Real-world outcomes of FLOT versus Chemoradiotherapy for Esophageal, Type I and II Junctional Tumors: A Bi-Center International Study

Summary The optimal multimodal strategy for esophageal and gastro-esophageal junction (GEJ) adenocarcinoma remains uncertain. Evidence comparing peri-operative FLOT chemotherapy with neoadjuvant chemoradiotherapy (CRT) is limited, and real-world data specific to true esophageal and Siewert I–II adenocarcinoma are sparse. This study evaluated contemporary oncological and surgical outcomes following FLOT or CRT in two high-volume international centers. A bi-national retrospective cohort study was conducted including patients treated between 2012 and 2024 who received neoadjuvant therapy followed by esophagectomy for locally advanced esophageal or Siewert I/II GEJ adenocarcinoma. Clinical, pathological, peri-operative, and survival outcomes were compared between peri-operative FLOT and CRT. Survival was analyzed using Kaplan–Meier and Cox regression; recurrence was evaluated using Fine–Gray competing-risk modeling. Of 402 patients, 139 (34.6%) received CRT and 263 (65.4%) FLOT. Baseline characteristics were similar except for a higher ASA class in the CRT cohort. Three-stage esophagectomy was more frequent after CRT, while FLOT patients more commonly underwent minimally invasive or hybrid procedures. Major postoperative morbidity was comparable after adjustment. Neoadjuvant completion exceeded 85% in both groups, while adjuvant FLOT completion was achieved in 66%. Pathological complete response rates were similar. FLOT yielded higher lymph node harvests but more advanced ypTNM staging; CRT produced more ypT1 tumors. R0 resection rates were equivalent. Adjusted overall survival favored FLOT (HR 1.67; P = 0.0025), with benefits maintained at 3 and 5 years. Recurrence risk was lower after FLOT. Stage-stratified analysis demonstrated advantages for FLOT in ypTNM II–III disease. In this large real-world cohort, peri-operative FLOT was associated with superior adjusted survival compared with CRT, despite similar Pathological Complete Response (pCR) and resection outcomes. These findings support FLOT as an effective multimodal strategy for esophageal and junctional adenocarcinoma.