Salah-Eddin Al-Batran1, Nils Homann2, Claudia Pauligk3, Thorsten O Goetze3, Johannes Meiler4, Stefan Kasper4, Hans-Georg Kopp5, Frank Mayer6, Georg Martin Haag7, Kim Luley8, Udo Lindig9, Wolff Schmiegel10, Michael Pohl11, Jan Stoehlmacher12, Gunnar Folprecht12, Stephan Probst13, Nicole Prasnikar14, Wolfgang Fischbach15, Rolf Mahlberg16, Jörg Trojan17, Michael Koenigsmann18, Uwe M Martens19, Peter Thuss-Patience20, Matthias Egger21, Andreas Block22, Volker Heinemann23, Gerald Illerhaus24, Markus Moehler25, Michael Schenk26, Frank Kullmann27, Dirk M Behringer28, Michael Heike29, Daniel Pink30, Christian Teschendorf31, Carmen Löhr32, Helga Bernhard33, Gunter Schuch34, Volker Rethwisch29, Ludwig Fischer von Weikersthal35, Jörg T Hartmann36, Michael Kneba37, Severin Daum38, Karsten Schulmann39, Jörg Weniger40, Sebastian Belle41, Timo Gaiser42, Fuat S Oduncu43, Martina Güntner44, Wael Hozaeel45, Alexander Reichart46, Elke Jäger46, Thomas Kraus47, Stefan Mönig48, Wolf O Bechstein49, Martin Schuler50, Harald Schmalenberg51, Ralf D Hofheinz52. 1. Institute of Clinical Cancer Research, Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt, Germany; IKF Klinische Krebsforschung GmbH am Krankenhaus Nordwest, Frankfurt, Germany. Electronic address: albatran@ikf-khnw.de. 2. Klinikum Wolfsburg, Wolfsburg, Germany. 3. Institute of Clinical Cancer Research, Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt, Germany; IKF Klinische Krebsforschung GmbH am Krankenhaus Nordwest, Frankfurt, Germany. 4. West German Cancer Center, Department of Medical Oncology, University Duisburg-Essen, Essen, Germany. 5. Robert Bosch Centrum für Tumorerkrankungen (RBCT), Stuttgart, Germany. 6. Universitätsklinikum der Eberhard-Karls-Universität, Medizinische Klinik II, Abt. Onkologie, Hämatologie, Immunologie, Rheumatologie, Pneumologie, Tübingen, Germany. 7. Nationales Centrum für Tumorerkrankungen, Abteilung Medizinische Onkologie, Universitätsklinikum Heidelberg, Heidelberg, Germany. 8. Klinik für Hämatologie und Onkologie, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany. 9. Universitätsklinikum Jena, Klinik für Innere Medizin II, Abt. Hämatologie und Onkologie, Jena, Germany. 10. Ruhr-University Bochum, Department of Medicine, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany; Department of Gastroenterology and Hepatology, Ruhr-University Bochum, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil gGmbH, Bochum, Germany. 11. Ruhr-University Bochum, Department of Medicine, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany. 12. Universitätsklinikum Carl Gustav Carus, Medizinische Klinik und Poliklinik I, Dresden, Germany. 13. Klinikum Bielefeld, Klinik für Hämatologie und Onkologie, Bielefeld, Germany. 14. Asklepios Klinik Barmbek, Hämatologie, Onkologie und Palliativmedizin, Hamburg, Germany. 15. Klinikum Aschaffenburg, Medizinische Klinik II, Gastroenterologie und Onkologie, Aschaffenburg, Germany. 16. Klinikum Mutterhaus der Borromäerinnen, Med. Klinik I, Trier, Germany. 17. Universitätsklinikum Frankfurt, Goethe-Universität, Med. Klinik I, Frankfurt, Germany. 18. MediProjekt, Gesellschaft für Medizinstatistik und Projektentwicklung, Hannover, Germany. 19. SLK-Kliniken GmbH, Cancer Center Heilbronn-Franken, Klinik für Innere Medizin III, Heilbronn, Germany. 20. Charité - Universitätsmedizin Berlin, Med. Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie, Berlin, Germany. 21. Ortenau Klinikum Lahr, Medizinische Klinik, Gastroenterologie und Onkologie, Sektion Hämatologie und Onkologie, Lahr, Germany. 22. Universitätsklinikum Hamburg-Eppendorf, UCCH, II. Medizinische Klinik und Poliklinik (Onkologie, Hämatologie, KMT mit Sektion Pneumologie), Hamburg, Germany. 23. Medizinische Klinik und Poliklinik III, Klinikum der Universität München, Campus Grosshadern, Münich, Germany. 24. Klinik für Hämatologie, Onkologie und Palliativmedizin, Klinikum Stuttgart, Stuttgart, Germany. 25. Johannes-Gutenberg Universität Mainz, I. Med. Klinik und Poliklinik, Mainz, Germany. 26. Krankenhaus Barmherzige Brüder Regensburg, Klinik für Onkologie und Hämatologie, Regensburg, Germany. 27. Klinikum Weiden, Med. Klinik I, Weiden, Germany. 28. Augusta-Krankenanstalt Bochum, Klinik für Hämatologie und Onkologie, Bochum, Germany. 29. Klinikum Dortmund gGmbH, Medizinische Klinik, Gastroenterologie, Hämatologie/Onkologie, Endokrinologie, Dortmund, Germany. 30. Helios Klinikum Bad Saarow, Klinik für Hämatologie, Onkologie und Palliativmedizin, Bad Saarow, Germany; Universitätsmedizin Greifswald, Klinik und Poliklinik für Innere Medizin C - Hämatologie und Onkologie und Transplantationszentrum, Greifswald, Germany. 31. St.- Josefs- Hospital, Klinik für Innere Medizin, Dortmund, Germany. 32. Horst-Schmidt-Kliniken, Innere Medizin 2, Wiesbaden, Germany. 33. Klinikum Darmstadt, Med. Klinik V, Hämatologie und Onkologie, Darmstadt, Germany. 34. Hämatologisch-Onkologische Praxis Altona (HOPA), Hamburg, Germany. 35. Hämatologie/Internistische Onkologie, MVZ Gesundheitszentrum St Marien GmbH, Amberg, Germany. 36. Catholic Hospital Consortium Eastern Westphalia, Franziskus Hospital Bielefeld, Klinik für Innere Medizin II, Hämatologie, Internistische Onkologie, Immunologie, Bielefeld, Germany. 37. Klinik für Innere Medizin II - Hämatologie und Onkologie, University Clinics Schleswig Holstein- Campus Kiel, Kiel, Germany. 38. Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Berlin, Germany. 39. MVZ Arnsberg, Praxis für Hämatologie und Onkologie, Arnsberg, Germany. 40. Gemeinschaftspraxis Dr. Weniger /Dr. Bittrich/Dr. Schütze, Erfurt, Germany. 41. II. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany. 42. Institut für Pathologie, Universitätsmedizin Mannheim, Mannheim, Germany. 43. Medizinische Klinik und Poliklinik III, Klinikum der Universität München, München, Germany. 44. Trium Analysis Online, München, Germany. 45. MVZ Onkologie GmbH, Am Marienhospital, Hagen, Germany. 46. Klinik für Onkologie und Hämatologie, Krankenhaus Nordwest, UCT- University Cancer Center, Frankfurt am Main, Frankfurt, Germany. 47. Klinik für Allgemein-, Viszeral- und Minimal Invasive Chirurgie, Krankenhaus Nordwest, UCT- University Cancer Center, Frankfurt, Germany. 48. Service de Chirurgie viscérale, Hôpitaux Universitaires de Genève, Genève, Switzerland. 49. Frankfurt University Hospital and Clinics, Department of General and Visceral Surgery, Frankfurt, Germany. 50. West German Cancer Center, Department of Medical Oncology, University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner site University Hospital Essen Essen, Germany. 51. Universitätsklinikum Jena, Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie, Jena, Germany. 52. Tagestherapiezentrum am ITM, III. Medizinische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany.
Abstract
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 threepostoperative 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.
RCT Entities:
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.
Authors: M Martín-Richard; A Carmona-Bayonas; Ana B Custodio; J Gallego; P Jiménez-Fonseca; J J Reina; P Richart; F Rivera; M Alsina; J Sastre Journal: Clin Transl Oncol Date: 2020-01-27 Impact factor: 3.405
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Authors: Haeseong Park; Ramon U Jin; Andrea Wang-Gillam; Rama Suresh; Caron Rigden; Manik Amin; Benjamin R Tan; Katrina S Pedersen; Kian-Huat Lim; Nikolaos A Trikalinos; Abhilasha Acharya; Megan L Copsey; Katherine A Navo; Ashley E Morton; Feng Gao; A Craig Lockhart Journal: JAMA Oncol Date: 2020-08-01 Impact factor: 31.777