Can Patients with Stage IVA Esophageal Squamous Cell Carcinoma Benefit from CROSS-based Neoadjuvant Therapy? A Single-center Retrospective Comparison with Stage II/III Disease

Abstract Background: Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is the standard of care for locally advanced esophageal cancer based on the CROSS trial. However, patients with clinical stage IVA disease were excluded from the CROSS trial, and no standard of care in this subgroup has been established. The benefit of neoadjuvant CCRT in this clinical setting remains uncertain. In this study, we explored the prognosis of patients with stage IVA disease who underwent neoadjuvant CCRT followed by esophagectomy, which is the standard of care for stage II/III disease. The study aimed were to investigate whether the same treatment modality administered to patients with more advanced stages would have comparable outcomes, and the influence of pathological response on prognosis in this setting. Materials and Methods: We retrospectively analyzed patients with clinical stage II–IVA (according to the AJCC 8 th edition definition) esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant CCRT followed by esophagectomy at MacKay Memorial Hospital between 2010 and 2023. Baseline characteristics, treatment patterns, and outcomes were compared between stage II/III and stage IVA patients. Kaplan–Meier survival analysis of overall survival (OS) and progression-free survival (PFS) was performed, stratified by pathological complete response (pCR). Results: A total of 215 patients were included (168 stage II/III; 47 stage IVA). The baseline characteristics were well balanced between the two groups. The median OS was significantly longer in the stage II/III patients compared to the stage IVA patients (31.18 vs. 19.00 months; hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.35–0.86, P = 0.0098). The median PFS was 19.47 versus 9.93 months (HR 0.54, 95% CI 0.36–0.85, P = 0.0065). In subgroup analysis stratified by pCR status, OS and PFS were similar among the patients without pCR regardless of the staging (stage II/III vs. stage IVA patients: median OS, 18.82 vs. 19.82 months; median PFS, 11.75 vs. 9.65 months). The stage IVA patients who achieved pCR had better outcomes compared to the stage II/III patients without pCR (median OS, 35.24 vs. 18.82 months; median PFS, 18.75 vs. 11.75 months). Conclusion: Neoadjuvant CCRT followed by surgery may offer meaningful survival benefits in select patients with stage IVA ESCC, particularly those who achieve pCR. Stage IVA was associated with a poorer prognosis overall compared to stage II/III, based on the same treatment strategy. However, pCR status appeared to be another important prognostic factor.