A prospective, multicentre, randomised, phase III ESOPEC study, conducted at 25 centres in Germany, shows superior overall survival (OS) with FLOT as compared with preoperative chemoradiotherapy among patients with resectable oesophageal adenocarcinoma, including those with a clinical lymph node stage cN+ and those with a clinical tumour stage cT3 or cT4, who made up most of the study population.
Whether de-escalation to a chemotherapy doublet or a switch to preoperative chemoradiotherapy is the preferred approach in patients to whom FLOT cannot be given because of coexisting conditions or in those with FLOT-related adverse events remains a question that ESOPEC study cannot answer according to Dr. Jens Hoeppner of the Department of Surgery, University Medical Center Ostwestfalen-Lippe–Campus Hospital Lippe, University of Bielefeld in Detmold, Germany and colleagues, who published the findings on 22 January 2025 in The New England Journal of Medicine.
The authors wrote in the background that two multimodal approaches, preoperative chemoradiotherapy plus surgery and perioperative chemotherapy plus surgery, have been shown to improve survival outcomes in patients with resectable oesophageal adenocarcinoma.
Based on findings from the German FLOT4-AIO study, which enrolled a mixed cohort of patients with oesophageal, oesophago-gastric junction, and gastric adenocarcinoma, the use of FLOT regimen (fluorouracil, leucovorin, oxaliplatin, and docetaxel) has been widely established as the preferred perioperative chemotherapy regimen for gastro-oesophageal adenocarcinoma.
Preoperative chemoradiotherapy and FLOT were recommended as standards of care for the treatment of non-metastatic resectable oesophageal and oesophago-gastric junction adenocarcinoma. Concerns remained about the preoperative-chemoradiotherapy regimen, particularly regarding inadequate control of systemic disease, and the FLOT regimen, owing to side effects of treatment and a somewhat low percentage of patients with R0 resection, which was only 84% in the intention-to-treat analysis in the FLOT4-AIO study.
In the ESOPEC study, the German investigators assessed whether FLOT was superior to preoperative chemoradiotherapy regarding OS among patients with resectable oesophageal adenocarcinoma. They assigned in a 1:1 ratio patients with resectable oesophageal adenocarcinoma to receive perioperative chemotherapy with FLOT plus surgery or preoperative chemoradiotherapy (radiotherapy at a dose of 41.4 Gy and carboplatin and paclitaxel) plus surgery. Eligibility criteria included a primary tumour with a clinical stage of cT1 cN+, cT2-4a cN+, or cT2-4a cN0 disease. The primary endpoint was OS.
From February 2016 through April 2020, the study team assigned 221 patients to the FLOT group and 217 patients to the preoperative chemoradiotherapy group. With a median follow-up of 55 months, OS at 3 years was 57.4% (95% confidence interval [CI] 50.1 to 64.0) in the FLOT group and 50.7% (95% CI 43.5 to 57.5) in the preoperative chemoradiotherapy group (hazard ratio [CI] for death 0.70; 95% CI 0.53 to 0.92; p = 0.01).
Progression-free survival at 3 years was 51.6% (95% CI 44.3 to 58.4) in the FLOT group and 35.0% (95% CI 28.4 to 41.7) in the preoperative chemoradiotherapy group (HR for disease progression or death 0.66; 95% CI 0.51 to 0.85).
Among the patients who started the assigned treatment, grade 3 or higher adverse events were observed in 120 of 207 patients (58.0%) in the FLOT group and in 98 of 196 patients (50.0%) in the preoperative chemoradiotherapy group. Serious adverse events were observed in 98 of 207 patients (47.3%) in the FLOT group and in 82 of 196 patients (41.8%) in the preoperative chemoradiotherapy group. Mortality at 90 days after surgery was 3.1% in the FLOT group and 5.6% in the preoperative chemoradiotherapy group.
Although the study was conducted in only one country, the epidemiology, quality of care, and treatment outcomes in Germany are largely reflective of the Western lifestyle and representative of those in high income countries, where the incidence of oesophageal adenocarcinoma is increasing.
The authors commented that their study was adequately powered; the chemoradiotherapy regimen used in this study should no longer be considered the best treatment in patients with resectable oesophageal adenocarcinoma.
In an accompanied editorial article, Dr. David P. Kelsen of the Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, both in New York, NY, US wrote that several questions about FLOT remain. For example, only 68.6% of the patients who started FLOT before surgery received any FLOT after surgery, and only 53.4% of the patients in the FLOT group received all four cycles of FLOT after surgery. Therefore, the editorialist questioned should all systemic therapy be given before surgery.
Dr. Kelsen also wrote that PET was not required in the ESOPEC study but may be used to assess the metabolic response after four cycles of chemotherapy and guide the decision to continue chemotherapy or perform surgery. The plasma ctDNA level may be assessed to determine the response to treatment and the presence of minimal residual disease and to guide decisions about postoperative therapy.
Overall, the results of the ESOPEC study, showed that FLOT, currently the most effective systemic chemotherapy, led to improved OS as compared with chemotherapy plus radiotherapy among patients with oesophageal adenocarcinoma. The use of perioperative systemic therapies with even greater effectiveness, including agents tailored to the tumour profile, is likely to further improve survival among patients with oesophageal adenocarcinoma.
References
- Hoeppner J, Brunner T, Schmoor C, et al. Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer. N Engl J Med 2025;392:323-335.
- Kelsen DP. Multimodal Treatment in Locally Advanced Esophageal Adenocarcinoma — Two Interventions Better Than Three? N Engl J Med 2025;392:396-398.