Real-World Outcomes Between Perioperative Chemotherapy (FLOT) and Preoperative Concurrent Chemoradiotherapy (CROSS) in Localized Esophageal and Esophagogastric Junction Adenocarcinoma: A Retrospective Cohort Study

<b>Background:</b> The management of localized esophageal and esophagogastric junction (EGJ) adenocarcinomas remains challenging. Although perioperative chemotherapy with the fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) regimen or preoperative concurrent chemoradiotherapy with carboplatin and paclitaxel (CROSS) regimen followed by surgery are standard options, the optimal approach is still debated. This study evaluated real-world outcomes of perioperative FLOT versus preoperative CROSS in such patients. <b>Methods:</b> A retrospective cohort study was conducted at a tertiary cancer center in Australia, including patients treated with FLOT or CROSS between 2014 and 2024. Multivariate Cox regression models adjusted for baseline differences, including demographics, tumor stage, differentiation, location, and surgical resection. <b>Results:</b> Among 70 patients, 15 received FLOT and 55 received CROSS. Median overall survival (OS) was 30.3 months for FLOT and 37.5 months for CROSS (<i>p</i> = 0.75). Median event-free survival (EFS) was not reached in the FLOT group and was 14.8 months in the CROSS group (<i>p</i> = 0.49). After multivariate adjustment, differences in OS and EFS were not significant. Compared to FLOT, CROSS was associated with higher treatment completion and response rates. CROSS also led to greater pathological tumor and nodal downstaging, as well as higher rates of complete pathological response. <b>Conclusions:</b> Both FLOT and CROSS appear to be effective treatment options for localized esophageal and EGJ adenocarcinomas. CROSS may offer advantages in terms of treatment tolerability and tumor response, and may be particularly suitable for patients with bulky tumors or reduced performance status. Owing to the limited sample size and follow-up, these findings should be interpreted cautiously. Personalized treatment decisions should be guided by multidisciplinary discussions, considering tumor characteristics, patient condition, and access to adjuvant immunotherapy.