Multinational cohort study of FLOT versus CROSS among patients with pathological complete response in esophageal adenocarcinoma

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 is uncertain. A cohort study at 14 high-volume European centers between 2018 and 2024 compared 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 versus the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) protocol. The primary outcome was overall survival (OS). Among 297 patients achieving pCR, 150 received CROSS and 147 FLOT. On unadjusted analysis, FLOT was associated with better OS (HR 0.32; p<0.001) and disease-free survival (DFS; HR 0.32; pxtagstartz0.001). After adjustment, FLOT remained independently associated with better OS (HR 0.34; p=0.003) and DFS (HR 0.35; p<0.001). 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, whereas recurrence patterns were more heterogeneous after FLOT.. The median time to recurrence was longer after FLOT than CROSS (16.8 versus 12.8 months). The authors conclude that 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 that the prognostic significance of pCR may vary by neoadjuvant modality.