Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial

Research output: Contribution to journalResearch articleContributedpeer-review


  • FLOT4-AIO Investigators - (Author)
  • Department of internal Medicine I
  • DRESDEN-concept
  • University Cancer Center Frankfurt (UCT)
  • Wolfsburg Hospital
  • University of Duisburg-Essen
  • Robert Bosch Centrum für Tumorerkrankungen (RBCT)
  • Universitätsklinikum der Eberhard-Karls-Universität
  • National Center for Tumor Diseases (NCT) Dresden
  • Jena University Hospital
  • Ruhr University Bochum
  • University Hospital Carl Gustav Carus Dresden
  • Central Hospital Bielefeld
  • Asklepios Hospital Hamburg-Barmbek
  • Klinikum Aschaffenburg
  • Klinikum Mutterhaus der Borromäerinnen
  • University Hospital Frankfurt
  • MediProjekt
  • Cancer Center Heilbronn-Franken
  • Charité – Universitätsmedizin Berlin
  • Ortenau Klinikum Lahr
  • University Hospital Hamburg Eppendorf
  • Klinik für Hämatologie
  • Johannes Gutenberg University Mainz
  • Barmherzige Brüder Hospital Regensburg
  • Klinikum Weiden
  • Augusta Hospitals Bochum Hattingen
  • Municipal Hospital Dortmund
  • Helios Hospital Group
  • St.-Josefs-Hospital Dortmund
  • Horst-Schmidt-Kliniken
  • Darmstadt Clinics
  • Hämatologisch-Onkologische Praxis Altona (HOPA)
  • Hämatologisch-Onkologische Praxis Eppendorf (HOPE)
  • Franziskus Hospital Bielefeld
  • University Hospital Schleswig-Holstein Campus Kiel
  • Klinik für Innere Medizin mit Schwerpunkt Gastroenterologie
  • MVZ Arnsberg
  • Gemeinschaftspraxis Dr. Weniger /Dr. Bittrich/Dr. Schütze
  • Leibniz University Hannover (LUH)
  • Trium Analysis Online GmbH
  • Am Marienhospital
  • Universitätsklinikum Schleswig-Holstein - Campus Lübeck


BACKGROUND: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours.

METHODS: In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with, number NCT01216644.

FINDINGS: Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [<1%] in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group.

INTERPRETATION: In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX.

FUNDING: The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.


Original languageEnglish
Pages (from-to)1948-1957
Number of pages10
JournalThe Lancet
Issue number10184
Publication statusPublished - 11 May 2019

External IDs

Scopus 85064895961
ORCID /0000-0002-9321-9911/work/142251969


Sustainable Development Goals


  • Adenocarcinoma/drug therapy, Administration, Oral, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols/administration & dosage, Capecitabine/administration & dosage, Cisplatin/administration & dosage, Digestive System Surgical Procedures, Disease-Free Survival, Docetaxel/administration & dosage, Esophagogastric Junction/pathology, Female, Fluorouracil/administration & dosage, Humans, Leucovorin/administration & dosage, Male, Middle Aged, Neoplasm Staging, Oxaliplatin/administration & dosage, Stomach Neoplasms/drug therapy, Treatment Outcome