LUGANO-MADRID –The superiority of docetaxel based triplet therapy over standard care in patients with resectable oesophago-gastric cancer has been confirmed in late-breaking results from the FLOT4 trial presented at the ESMO 2017 Congress in Madrid. (1)
Survival in resectable oesophago-gastric cancer is poor. Five-year overall survival is around 25% with surgery, and is increased to 36% by adding a perioperative regimen of epirubicin, cisplatin, and infused fluorouracil (ECF). (2) Phase II studies have shown encouraging pathological response rates with perioperative docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT).
The phase III FLOT4 trial randomised 716 patients with resectable gastric or gastroesophageal junction adenocarcinoma to perioperative FLOT or ECF. As previously reported, FLOT was superior to ECF for all efficacy endpoints including curative resection rates, progression-free survival and overall survival.
Today researchers reveal the results of multivariate, subgroup and sensitivity analyses for the first time. The relative effect of FLOT was observed in all subgroups, including the elderly and signet cell tumours, and was particularly pronounced in Siewert type 1 oesophageal tumours (hazard ratio [HR], 0.60), Barrett tumours (HR, 0.62), small tumours (HR, 0.66) and nodal negative tumours (HR, 0.64).
Lead author Professor Salah-Eddin Al-Batran, director, Institute of Clinical Cancer Research, UCT-University Cancer Centre, Krankenhaus Nordwest, Frankfurt, Germany, said: “These new analyses confirm the superiority of FLOT, which is the new standard of care in the perioperative treatment of patients with resectable gastric or gastroesophageal junction adenocarcinoma.”
He concluded: “Some oncologists believe that patients with small tumours and those with signet cell cancer should not be treated preoperatively. The results of the FLOT4 trial contradict this and show that these patients do benefit.”
Commenting for ESMO, Professor Michel Ducreux, head, Gastrointestinal Oncology Unit, Gustave Roussy, Villejuif, France, said: “The triplet regimen used in the FLOT4 trial was developed to improve the results of ECF. It decreased toxicity by replacing epirubicin with low-dose docetaxel, and using oxaliplatin instead of cisplatin. FLOT is also more convenient to use, with one 24-hour infusion every two weeks rather than continuous infusion of fluorouracil in the ECF protocol.”
“The results show that FLOT is clearly the new standard of care,” continued Ducreux. “The new analysis presented at the ESMO 2017 Congress shows that the advantage of the FLOT regimen was seen across all subgroups, including those with a very poor prognosis such as the elderly and patients with signet cell tumours.”
He concluded: “FLOT will be the best backbone of chemotherapy that we can use in this setting. A step forward would be to try to improve the results by adding targeted therapies or immune checkpoint inhibitors. It would also be interesting to know if the FLOT regimen shows different levels of effectiveness in the four molecular biological subgroups of gastric cancer.”
Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress
- Abstract LBA27_PR ‘Docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) for resectable esophagogastric cancer: updated results from multicenter, randomized phase 3 FLOT4-AIO trial (German Gastric Group at AIO)‘ will be presented by Professor Salah-Eddin Al-Batran during Proffered Paper Session ‘Gastrointestinal tumours, non-colorectal’ on Friday, 8 September 2017, 14:00 to 15:30 (CEST) in the Barcelona Auditorium.
- Cunningham D, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20.
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Docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) for resectable esophagogastric cancer: updated results from multicenter, randomized phase 3 FLOT4-AIO trial (German Gastric Group at AIO)
S-E. Al-Batran1, C. Pauligk1, N. Homann2, H. Schmalenberg3, H.-G. Kopp4, G.M. Haag5, K. Luley6, G. Folprecht7, S. Probst8, P. Thuss-Patience9, J. Trojan10, M. Koenigsmann11, U. Lindig12, M. Pohl13, S. Kasper14, M. Möhler15, T. Goetze1, M. Schuler16, E. Jaeger17, R.D. Hofheinz18
1Institute of Clinical Cancer Research (IKF), UCT-University Cancer Center, Krankenhaus Nordwest, Frankfurt, Germany, 2Department of Internal Medicine II, Klinikum Wolfsburg, Wolfsburg, Germany, 3IV. Medizinische Klinik, Städtisches Krankenhaus Dresden, Dresden, Germany, 4Medical Center II, Universitätsklinikum Tübingen Medizinische Universitätsklinik, Tübingen, Germany, 5Department of Medical Oncology, Nationales Zentrum für Tumorerkrankungen (NCT), Heidelberg, Germany, 6Med. Klinik I, University SH.-Lübeck, Lübeck, Germany, 7University Cancer Center, Medical Dept. I , University Hospital Carl Gustav Carus, Dresden , Dresden, Germany, 8Klinik für Hämatologie und Onkologie, Klinikum Bielefeld, Bielefeld, Germany, 9Department of Hematology, Oncology, and Tumor Immunology, Charité University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany, 10Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany, 11MediProjekt, Onkologisches Ambulanzzentrum OAZ, Hannover, Germany, 12Klinik für Innere Medizin II, University Hospital Jena, Friedrich-Schiller-University, Jena, Germany, 13Medical Clinic, Ruhr University Bochum Medizinische Universitätsklinik, Bochum, Germany, 14Westdeutsches Tumorzentrum, University Hospital Essen, Essen, Germany, 15I. Med. Klinik und Poliklinik, Johannes Gutenberg University, Mainz, Germany, 16Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany, 17Department of Medical Oncology, Krankenhaus Nordwest, Frankfurt, Germany, 18III. Medizinische Klinik, Universitätsklinikum Mannheim, Mannheim, Germany
Background: FLOT4 is the first study to show improvement of outcome over another well-established bimodality therapy in patients with esophagogastric cancer. To consolidate initial results, we performed multivariate, subgroup and sensitivity analyses.
Methods: In the FLOT4, pts with resectable gastric or GEJ adenocarcinoma of stage ≥cT2 and/or cN+ (n=716) were randomized to either 3 pre-operative and 3 post-operative 3-week cycles of ECF/ECX (epirubicin 50 mg/m2 i.v., cisplatin 60 mg/m² i.v., both on day 1, and 5-FU 200 mg/m² as continuous i.v. infusion or capecitabine 1250 mg/m2 orally on days 1 to 21) or 4 pre-operative and 4 post-operative 2-week cycles of FLOT (docetaxel 50 mg/m2 i.v., oxaliplatin 85 mg/m² i.v., leucovorin 200 mg/m² i.v., and 5-FU 2600 mg/m² as 24-hour i.v, infusion, all on day 1). The primary endpoint was overall survival.
Results: Compared to ECF, FLOT was associated with less progressive disease cases during/after preoperative therapy (1% vs. 5%; p<0.001), more R0-resections (84% vs. 77%; p=0.011), higher number of pT0/pT1 tumors (25% vs. 15%; p=0.001), longer progression-free (30 vs. 18 months; HR 0.75; p=0.001) and overall survival (50 vs. 35 months; HR0.77; p=0.012). The relative effect from FLOT was observed in all subgroups, including elderly and signet cell tumors, and was numerically pronounced in Siewert type 1 esophageal tumors (HR 0.60), Barrett tumors (HR 0.62), small tumors T1/2 (HR 0.66) or nodal negative tumors (HR 0.64). In multivariate analyses, parameters associated with favorable survival were FLOT therapy (HR 0.75, p=0.006); stomach as the primary (HR 0.74; p=0.005), and nodal negativity (HR 0.72, p=0.022). ECOG PS of 0 showed a trend (HR 0.82; p=0.078). Age and Lauren’s type of histology had no impact on survival. Post-hoc analyses of relapse-free survival (PFS excluding pts without R0-resection) still favored FLOT (HR 0.8; p=0.049). 87% of relapses were systemic or both systemic and locoregional. The most frequent sites of relapse were peritoneal (31%) followed by lymphatic (26%), and liver (19%). Further Analysis will be presented at the meeting.
Conclusions: Updated analysis confirmed the superiority of FLOT. Pts derived benefit from FLOT even if they were old (>=70), had small tumors, a nodal negative status, or a signet cell component. The presence of one of these factors should no longer be a reason for not considering perioperative therapy in daily practice.
Clinical trial identification: FLOT4: NCT01216644
Legal entity responsible for the study: Krankenhaus Nordwest GmbH
Funding: Deutsche Krebshilfe, Sanofi
Disclosure:S-E. Al-Batran: Advisory role: Merck, Roche, Celgene, Lilly, Nordic Pharma Speaker: Roche, Celgene, Lilly , Nordic Pharma Research grants: Merck, Roche, Celgene, Vifor, Medac, Hospira, Lilly
N. Homann: Consulting or Advisory Role: Sanofi, Roche, Amgen, Cellgene, Lilly
H. Schmalenberg: Consulting or Advisory Role: Lilly, Baxalter; Research Funding: Sanofi; Travel, Accomodations, expenses: Merck
G.M. Haag: Consulting or Advisory Role: Sanofi, Roche, Taiho, Lilly, Pfizer, Nordic; Research Funding: Taiho, Nordic; Travel, Accomodations, expenses: Amgen, Ipsen, Celgene
K. Luley: Travel, accomodations, expenses: Ipsen, Novartis, Sanofi
P. Thuss-Patience: Consulting or Advisory Role: Roche, Lilly, BMS, MSD, Nordic, Pfizer; Research Funding: Novartis; Travel, Accomodations, expenses: Roche, Merck, Teva
M. Koenigsmann: Honoraria: Novartis, Celgene; Consulting or Advisory Role: Novartis, Celgene; Travel, Accomodations, expenses: Novartis
M. Pohl: Research Funding: Amgen, Baxalta, Celgene, Lilly
T. Goetze: Honoraria: MSD, Celgene Advisory board: BMS, Baxalta- Shire
M. Schuler: Honoraria: AstraZeneca, Alexion, Boehringer Ingelheim, Celgene, Lilly, MSD, Novartis, Roche; Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Celgene, Lilly, Novartis, Roche; Research Funding: Boehringer Ingelheim, BMS, Novartis
All other authors have declared no conflicts of interest.
Keywords: FLOT, neoadjuvant chemotherapy, gastric cancer, perioperative chemotherapy