Nodal status and advanced clinical stage as determinants of response and survival after induction chemoradiotherapy in esophageal and gastroesophageal junction cancer: a single-centre retrospective cohort study.

BACKGROUND: Induction (neoadjuvant) chemoradiotherapy based on the CROSS regimen (weekly carboplatin/paclitaxel with concurrent radiation) is a standard of care for resectable esophageal and gastroesophageal junction (GEJ) cancer. However, the pivotal trials enrolled predominantly cT2-3 tumors with limited nodal involvement, did not stratify by nodal status, and largely excluded cT4, cN2-3, and oligometastatic (cM1) disease. Because these higher-risk patients are common in routine practice yet under-represented in trials, real-world data are needed to clarify how baseline nodal and clinical-stage affect outcomes after CROSS-based treatment. We evaluated the association between baseline clinical-stage and outcomes following CROSS-based treatment in a real-world cohort. METHODS: We performed a single-centre retrospective cohort study of consecutive patients treated with CROSS-based induction chemoradiotherapy [weekly carboplatin area under the curve (AUC) =2 and paclitaxel 50 mg/m2 with concurrent 41.4 Gy] for esophageal/GEJ cancer between 2012 and 2022 at a Canadian regional cancer centre. Patients were identified from institutional pathology and systemic-therapy databases, cross-referenced with electronic records, and stratified a priori by initial clinical staging: group 1 (cT1-3N0M0), group 2 (cT1-3N1M0), and group 3 (cT4 and/or cN2-3 and/or oligometastatic cM1), the latter largely excluded from CROSS-based trials. Overall survival (OS) and progression-free survival (PFS), both measured from diagnosis, were primary outcomes; resection rate and pathologic complete response (pCR) were secondary. Survival was estimated using Kaplan-Meier methods and compared with log-rank testing; multivariable Cox models adjusted for age, sex, and Eastern Cooperative Oncology Group (ECOG) status, with two-sided statistical significance defined as P<0.05. RESULTS: Among 138 patients (median age, 67 years; 81% male; 11% ECOG 2-3), 49% were group 1, 39% group 2, and 12% group 3, with no significant differences in age, sex, ECOG performance status, tumor location, histology, grade, or human epidermal growth factor receptor 2 (HER2) status. Overall, 86 deaths and 102 progression events occurred. Resection rates decreased with advancing clinical burden (70.6%, 57.4%, and 25.0%, respectively; P=0.004). Among resected patients, pCR occurred in 18.8%, 12.9%, and 0% (P=0.77). Median PFS was 34, 13, and 6 months, respectively (global log-rank P=0.001). Median OS was 46, 19, and 17 months (P=0.09). In adjusted models, PFS was significantly worse in group 2 [hazard ratio (HR) =1.86; 95% confidence interval (CI): 1.20-2.89] and group 3 (HR =2.84; 95% CI: 1.54-5.25), whereas the OS difference for group 3 was imprecise (HR =1.85; 95% CI: 0.91-3.78; P=0.09). CONCLUSIONS: Greater baseline clinical disease burden was associated with progressively lower resection and pCR rates and significantly shorter PFS following CROSS-based induction chemoradiotherapy, with outcomes for cN1 (group 2) patients approaching those of the advanced-stage group. Given the retrospective design and the small advanced-stage cohort, these findings are hypothesis-generating but are consistent with a need for intensified, systemic-dominant perioperative strategies for clinically node-positive, advanced locoregional, or oligometastatic esophageal/GEJ cancer.