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 - 15/03/17

Doi : 10.1016/S1470-2045(16)30531-9

Salah-Eddin Al-Batran, ProfMD ^a,^⁎ , Ralf D Hofheinz, ProfMD ^c, Claudia Pauligk, PhD ^a, Hans-Georg Kopp, MD ^f, Georg Martin Haag, MD ^h, Kim Barbara Luley, MD ^j, Johannes Meiler, MD ^k, Nils Homann, ProfMD ^l, Sylvie Lorenzen, MD ^m, Harald Schmalenberg, MD ⁿ, Stephan Probst, MD ^o, Michael Koenigsmann, ProfMD ^p, Matthias Egger, MD ^q, Nicole Prasnikar, MD ^r, Karel Caca, ProfMD ^r, Jörg Trojan, ProfMD ^s, Uwe M Martens, ProfMD ^u, Andreas Block, MD ^v, Wolfgang Fischbach, ProfMD ^w, Rolf Mahlberg, MD ^x, Michael Clemens, ProfMD ^x, Gerald Illerhaus, ProfMD ^y, Katja Zirlik, MD ^y, Dirk M Behringer, ProfMD ^z, Wolff Schmiegel, ProfMD ^aa, Michael Pohl, MD ^aa, Michael Heike, ProfMD ^ac, Ulrich Ronellenfitsch, MD ^d, Martin Schuler, ProfMD ^k, Wolf O Bechstein, ProfMD ^t, Alfred Königsrainer, ProfMD ^g, Timo Gaiser, ProfMD ^e, Peter Schirmacher, ProfMD ⁱ, Wael Hozaeel, MD ^a, Alexander Reichart, MD ^a, Thorsten O Goetze, MD ^a, Mark Sievert, MD ^ad, Elke Jäger, ProfMD ^b, Stefan Mönig, ProfMD ^ae, Andrea Tannapfel, ProfMD ^ab

^a Institute of Clinical Cancer Research, UCT University Cancer Center, Krankenhaus Nordwest, Frankfurt, Germany

^b Department of Hematology-Oncology, Krankenhaus Nordwest, Frankfurt, Germany

^c Medical Department III, Universitätsmedizin Mannheim, Mannheim, Germany

^d Department of Surgery, Universitätsmedizin Mannheim, Mannheim, Germany

^e Department of Pathology, Universitätsmedizin Mannheim, Mannheim, Germany

^f Medical Department II, University Hospital, Tübingen, Germany

^g Department of Surgery and Transplantation, University Hospital, Tübingen, Germany

^h National Center for Tumor Diseases, University Hospital Heidelberg, Medical Oncology, Heidelberg, Germany

ⁱ Institute of Pathology, University Hospital Heidelberg, Medical Oncology, Heidelberg, Germany

^j Universitätsklinikum Schleswig-Holstein, Medical Department I Hematology/Oncology, Lübeck, Germany

^k West German Cancer Center, Department of Medical Oncology, and German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany

^l Klinikum Wolfsburg, Medical Department II, Wolfsburg, Germany

^m Klinikum rechts der Isar der TU München, Medical Department III, Munich, Germany

ⁿ Department of Internal Medicine II, University Hospital Jena, Germany

^o Klinikum Bielefeld, Department for Hematology and Oncology, Bielefeld, Germany

^p MediProjekt, Gesellschaft für Medizinstatistik und Projektentwicklung, Hannover, Germany

^q Ortenau Klinikum Lahr, Medical Department, Lahr, Germany

^r Klinikum Ludwigsburg, Medical Department I, Ludwigsburg, Germany

^s Medical Department I, Goethe University Medical Center, Frankfurt, Germany

^t Department of General and Visceral Surgery, Goethe University Medical Center, Frankfurt, Germany

^u SLK-Kliniken, Medical Department III, Cancer Center Heilbronn-Franken, Heilbronn, Germany

^v University Hospital Hamburg-Eppendorf, Department for Oncology and Hematology, Hamburg, Germany

^w Klinikum Aschaffenburg, Medical Department II, Aschaffenburg, Germany

^x Klinikum Mutterhaus der Borromäerinnen, Medical Department I, Trier, Germany

^y Universitätsklinikum Freiburg, Medical Department I, Freiburg, Germany

^z Augusta-Krankenanstalt, Department for Hematology, Oncology and Palliative Medicine, Bochum, Germany

^aa Department of Internal Medicine, Ruhr-University Bochum, Bochum, Germany

^ab Institute for Pathology, Ruhr-University Bochum, Bochum, Germany

^ac Klinikum Dortmund, Medical Department, Dortmund, Germany

^ad Sanofi Genzymy, Berlin, Germany

^ae Hôpitaux Universitaires de Genève, Service de Chirurgie Viscérale, Geneva, Switzerland

^* Correspondence to: Prof Salah-Eddin Al-Batran, Institute of Clinical Research, Krankenhaus Nordwest, UCT University Cancer Center, Steinbacher Hohl 2-26, 60488 Frankfurt am Main, Germany Correspondence to: Prof Salah-Eddin Al-Batran Institute of Clinical Research Krankenhaus Nordwest UCT University Cancer Center Steinbacher Hohl 2-26 Frankfurt am Main 60488 Germany

Summary

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/m² on day 1, intravenous cisplatin 60 mg/m² on day 1, and either fluorouracil 200 mg/m² as continuous intravenous infusion or capecitabine 1250 mg/m² orally (two doses of 625 mg/m² per 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/m² as 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.

Findings

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%]).

Interpretation

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.

Funding

None.

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Vol 17 - N° 12

P. 1697-1708 - décembre 2016 Retour au numéro

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