Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial

Summary

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.

Introduction

The prognosis of patients with gastric and gastro-oesophageal junction adenocarcinoma is poor.¹ Compared with surgery alone, several therapeutic approaches including perioperative chemotherapy or adjuvant or neoadjuvant chemoradiation improve survival.2, 3, 4, 5 The first and largest study to show a survival benefit of perioperative chemotherapy was the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial.² 503 patients with locally advanced, resectable oesophagogastric adenocarcinoma were treated with either three cycles of epirubicin, cisplatin, and fluorouracil (ECF) administered before and after surgery or surgery alone. The chemotherapy arm showed a significant improvement in overall survival (5-year survival rates, 36% vs 23%) compared with surgery alone. However, despite these advances, the outcome for patients with gastric or gastro-oesophageal junction adenocarcinoma remains unsatisfactory. Subsequent trials aiming to achieve a substantial improvement over the established regimens failed.6, 7, 8, 9

Research in context

Evidence before this study

For this manuscript we searched PubMed and the abstracts of major oncology congresses (American Society of Clinical Oncology [ASCO] and ASCO Gastrointestinal Symposium, and European Society for Medical Oncology) from Jan 1 to May 25, 2018. For the PubMed search, we used full-text search terms for “gastric cancer”, “oesophageal cancer” or “gastro-oesophageal junction cancer” in conjunction with “neoadjuvant treatment” or “perioperative treatment” as well as “resectable” or “operable stage” or “operable patients”. We limited our discussion to trials and reports that we found relevant to the setting of our trial as well as our population, and results. The prognosis of patients with gastric cancer was poor in the more advanced tumours. Perioperative chemotherapy for gastric and gastro-oesophageal junction adenocarcinoma was established and shown to improve survival in two landmark clinical trials: the MAGIC trial using three 3-week cycles of ECF (epirubicin and cisplatin plus fluorouracil) followed by surgery followed by three additional ECF cycles showing significant improvement in 5-year overall survival (36% vs 23%) and the French FNCLCC/FFCD 9703·3 study, in which patients received 2–3 cycles of cisplatin with flourouracil before and after surgery or surgery alone, resulting in a significant and similar improvement of 5-year overall survival (38% vs 24%). However, despite these advances, the outcome for patients with advanced gastric or gastric and gastro-oesophageal junction adenocarcinoma remained unsatisfactory. At that time, docetaxel had proven efficacy in metastatic gastric cancer, both in first-line and second-line settings. Our group previously demonstrated the activity and safety of the docetaxel-based triple combination FLOT, consisting of fluorouracil, leucovorin, oxaliplatin, and docetaxel, administered every 2 weeks in the treatment of patients with metastatic gastric cancer and found FLOT induced pathological complete regression of up to 17% in phase 2 and retrospective studies.

Added value of this study

To our knowledge, this is the first trial to show significant improvement over the available standard of care ECF in the treatment of patients with locally advanced, potentially resectable gastric and gastro-oesophageal junction adenocarcinoma. The study showed that perioperative FLOT significantly improved overall survival as compared with perioperative ECF or ECX (epirubicin and cisplatin plus either fluorouracil or capecitabine.

Implications of all the available evidence

The study expands the available options for the treatment of locally advanced, resectable gastric and gastro-oesophageal adenocarcinoma.

The cytotoxic drug docetaxel has shown efficacy in the metastatic settings, both in first-line (docetaxel, cisplatin, and fluorouracil [DCF] administered every 3 weeks)¹⁰ and second-line (docetaxel monotherapy) therapy.¹¹ However, the parent DCF regimen was associated with high toxicity and this prompted us to develop a modified regimen delivered once every 2 weeks using oxaliplatin instead of cisplatin to reduce the toxicity. In several phase 2 studies, we evaluated this new combination consisting of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for metastatic12, 13, 14 and locally advanced15, 16 gastric and gastro-oesophageal junction adenocarcinoma, and showed that FLOT was more tolerable than the parent DCF regimen and that it induced more tumour responses in locally advanced, resectable tumours than other regimens, including the anthracycline-based triplets.15, 16, 17 This prompted us to evaluate FLOT in a randomised, phase 2/3 trial, comparing perioperative epirubicin and cisplatin plus either fluorouracil or capecitabine (ECF/ ECX) with perioperative FLOT. The results of the phase 2 study (comprising the first 300 patients of the total population) were published in 2017¹⁸ and showed that FLOT was superior to ECF/ECX in terms of complete pathological regression (15% vs 6%; p=0·02). In the phase 3 trial portion reported here, we aimed to assess overall survival in an expanded population.