The Landmark Series: Neoadjuvant Therapy for Patients with Resectable Gastroesophageal Junction Adenocarcinomas

Neoadjuvant therapy is a cornerstone of treatment for resectable gastroesophageal junction (GEJ) tumors. Despite substantial advancements, optimal regimen selection remains challenging owing to heterogeneity in clinical trial inclusion criteria and treatment algorithms. This review synthesizes findings from pivotal randomized trials to guide evidence-based selection of neoadjuvant treatment for GEJ adenocarcinoma. In 2006, the MAGIC trial established a survival benefit with perioperative chemotherapy with epirubicin, cisplatin, and fluorouracil (ECF) compared with surgery alone. Subsequently, in 2012, CROSS demonstrated improved overall survival (OS) and R0 resection rates with neoadjuvant chemoradiotherapy (CRT) using carboplatin and paclitaxel compared with surgery alone. CRT increased pathologic complete response (pCR) rates and decreased local recurrence rates, though it had limited impact on distant recurrence rates. In 2018, the FLOT4 trial demonstrated that perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) improved overall survival and pCR rates compared with ECF, making FLOT the new standard for perioperative chemotherapy. Several trials have since compared perioperative chemotherapy with neoadjuvant CRT. Neo-AEGIS found no survival difference; however, the predominance of ECF rather than FLOT in the chemotherapy arm limits its pertinence in the modern era. TOPGEAR demonstrated improved pCR with the addition of preoperative radiotherapy to FLOT, but no survival advantage. More recently, ESOPEC established FLOT's superiority over CROSS for OS, and MATTERHORN demonstrated improved event-free survival with the addition of immunotherapy to perioperative FLOT. FLOT is the current standard for neoadjuvant treatment in GEJ adenocarcinoma due to its superior survival outcomes. Integration of immunotherapy represents a promising avenue to further improve outcomes.