Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial

PURPOSE: Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen. METHODS: From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses. RESULTS: The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent (P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13). CONCLUSION: The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years