Background
Phase II/III RCT (FLOT4-AIO). 716 patients with locally advanced (≥cT2 or cN+), resectable gastric or gastroesophageal junction adenocarcinoma at 38 German centers. Randomized 1:1 to perioperative FLOT vs ECF/ECX. Standard-of-care control based on the MAGIC trial.
Interventions and follow up
Arm A: FLOT — docetaxel 50 mg/m² + oxaliplatin 85 mg/m² + leucovorin 200 mg/m² + 5-FU 2600 mg/m² (24-h infusion) q2wks × 4 preop + 4 postop cycles
Arm B: ECF/ECX — epirubicin 50 mg/m² + cisplatin 60 mg/m² + 5-FU 200 mg/m²/day (continuous) or capecitabine 1250 mg/m²/day q3wks × 3 preop + 3 postop cycles
Primary endpoint: Overall survival
Median follow-up: ~43 months
Arm B: ECF/ECX — epirubicin 50 mg/m² + cisplatin 60 mg/m² + 5-FU 200 mg/m²/day (continuous) or capecitabine 1250 mg/m²/day q3wks × 3 preop + 3 postop cycles
Primary endpoint: Overall survival
Median follow-up: ~43 months
Results
OS: Median 50 vs 35 months, HR 0.77 (95% CI 0.63–0.94)
pCR rate: 16% (FLOT) vs 6% (ECF/ECX)
R0 resection: 84% vs 75%
pCR rate: 16% (FLOT) vs 6% (ECF/ECX)
R0 resection: 84% vs 75%
Adverse events
Overall: Serious adverse events similar (27% vs 27%); toxic deaths <1% in both groups; treatment-related hospitalizations 25% (FLOT) vs 26% (ECF/ECX).
FLOT-predominant: Higher rates of peripheral neuropathy and neutropenia.
ECF/ECX-predominant: Higher rates of nausea and alopecia.
FLOT-predominant: Higher rates of peripheral neuropathy and neutropenia.
ECF/ECX-predominant: Higher rates of nausea and alopecia.
Conclusions
Perioperative FLOT improved OS (50 vs 35 months, HR 0.77) and significantly increased pCR rates compared to ECF/ECX in resectable gastric and GEJ adenocarcinoma, establishing FLOT as the new perioperative chemotherapy standard of care.
Key Limitations
Key Limitations: German-only enrollment limits generalizability. FLOT requires biweekly IV administration — more complex scheduling than q3wk ECF. pCR is a surrogate endpoint. Postoperative FLOT completion rates were not fully reported. No D2 dissection mandate; surgical quality varied across community and academic sites.
Clinical Context
FLOT4 directly supersedes the MAGIC trial in perioperative gastric cancer management. FLOT is now guideline-recommended (ASCO, ESMO) as first-line perioperative therapy for resectable gastric/GEJ adenocarcinoma in Western patients. Ongoing trials are adding immunotherapy (e.g., MATTERHORN with durvalumab, KEYNOTE-585 with pembrolizumab) to the FLOT backbone.
References
References: Al-Batran SE et al, Lancet 2019 (FLOT4)