Salah-Eddin Al-Batran1, Nils Homann2, Claudia Pauligk1, Gerald Illerhaus3,4, Uwe M Martens5, Jan Stoehlmacher6,7, Harald Schmalenberg8,9, Kim B Luley10, Nicole Prasnikar11,12, Matthias Egger13, Stephan Probst14, Helmut Messmann15, Markus Moehler16, Wolfgang Fischbach17, Jörg T Hartmann18,19, Frank Mayer18,20, Heinz-Gert Höffkes21, Michael Koenigsmann22, Dirk Arnold23,24, Thomas W Kraus25, Kersten Grimm25, Stefan Berkhoff25, Stefan Post26, Elke Jäger27, Wolf Bechstein28, Ulrich Ronellenfitsch26, Stefan Mönig29, Ralf D Hofheinz26. 1. Institute of Clinical Cancer Research, Krankenhaus Nordwest, Universitären University Cancer Center, Frankfurt, Germany. 2. Medical Department II, Klinikum Wolfsburg, Wolfsburg, Germany. 3. Medical Department I, Universitätsklinikum Freiburg, Freiburg, Germany. 4. now with Clinic for Hematology, Oncology, and Palliative Care, Klinikum Stuttgart, Kriegsbergstraße, Stuttgart, Germany. 5. Medical Department III, SLK-Kliniken GmbH, Heilbronn, Germany. 6. Medical Clinic and Polyclinic, Universitätsklinikum Carl Gustav Carus, Dresden, Germany. 7. now with Institute for Clinical Genetics, Bonn, Germany. 8. Medical Department II, Universitätsklinikum Jena, Jena, Germany. 9. now with Medical Department IV, Krankenhaus Dresden-Friedrichstadt, Dresden, Germany. 10. Medical Department I Hematology/Oncology, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany. 11. Medical Department I, Klinikum Ludwigsburg, Ludwigsburg, Germany. 12. now with Medical Department II, Asklepios Klinik Altona, Hamburg, Germany. 13. Medical Department, Ortenau Klinikum Lahr, Lahr, Germany. 14. Department of Hematology and Oncology, Klinikum Bielefeld, Bielefeld, Germany. 15. Medical Department III, Zentralklinikum Augsburg, Augsburg, Germany. 16. Medical Department I, Universitätsklinik Mainz, Mainz, Germany. 17. Medical Department II, Klinikum Aschaffenburg, Aschaffenburg, Germany. 18. Medical Department II, Universitätsklinikum der Eberhard-Karl-Universität, Tübingen, Germany. 19. now with Clinic for Hematology, Oncology, and Immunology, Franziskus Hospital Bielefeld, Bielefeld, Germany. 20. now with Gemeinschaftspraxis, Friedrichshafen, Germany. 21. Tumorclinic, Klinikum Fulda, Fulda, Germany. 22. MediProjekt, Gesellschaft für Medizinstatistik und Projektentwicklung, Hannover, Germany. 23. Clinic and Polyclinic for Internal Medicine IV, Universitätsklinikum Halle, Halle, Germany. 24. now with CUF Hospitals Cancer Centre, Lisboa, Portugal. 25. Department of Surgery, Krankenhaus Nordwest, Frankfurt, Germany. 26. Medical Department, Universitätsmedizin Mannheim, Mannheim, Germany. 27. Department of Oncology and Hematology, Krankenhaus Nordwest, Frankfurt, Germany. 28. Department of General and Visceral Surgery, University Hospital Frankfurt, Frankfurt, Germany. 29. Department of General and Visceral Surgery, Universitätsklinik Köln, Köln, Germany.
Abstract
IMPORTANCE: Surgical resection has a potential benefit for patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction. OBJECTIVE: To evaluate outcome in patients with limited metastatic disease who receive chemotherapy first and proceed to surgical resection. DESIGN, SETTING, AND PARTICIPANTS: The AIO-FLOT3 (Arbeitsgemeinschaft Internistische Onkologie-fluorouracil, leucovorin, oxaliplatin, and docetaxel) trial is a prospective, phase 2 trial of 252 patients with resectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients were enrolled from 52 cancer care centers in Germany between February 1, 2009, and January 31, 2010, and stratified to 1 of 3 groups: resectable (arm A), limited metastatic (arm B), or extensive metastatic (arm C). Data cutoff was January 2012, and the analysis was performed in March 2013. INTERVENTIONS: Patients in arm A received 4 preoperative cycles of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) followed by surgery and 4 postoperative cycles. Patients in arm B received at least 4 cycles of neoadjuvant FLOT and proceeded to surgical resection if restaging (using computed tomography and magnetic resonance imaging) showed a chance of margin-free (R0) resection of the primary tumor and at least a macroscopic complete resection of the metastatic lesions. Patients in arm C were offered FLOT chemotherapy and surgery only if required for palliation. Patients received a median (range) of 8 (1-15) cycles of FLOT. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. RESULTS: In total, 238 of 252 patients (94.4%) were eligible to participate. The median (range) age of participants was 66 (36-79) years in arm A (n = 51), 63 (28-79) years in arm B (n = 60), and 65 (23-83) years in arm C (n = 127). Patients in arm B (n = 60) had only retroperitoneal lymph node involvement (27 patients [45%]), liver involvement (11 [18.3%]), lung involvement (10 [16.7%]), localized peritoneal involvement (4 [6.7%]), or other (8 [13.3%]) incurable sites. Median overall survival was 22.9 months (95% CI, 16.5 to upper level not achieved) for arm B, compared with 10.7 months (95% CI, 9.1-12.8) for arm C (hazard ratio, 0.37; 95% CI, 0.25-0.55) (P < .001). The response rate for arm B was 60% (complete, 10%; partial, 50%), which is higher than the 43.3% for arm C. In arm B, 36 of 60 patients (60%) proceeded to surgery. The median overall survival was 31.3 months (95% CI, 18.9-upper level not achieved) for patients who proceeded to surgery and 15.9 months (95% CI, 7.1-22.9) for the other patients. CONCLUSIONS AND RELEVANCE: Patients with limited metastatic disease who received neoadjuvant chemotherapy and proceeded to surgery showed a favorable survival. The AIO-FLOT3 trial provides a rationale for further randomized clinical trials. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00849615.
IMPORTANCE: Surgical resection has a potential benefit for patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction. OBJECTIVE: To evaluate outcome in patients with limited metastatic disease who receive chemotherapy first and proceed to surgical resection. DESIGN, SETTING, AND PARTICIPANTS: The AIO-FLOT3 (Arbeitsgemeinschaft Internistische Onkologie-fluorouracil, leucovorin, oxaliplatin, and docetaxel) trial is a prospective, phase 2 trial of 252 patients with resectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients were enrolled from 52 cancer care centers in Germany between February 1, 2009, and January 31, 2010, and stratified to 1 of 3 groups: resectable (arm A), limited metastatic (arm B), or extensive metastatic (arm C). Data cutoff was January 2012, and the analysis was performed in March 2013. INTERVENTIONS: Patients in arm A received 4 preoperative cycles of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) followed by surgery and 4 postoperative cycles. Patients in arm B received at least 4 cycles of neoadjuvant FLOT and proceeded to surgical resection if restaging (using computed tomography and magnetic resonance imaging) showed a chance of margin-free (R0) resection of the primary tumor and at least a macroscopic complete resection of the metastatic lesions. Patients in arm C were offered FLOT chemotherapy and surgery only if required for palliation. Patients received a median (range) of 8 (1-15) cycles of FLOT. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. RESULTS: In total, 238 of 252 patients (94.4%) were eligible to participate. The median (range) age of participants was 66 (36-79) years in arm A (n = 51), 63 (28-79) years in arm B (n = 60), and 65 (23-83) years in arm C (n = 127). Patients in arm B (n = 60) had only retroperitoneal lymph node involvement (27 patients [45%]), liver involvement (11 [18.3%]), lung involvement (10 [16.7%]), localized peritoneal involvement (4 [6.7%]), or other (8 [13.3%]) incurable sites. Median overall survival was 22.9 months (95% CI, 16.5 to upper level not achieved) for arm B, compared with 10.7 months (95% CI, 9.1-12.8) for arm C (hazard ratio, 0.37; 95% CI, 0.25-0.55) (P < .001). The response rate for arm B was 60% (complete, 10%; partial, 50%), which is higher than the 43.3% for arm C. In arm B, 36 of 60 patients (60%) proceeded to surgery. The median overall survival was 31.3 months (95% CI, 18.9-upper level not achieved) for patients who proceeded to surgery and 15.9 months (95% CI, 7.1-22.9) for the other patients. CONCLUSIONS AND RELEVANCE: Patients with limited metastatic disease who received neoadjuvant chemotherapy and proceeded to surgery showed a favorable survival. The AIO-FLOT3 trial provides a rationale for further randomized clinical trials. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00849615.
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