 3, open-label Neo-AEGIS trial demonstrated no evidence that perioperative chemotherapy (i.e. modified MAGIC or FLOT regimen) was inferior to multimodal therapy (i.e. CROSS regimen) in patients with oesophageal adenocarcinoma (EAC) and gastric-oesophageal junction cancer (GEJ).

The optimum combination curative approach to locally advanced GEJ/EAC is unknown. A key question is whether neoadjuvant multimodal therapy, specifically the CROSS regimen (i.e. carboplatin/paclitaxel, 41.4 Gy radiation therapy), is superior to optimum perioperative chemotherapeutic regimens including modified MAGIC (i.e. epirubicin, cisplatin [oxaliplatin], 5-FU [capecitabine]) and more recently FLOT (i.e. docetaxel, 5-FU, leucovorin, oxaliplatin).

The Neo-AEGIS trial (NCT01726452) is the first randomised controlled trial designed to address this question. At 24 European sites, 377 patients with cT2-3N0-3M0 EAC or GEJ were randomly assigned to CROSS or perioperative chemotherapy. The primary outcome was overall survival. The initial power calculation was based on CROSS superiority of 10%. After the first futility analysis (70 events), this was modified to a non-inferiority margin of 5%. Secondary endpoints included toxicity, pathologic measures of response, and postoperative complications. Prof. John Reynolds (Trinity St James Cancer Institute, Ireland) presented the results of the second futility analysis [1].

A total of 362 patients were evaluated; 178 receiving CROSS, 184 receiving MAGIC/FLOT (157/27), 90% male, median age 64 years, 84% cT3, and 58% cN1. At a median follow-up of 24.5 months, 143 deaths occurred (70 in the CROSS and 73 in the MAGIC/FLOT arm). The second futility analysis (60% of planned events) showed a 3-year estimated survival probability of 56% in the CROSS arm and 57% in the MAGIC/FLOT arm (HR 1.02; 95% CI 0.74–1.42). Markers of response (pathologic complete response, major pathologic response, R0 rate, and nodal downstaging) were significantly better in the CROSS arm. Neutropenia, diarrhoea, and vomiting were significantly increased in the chemotherapy arm compared with CROSS. However, there were no differences in toxic deaths, neutropenic sepsis, or pulmonary embolism. Based on the absence of futility, evidenced recruitment was closed in December 2020.

  1. Reynolds JV, et al. Neo-AEGIS (Neoadjuvant trial in Adenocarcinoma of the Esophagus and Esophago-Gastric Junction International Study): Preliminary results of phase III RCT of CROSS versus perioperative chemotherapy (Modified MAGIC or FLOT protocol). Abstract 4004, ASCO 2021 Virtual Meeting, 4–8 June.

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