Elsevier

The Lancet Oncology

Volume 17, Issue 12, December 2016, Pages 1697-1708
The Lancet Oncology

Articles
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

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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.

Introduction

The prognosis of gastric cancer patients is poor. Endoscopic or surgical resection is curative in about 90% of early-stage (T1) tumours, but survival drops dramatically for more advanced tumours (T2–4) or those with regional lymph node involvement. In Europe and North America, 5-year overall survival is about 20% for T3/4 tumours.1 Many investigators around the world have assessed multidisciplinary strategies in an attempt to improve survival. Several therapeutic approaches, including perioperative or neoadjuvant chemotherapy for gastric cancer and adenocarcinoma of the gastro-oesophageal junction, and neoadjuvant chemoradiation therapy for oesophageal or gastro-oesophageal junction cancers, were established.2, 3, 4, 5, 6 The first study to show a survival benefit of perioperative chemotherapy compared with surgery alone was the MAGIC trial.2 503 patients with clinical stage II or III adenocarcinoma of the stomach (75%), gastro-oesophageal junction (12%), or lower oesophagus (15%) were treated with either three cycles of epirubicin, cisplatin, and fluorouracil (ECF) before and after surgery or surgery alone. Patients in the chemotherapy group showed a significant improvement in 5-year overall survival compared with surgery only (36% vs 23%; p=0·009). In the French FNCLCC/FFCD 9703 phase 3 study,3 224 patients with gastro-oesophageal junction (64%), oesophageal (11%), or stomach (24%) adenocarcinoma were enrolled into the study. Patients received two to three cycles of cisplatin and fluorouracil before and after surgery or surgery alone. Patients in the chemotherapy group had significantly improved 5-year overall survival compared with surgery alone (38% vs 24%; p=0·02). However, despite these advances, the outcome of patients with advanced gastric or gastro-oesophageal junction cancer remains unsatisfactory. Considerable investigation is still needed to improve perioperative protocols. Furthermore, available studies do not recommend a preferred chemotherapy regimen. Combinations of fluoropyrimidines and platinum with or without an anthracycline have been the most frequently tested regimens. The contribution of adding docetaxel to this combination has not yet been addressed.

Docetaxel has proven efficacy in metastatic gastric cancer, both in first-line and second-line settings. In previous studies,7, 8 our group showed the activity and safety of the docetaxel-based combination consisting of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT), given every 2 weeks in the treatment of patients with metastatic gastric cancer. We also showed that neoadjuvant FLOT induced high frequencies of pathological complete regression (tumour regression grade TRG1a);9 17% after four cycles and 20% after six cycles in patients with resectable disease.10, 11 These proportions were better than those reported for anthracycline-based triplet regimens, which, for example, was 5·6% after four cycles of epirubicin, cisplatin, and capecitabine (ECX) in a phase 2 trial specifically done to explore this endpoint.12

These findings provided the rationale for the randomised phase 2/3 FLOT4 trial, which compared ECF or ECX with FLOT as perioperative therapy for patients with potentially resectable adenocarcinoma of the stomach or gastro-oesophageal junction. Here, we present the results of the phase 2 part of the study, which compared histopathological regression in patients treated with either FLOT or ECF/ECX.

Section snippets

Study design and participants

The FLOT4 study was an investigator-initiated, randomised, open-label, phase 2/3 study done at 28 German oncology centres (appendix p 6).

Patients were eligible if they had histologically confirmed adenocarcinoma of the stomach or gastro-oesophageal junction (types I to III) and were regarded as having clinical stage ≥cT2 or nodal positive (cN+) disease as assessed by CT or MRI of the chest, abdomen, and pelvis, and by endoscopic ultrasound. Clinical lymph node positivity was assessed by the

Results

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 FLOT4 trial. We were unable to collect the resection specimens for central pathology review in 35 patients (12% of all randomised patients) who were resected (figure 1). The most frequent reason that specimens were not available for central evaluation was refusal of the local pathologist to send all resection specimens (nine of 15

Discussion

The phase 2 part of the FLOT4 trial constitutes, to our knowledge, the largest series of prospectively collected data on centrally reviewed pathological complete regression, comparing a docetaxel-based triplet with an anthracycline-based triplet in the perioperative therapy of gastric and gastro-oesophageal junction cancer. The observed proportion of patients who achieved TRG1a with FLOT treatment versus ECF/ECX confirmed our hypothesis that FLOT treatment would result in an increased chance of

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