Background
Phase III RCT, N=438, resectable esophageal or GEJ adenocarcinoma (cT1N+ or cT2–4a, cN0/+, cM0). 25 sites in Germany (2016–2020). Directly compared perioperative FLOT chemotherapy versus neoadjuvant CROSS chemoradiotherapy to determine the optimal preoperative strategy for resectable esophageal adenocarcinoma.
Interventions and follow up
Arm A: FLOT: 5-FU 2600 mg/m² + leucovorin 200 mg/m² + oxaliplatin 85 mg/m² + docetaxel 50 mg/m² q2wk × 4 preoperative cycles → surgery → 4 postoperative cycle
Arm B: CROSS: carboplatin AUC2 + paclitaxel 50 mg/m² weekly × 5 weeks + concurrent RT 41.4 Gy (23 fx) → surgery
Primary endpoint: Overall survival
mFollow up: 55 mo
Arm B: CROSS: carboplatin AUC2 + paclitaxel 50 mg/m² weekly × 5 weeks + concurrent RT 41.4 Gy (23 fx) → surgery
Primary endpoint: Overall survival
mFollow up: 55 mo
Results
mOS: 66 vs 37 mo, HR 0.70, 95% CI 0.53–0.92, P=.012
mPFS: 38 vs 16 mo, HR 0.66, 95% CI 0.51–0.85, P=.001
R0 resection: 78.9% vs 81.9% (ns)
mPFS: 38 vs 16 mo, HR 0.66, 95% CI 0.51–0.85, P=.001
R0 resection: 78.9% vs 81.9% (ns)
Adverse events
Chemotherapy-related: Grade ≥3 toxicities more common during FLOT (neutropenia, nausea, peripheral neuropathy)
Surgical/mortality: 30-day postoperative mortality 1.0% (FLOT) vs 1.7% (CROSS); 90-day 3.2% vs 5.6%; perioperative complication rates similar between arms
Surgical/mortality: 30-day postoperative mortality 1.0% (FLOT) vs 1.7% (CROSS); 90-day 3.2% vs 5.6%; perioperative complication rates similar between arms
Conclusions
Perioperative FLOT significantly improved OS versus neoadjuvant CROSS in resectable esophageal/GEJ adenocarcinoma (mOS 66 vs 37 months, HR 0.70). ESOPEC establishes perioperative FLOT as the preferred strategy over neoadjuvant CRT for adenocarcinoma histology in fit patients.
Key Limitations
Key Limitations: Enrolled adenocarcinoma predominantly; findings not applicable to esophageal SCC. Single-country (German) trial at specialized surgical centers, limiting generalizability. FLOT toxicity may preclude delivery in older or unfit patients. CROSS pCR rate (10%) was at the lower end of expected, raising concern about protocol adherence in some sites. Does not incorporate immunotherapy, which may further improve outcomes (see MATTERHORN).
Clinical Context
ESOPEC is practice-changing for Western centers where neoadjuvant CROSS was standard for esophageal adenocarcinoma. FLOT is now the preferred perioperative approach for resectable esophageal/GEJ adenocarcinoma in Europe and increasingly North America. Perioperative durvalumab + FLOT (MATTERHORN, NEJM 2025) further extends outcomes and is FDA-approved, potentially superseding FLOT monotherapy.
References
References: Hoeppner J et al, NEJM 2025 (primary)