ArticlesHistopathological 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
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
References (25)
- et al.
Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: systematic review with meta-analysis combining individual patient and aggregate data
Eur J Cancer
(2013) - et al.
Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie
Ann Oncol
(2008) - et al.
The feasibility of triple-drug chemotherapy combination in older adult patients with oesophagogastric cancer: a randomised trial of the Arbeitsgemeinschaft Internistische Onkologie (FLOT65+)
Eur J Cancer
(2013) - et al.
Peri-operative chemotherapy ± bevacizumab for resectable gastro-oesophageal adenocarcinoma: results from the UK Medical Research Council randomised ST03 trial (ISRCTN 46020948)
Eur J Cancer
(2015) - et al.
Split-dose docetaxel, cisplatin and leucovorin/fluorouracil as first-line therapy in advanced gastric cancer and adenocarcinoma of the gastroesophageal junction: results of a phase II trial
Ann Oncol
(2007) - et al.
Perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in gastro-oesophageal adenocarcinoma: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
Ann Oncol
(2012) - et al.
Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy
Ann Oncol
(2013) - et al.
Prognostic implications of the seventh edition of the International Union Against Cancer classification for patients with gastric cancer: the Western experience of patients treated in a single-center European institution
J Clin Oncol
(2013) - et al.
Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer
N Engl J Med
(2006) - et al.
Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial
J Clin Oncol
(2011)