FLOT vs CROSS Among Patients With Pathological Complete Response in Esophageal Adenocarcinoma

Importance: Pathological complete response (pCR) following neoadjuvant therapy is associated with favorable prognosis in esophageal adenocarcinoma. However, whether long-term outcomes differ by neoadjuvant modality among patients achieving pCR remains uncertain. Objective: To compare survival outcomes and recurrence patterns in patients with esophageal or gastroesophageal junction adenocarcinoma achieving pCR after perioperative 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy vs the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study protocol (CROSS). Design, Setting, and Participants: This cohort study was conducted at 14 high-volume European esophagogastric cancer centers between January 2018 and December 2024 with follow-up from surgery to death or last contact among patients with esophageal or junctional adenocarcinoma treated with neoadjuvant therapy followed by curative esophagectomy. Patients with squamous carcinoma, noncurative resection, incomplete pathological response, or 90-day mortality were excluded. Exposure: Neoadjuvant perioperative FLOT chemotherapy or CROSS chemoradiotherapy followed by curative-intent esophagectomy. Main Outcomes and Measures: The primary outcome was overall survival. Secondary outcomes included disease-free survival, recurrence patterns, and nodal stage-stratified survival. Survival was estimated using Kaplan-Meier methods and multivariable Cox proportional hazards models. Results: Among 2717 eligible patients, 297 achieved pCR and were analyzed (mean [SD] age, 64.4 [9.7] years; 256 [79.5%] men). Of these, 150 received CROSS and 147 FLOT. FLOT patients were younger and more frequently clinically node-positive at baseline, while postoperative outcomes were similar. On unadjusted analysis, FLOT was associated with better overall survival (hazard ratio [HR], 0.32; 95% CI, 0.17-0.60; P < .001) and disease-free survival (HR, 0.32; 95% CI, 0.19-0.55; P < .001). After adjustment, FLOT remained independently associated with better overall survival (HR, 0.34; 95% CI, 0.16-0.69; P = .003) and disease-free survival (HR, 0.35; 95% CI, 0.19-0.62; P < .001). Recurrence occurred in 13 of 147 patients receiving FLOT (8.8%) compared with 37 of 150 receiving CROSS (24.7%). Distant metastases predominated in the CROSS group (27 of 37 recurrences [70.3%]), whereas recurrence patterns were more heterogeneous after FLOT (locoregional, 2 of 13 recurrences [15.4%]; distant, 2 of 13 recurrences [38.5%]; both, 6 of 13 recurrences [30.8%]). The median (IQR) time to recurrence was longer after FLOT than CROSS (16.8 [12.3-21.5] vs 12.8 [7.1-26.7] months). In subgroup analyses, FLOT was associated with better survival in cN0 or 1 disease (HR, 0.32; 95% CI, 0.15-0.67; P = .002). Conclusions and Relevance: In this cohort study, perioperative FLOT in patients achieving pCR for esophageal adenocarcinoma was associated with superior survival, lower recurrence risk, and later recurrence compared with CROSS. These findings suggest the prognostic significance of pCR may vary by neoadjuvant modality and should be interpreted in the context of treatment strategy.