By Lynda Williams, medwireNews Reporter
medwireNews: Perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) offers better overall survival (OS) than preoperative chemoradiotherapy for patients with locally advanced oesophageal adenocarcinoma, the ESOPEC trial investigators report.
The phase 3 trial was designed to clarify the optimal multimodal regimen, balancing concerns about toxicity and lower R0 resection rate with FLOT versus “inadequate control of systemic disease” with the low-dose preoperative chemoradiotherapy protocol, explain Jens Hoeppner (University of Bielefeld, Germany) and co-workers.
For the study, patients with a clinical stage cT1 or cT2–4a node-positive or cT2–4a node-negative primary tumour were randomly assigned to receive perioperative FLOT plus surgery (n=221) or preoperative 41.4 Gy of radiation plus carboplatin and paclitaxel, followed by surgery (n=217).
Overall, 193 patients given FLOT completed the planned four preoperative cycles and 118 the four postoperative cycles, while 147 of the preoperative chemoradiotherapy group received all five chemotherapy cycles and 193 the full radiation dose. Surgery was completed by 193 patients receiving FLOT and 181 patients receiving chemoradiotherapy.
After a median 55 months of follow-up, the 3-year rate of OS was 57.4% with FLOT and 50.7% with chemoradiotherapy, giving a significant hazard ratio (HR) for death of 0.70 in favour of FLOT. Median OS was 66 months and 37 months, respectively, and subgroup analyses found comparable OS regardless of factors such as age, sex, and clinical T and N stage.
Three-year progression-free survival was also significantly better in the FLOT arm, at 51.6% versus 35.0% with chemoradiotherapy, and a HR for progression or death of 0.66, the researchers say.
Pathological staging after surgery was “similar” in the FLOT and chemoradiotherapy arms, with 50.5% and 54.7%, respectively, free from residual cancer in their resected lymph nodes, and a corresponding 16.7% and 10.1% achieving a complete pathological response.
FLOT was associated with a higher rate of grade 3 or more severe adverse events (AEs) than chemoradiotherapy (58.0 vs 50.0%), with neutropenia and diarrhoea the most commonly reported with FLOT (19.8 and 6.8%, respectively), and leukopenia and pneumonia the most common with chemoradiotherapy (9.7 and 9.2%, respectively)
FLOT was also associated with a higher rate of serious AEs than chemoradiotherapy (47.3 vs 41.8%), the most frequent of which was pneumonia (5.3 vs 8.7%), but comparable rates of mortality at 30 days (1.0 vs 1.7%) and 90 days after surgery (3.1 vs 5.6%).
“The current trial showed that overall survival was better with FLOT than with preoperative chemoradiotherapy among patients with resectable esophageal adenocarcinoma, including those with a clinical lymph-node stage of cN+ and those with a clinical tumor stage of cT3 or cT4, who made up most of the trial population”, Hoeppner et al conclude.
“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 our trial cannot answer”, they remark.
Writing in an accompanying editorial, David Kelsen (Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, USA) notes that just 68.6% of FLOT patients received any of their planned chemotherapy cycles after surgery, and questions whether “all systemic therapy [should] be given before surgery, as it is for rectal cancer?”
He also highlights that since the ESOPEC trial began, treatments targeting genomic and molecular subgroups of patients with oesophageal cancer have been under investigation, including in the CheckMate 577 trial that showed improved disease-free survival with adjuvant nivolumab after preoperative chemoradiotherapy, especially among patients with higher baseline PD-L1 expression.
Kelsen therefore concludes: “The use of perioperative systemic therapies with even greater effectiveness, including agents tailored to the tumor profile, is likely to further improve survival among patients with esophageal adenocarcinoma.”
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