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

TY - JOUR

T1 - 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

AU - Al-Batran, Salah-Eddin

AU - Homann, Nils

AU - Pauligk, Claudia

AU - Goetze, Thorsten O

AU - Meiler, Johannes

AU - Kasper, Stefan

AU - Kopp, Hans-Georg

AU - Mayer, Frank

AU - Haag, Georg Martin

AU - Luley, Kim

AU - Lindig, Udo

AU - Schmiegel, Wolff

AU - Pohl, Michael

AU - Stoehlmacher, Jan

AU - Folprecht, Gunnar

AU - Probst, Stephan

AU - Prasnikar, Nicole

AU - Fischbach, Wolfgang

AU - Mahlberg, Rolf

AU - Trojan, Jörg

AU - Koenigsmann, Michael

AU - Martens, Uwe M

AU - Thuss-Patience, Peter

AU - Egger, Matthias

AU - Block, Andreas

AU - Heinemann, Volker

AU - Illerhaus, Gerald

AU - Moehler, Markus

AU - Schenk, Michael

AU - Kullmann, Frank

AU - Behringer, Dirk M

AU - Heike, Michael

AU - Pink, Daniel

AU - Teschendorf, Christian

AU - Löhr, Carmen

AU - Bernhard, Helga

AU - Schuch, Gunter

AU - Rethwisch, Volker

AU - von Weikersthal, Ludwig Fischer

AU - Hartmann, Jörg T

AU - Kneba, Michael

AU - Daum, Severin

AU - Schulmann, Karsten

AU - Weniger, Jörg

AU - Belle, Sebastian

AU - Gaiser, Timo

AU - Oduncu, Fuat S

AU - Güntner, Martina

AU - Hozaeel, Wael

AU - Reichart, Alexander

AU - Jäger, Elke

AU - Kraus, Thomas

AU - Mönig, Stefan

AU - Bechstein, Wolf O

AU - Schuler, Martin

AU - Schmalenberg, Harald

AU - Hofheinz, Ralf D

AU - FLOT4-AIO Investigators

N1 - Copyright © 2019 Elsevier Ltd. All rights reserved.

PY - 2019/5/11

Y1 - 2019/5/11

N2 - 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 ClinicalTrials.gov, 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.

AB - 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 ClinicalTrials.gov, 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.

KW - Adenocarcinoma/drug therapy

KW - Administration, Oral

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols/administration & dosage

KW - Capecitabine/administration & dosage

KW - Cisplatin/administration & dosage

KW - Digestive System Surgical Procedures

KW - Disease-Free Survival

KW - Docetaxel/administration & dosage

KW - Esophagogastric Junction/pathology

KW - Female

KW - Fluorouracil/administration & dosage

KW - Humans

KW - Leucovorin/administration & dosage

KW - Male

KW - Middle Aged

KW - Neoplasm Staging

KW - Oxaliplatin/administration & dosage

KW - Stomach Neoplasms/drug therapy

KW - Treatment Outcome

U2 - 10.1016/S0140-6736(18)32557-1

DO - 10.1016/S0140-6736(18)32557-1

M3 - SCORING: Journal article

C2 - 30982686

VL - 393

SP - 1948

EP - 1957

JO - LANCET

JF - LANCET

SN - 0140-6736

IS - 10184

ER -