Esophagus to Small Intestine
N Engl J Med. 2025;392(4):323-335
Perioperative chemotherapy or preoperative chemoradiotherapy in esophageal cancer
Background: The best multimodal approach for resectable locally advanced esophageal adenocarcinoma is unclear. An important question is whether perioperative chemotherapy is preferable to preoperative chemoradiotherapy. Methods: In this phase 3, multicenter, randomized trial, the authors assigned in a 1:1 ratio patients with resectable esophageal adenocarcinoma to receive perioperative chemotherapy with FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) plus surgery or preoperative chemoradiotherapy (radiotherapy at a dose of 41.4 Gy and carboplatin and paclitaxel) plus surgery. Eligibility criteria included a primary tumor with a clinical stage of cT1 cN+, cT2–4a cN+, or cT2–4a cN0 disease, in which T indicates the size and extent of the tumor (higher numbers indicate a more advanced tumor), and N indicates the presence (N+) or absence (N0) of cancer spread to the lymph nodes, without evidence of metastatic spread. The primary end point was overall survival. Results: From February 2016 through April 2020, the authors assigned 221 patients to the FLOT group and 217 patients to the preoperative-chemoradiotherapy group. With a median follow-up of 55 months, overall survival at 3 years was 57.4% (95% confidence interval [CI]: 50.1–64.0) in the FLOT group and 50.7% (95% CI: 43.5–57.5) in the preoperative-chemoradiotherapy group (hazard ratio [HR] for death = 0.70; 95% CI: 0.53–0.92; p = 0.01). Progression-free survival at 3 years was 51.6% (95% CI: 44.3–58.4) in the FLOT group and 35.0% (95% CI: 28.4–41.7) in the preoperative-chemoradiotherapy group (HR for disease progression or death = 0.66; 95% CI: 0.51–0.85). 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.
Conclusions: Perioperative chemotherapy with FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) led to improved survival among patients with resectable esophageal adenocarcinoma as compared with preoperative chemoradiotherapy.