title: Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial.
abstract: BACKGROUND
  Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection.
  
  
  METHODS
  In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1:1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m2on day 1, intravenous cisplatin 60 mg/m2on day 1, and either fluorouracil 200 mg/m2as continuous intravenous infusion or capecitabine 1250 mg/m2orally (two doses of 625 mg/m2per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m2, intravenous oxaliplatin 85 mg/m2, intravenous leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including the phase 3 part) has completed enrolment, but follow-up is ongoing and this is an interim analysis. The trial is registered with ClinicalTrials.gov, number NCT01216644.
  
  
  RESULTS
  Between Aug 18, 2010, and Aug 10, 2012, 300 patients (152 patients in the ECF/ECX group; 148 patients in the FLOT group) were enrolled into the phase 2 part of the study, 265 of whom (137 in the ECF/ECX group; 128 in the FLOT group) were assessable on a modified intention-to-treat basis. 119 (93%) of 128 patients in the FLOT group and 126 (92%) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment. FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX (20 [16%; 95% CI 10-23] of 128 patients vs eight [6%; 3-11] of 137 patients; p=0·02). 44 (40%) of 111 patients in the ECF/ECX group and 30 (25%) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication. The most common non-surgical grade 3-4 adverse events were neutropenia (52 [38%] of 137 patients in the ECF/ECX group vs 67 [52%] of 128 patients in the FLOT group), leucopenia (28 [20%] vs 36 [28%]), nausea (23 [17%] vs 12 [9%]), infection (16 [12%] vs 15 [12%]), fatigue (19 [14%] vs 11 [9%]), and vomiting (13 [10%] vs four [3%]).
  
  
  CONCLUSIONS
  Perioperative FLOT was active and feasible to administer, and might represent an option for patients with locally advanced, resectable gastric or gastro-eosophageal junction adenocarcinoma.
  
  
  BACKGROUND
  None.
authors: Institute of Clinical Cancer Research, UCT University Cancer Center, Krankenhaus Nordwest, Frankfurt, Germany. Electronic address: albatran.salah@khnw.de.
authors: Salah-Eddin
authors: SE
authors: Al-Batran
authors: Medical Department III, Universitätsmedizin Mannheim, Mannheim, Germany.
authors: Ralf D
authors: RD
authors: Hofheinz
authors: Institute of Clinical Cancer Research, UCT University Cancer Center, Krankenhaus Nordwest, Frankfurt, Germany.
authors: Claudia
authors: C
authors: Pauligk
authors: Medical Department II, University Hospital, Tübingen, Germany.
authors: Hans-Georg
authors: HG
authors: Kopp
authors: National Center for Tumor Diseases, University Hospital Heidelberg, Medical Oncology, Heidelberg, Germany.
authors: Georg Martin
authors: GM
authors: Haag
authors: Universitätsklinikum Schleswig-Holstein, Medical Department I Hematology/Oncology, Lübeck, Germany.
authors: Kim Barbara
authors: KB
authors: Luley
authors: West German Cancer Center, Department of Medical Oncology, and German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany.
authors: Johannes
authors: J
authors: Meiler
authors: Klinikum Wolfsburg, Medical Department II, Wolfsburg, Germany.
authors: Nils
authors: N
authors: Homann
authors: Klinikum rechts der Isar der TU München, Medical Department III, Munich, Germany.
authors: Sylvie
authors: S
authors: Lorenzen
authors: Department of Internal Medicine II, University Hospital Jena, Germany.
authors: Harald
authors: H
authors: Schmalenberg
authors: Klinikum Bielefeld, Department for Hematology and Oncology, Bielefeld, Germany.
authors: Stephan
authors: S
authors: Probst
authors: MediProjekt, Gesellschaft für Medizinstatistik und Projektentwicklung, Hannover, Germany.
authors: Michael
authors: M
authors: Koenigsmann
authors: Ortenau Klinikum Lahr, Medical Department, Lahr, Germany.
authors: Matthias
authors: M
authors: Egger
authors: Klinikum Ludwigsburg, Medical Department I, Ludwigsburg, Germany.
authors: Nicole
authors: N
authors: Prasnikar
authors: Klinikum Ludwigsburg, Medical Department I, Ludwigsburg, Germany.
authors: Karel
authors: K
authors: Caca
authors: Medical Department I, Goethe University Medical Center, Frankfurt, Germany.
authors: Jörg
authors: J
authors: Trojan
authors: SLK-Kliniken, Medical Department III, Cancer Center Heilbronn-Franken, Heilbronn, Germany.
authors: Uwe M
authors: UM
authors: Martens
authors: University Hospital Hamburg-Eppendorf, Department for Oncology and Hematology, Hamburg, Germany.
authors: Andreas
authors: A
authors: Block
authors: Klinikum Aschaffenburg, Medical Department II, Aschaffenburg, Germany.
authors: Wolfgang
authors: W
authors: Fischbach
authors: Klinikum Mutterhaus der Borromäerinnen, Medical Department I, Trier, Germany.
authors: Rolf
authors: R
authors: Mahlberg
authors: Klinikum Mutterhaus der Borromäerinnen, Medical Department I, Trier, Germany.
authors: Michael
authors: M
authors: Clemens
authors: Universitätsklinikum Freiburg, Medical Department I, Freiburg, Germany.
authors: Gerald
authors: G
authors: Illerhaus
authors: Universitätsklinikum Freiburg, Medical Department I, Freiburg, Germany.
authors: Katja
authors: K
authors: Zirlik
authors: Augusta-Krankenanstalt, Department for Hematology, Oncology and Palliative Medicine, Bochum, Germany.
authors: Dirk M
authors: DM
authors: Behringer
authors: Department of Internal Medicine, Ruhr-University Bochum, Bochum, Germany.
authors: Wolff
authors: W
authors: Schmiegel
authors: Department of Internal Medicine, Ruhr-University Bochum, Bochum, Germany.
authors: Michael
authors: M
authors: Pohl
authors: Klinikum Dortmund, Medical Department, Dortmund, Germany.
authors: Michael
authors: M
authors: Heike
authors: Department of Surgery, Universitätsmedizin Mannheim, Mannheim, Germany.
authors: Ulrich
authors: U
authors: Ronellenfitsch
authors: West German Cancer Center, Department of Medical Oncology, and German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany.
authors: Martin
authors: M
authors: Schuler
authors: Department of General and Visceral Surgery, Goethe University Medical Center, Frankfurt, Germany.
authors: Wolf O
authors: WO
authors: Bechstein
authors: Department of Surgery and Transplantation, University Hospital, Tübingen, Germany.
authors: Alfred
authors: A
authors: Königsrainer
authors: Department of Pathology, Universitätsmedizin Mannheim, Mannheim, Germany.
authors: Timo
authors: T
authors: Gaiser
authors: Institute of Pathology, University Hospital Heidelberg, Medical Oncology, Heidelberg, Germany.
authors: Peter
authors: P
authors: Schirmacher
authors: Institute of Clinical Cancer Research, UCT University Cancer Center, Krankenhaus Nordwest, Frankfurt, Germany.
authors: Wael
authors: W
authors: Hozaeel
authors: Institute of Clinical Cancer Research, UCT University Cancer Center, Krankenhaus Nordwest, Frankfurt, Germany.
authors: Alexander
authors: A
authors: Reichart
authors: Institute of Clinical Cancer Research, UCT University Cancer Center, Krankenhaus Nordwest, Frankfurt, Germany.
authors: Thorsten O
authors: TO
authors: Goetze
authors: Sanofi Genzymy, Berlin, Germany.
authors: Mark
authors: M
authors: Sievert
authors: Department of Hematology-Oncology, Krankenhaus Nordwest, Frankfurt, Germany.
authors: Elke
authors: E
authors: Jäger
authors: Hôpitaux Universitaires de Genève, Service de Chirurgie Viscérale, Geneva, Switzerland.
authors: Stefan
authors: S
authors: Mönig
authors: Institute for Pathology, Ruhr-University Bochum, Bochum, Germany.
authors: Andrea
authors: A
authors: Tannapfel
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D000077143:Docetaxel; D015251:Epirubicin / Q000008:administration & dosage; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D004943:Esophagogastric Junction; D005260:Female; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D015251:Epirubicin; D002945:Cisplatin; D002955:Leucovorin