Perioperative FLOT chemotherapy versus neoadjuvant chemoradiotherapy (CROSS protocol) in locally advanced adenocarcinoma of the lower oesophagus and oesophagogastric junction (Siewert types I-II): systematic review and narrative synthesis (SWiM)

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Abstract

BACKGROUND: Adenocarcinoma of the lower oesophagus and oesophagogastric junction (OGJ) is a malignancy of rising incidence in Western countries. Two multimodal strategies have dominated perioperative management: perioperative chemotherapy with the FLOT regimen (fluorouracil, leucovorin, oxaliplatin, docetaxel) and neoadjuvant chemoradiotherapy following the CROSS protocol (carboplatin/paclitaxel with concurrent 41.4 Gy). The optimal approach has recently been evaluated in the ESOPEC phase III randomised controlled trial. OBJECTIVE: To appraise and synthesise the current comparative evidence-including randomised, observational, and real-world data-on FLOT versus CROSS in resectable lower oesophageal adenocarcinoma (Siewert types I-II). METHODS: A systematic review was conducted and reported in line with the PRISMA 2020 statement. PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched (last run 30 June 2026), together with ClinicalTrials.gov. Thirteen reports from nine underlying studies were included. Risk of bias was assessed using RoB 2 (RCTs) and ROBINS-I (observational studies); certainty of evidence was appraised using GRADE. Synthesis followed the SWiM (Synthesis Without Meta-analysis) framework. RESULTS: ESOPEC (n=438, median follow-up 55 months) is the only direct phase III RCT comparing FLOT with CROSS. Perioperative FLOT was associated with improved overall survival (median OS 66 vs. 37 months; HR 0.70, 95% CI 0.53-0.92; p=0.012) and progression-free survival (HR 0.66, 95% CI 0.51-0.85; p=0.001). Distant recurrence was significantly reduced with FLOT (3-year cumulative incidence 31.5% vs. 47.2%; HR 0.59; p<0.001), whilst locoregional control was equivalent (HR 1.00; p=0.99). The Neo-AEGIS trial (n=377) did not demonstrate a survival difference between CROSS and perioperative chemotherapy (3-year OS 57% vs. 55%; HR 1.03; p=0.82), but used a heterogeneous chemotherapy backbone. A propensity-matched retrospective cohort (n=222, 111/arm) and the Dutch real-world CROSS cohort (n=4,765; median OS 33.7 months) provide context. GRADE certainty for the OS benefit is rated moderate. Patient-reported outcomes from ESOPEC are available as conference abstracts (EORTC QLQ-C30, QLQ-OES18 and CIPN20). CONCLUSIONS: ESOPEC provides the strongest available evidence supporting perioperative FLOT over CROSS; however, because this conclusion is based primarily on a single open-label phase III trial, the evidence supports that FLOT is likely, rather than definitively, superior to CROSS.

Abstract as published, via PubMed.