Real-world evidence on the influence of node positivity and advanced clinical stage on response and survival after CROSS regimen in esophageal/GEJ cancer.

e16103 Background: The CROSS regimen (weekly carboplatin/paclitaxel with concurrent radiation) improves outcomes in resectable esophageal and gastroesophageal junction (GEJ) cancer, but real-world performance across the full spectrum of clinical stage--including patients with cT4, cN2-3, or limited metastatic (cM1) disease--remains unclear. Methods: We performed a retrospective cohort study of all patients treated with CROSS-based neoadjuvant chemoradiotherapy from 2012–2022 at a regional cancer center. Patients were stratified into three prespecified groups based on initial clinical staging: Group 1: cT1-3N0M0, Group 2: cT1-3N1M0, and Group 3: cT4 and/or cN2–3 and/or oligometastatic cM1. Outcomes included overall survival (OS), progression-free survival (PFS), surgical resection, and pathologic complete response (pCR). Survival was estimated using Kaplan-Meier methods and compared using log-rank testing; multivariable Cox models adjusted for age, sex, and ECOG performance status. Results: Among 138 patients, 68 (49%) were in Group 1, 54 (39%) in Group 2, and 16 (12%) in Group 3. Surgical resection rates decreased with advancing clinical burden: 70.6% in Group 1, 57.4% in Group 2, and 25.0% in Group 3 (p=0.004). pCR rates were 13.2%, 7.4%, and 0%, respectively (p=0.26). Median PFS was 34 months, 13 months, and 6 months for Groups 1-3, respectively (global log-rank p=0.001). Median OS was 46 months, 19 months, and 17 months, with a nonsignificant trend across groups (p=0.09). Conclusions: In this real world cohort, higher clinical disease burden--including cT4 tumors, bulky nodal involvement, or limited metastatic disease--was associated with sharply reduced resection rates, absence of pCR, and significantly inferior PFS following CROSS neoadjuvant chemoradiotherapy. Survival outcomes for Group 3 patients were poor and overlapped substantially with those of cN1 disease, suggesting that CROSS alone is inadequate for node-positive presentations. These findings support the need for intensified or systemic-dominant perioperative strategies for patients with advanced locoregional or oligometastatic esophageal cancer.