Flot chemotherapy shows a clear survival advantage over the Cross protocol for esophageal adenocarcinoma, impacting treatment choices.

• Esopec trial: median overall survival (OS) for Flot at 66 months vs. 37 months for Cross (HR: 0.70, p=0.01).
• Real-world data: Cross cohort median OS at 33.7 months, with a higher pathological complete response (PCR) of 20.5% versus 10.1% in Cross from Esopec.

Surgeons should tailor treatment based on fitness, tumor location, and toxicity, while emphasizing standardized PCR assessment to integrate trial and real-world outcomes.