10-year Outcome of a Randomized Trial Comparing Neoadjuvant Chemoradiotherapy and Surgery with Surgery Alone for Esophageal Cancer (CROSS trial)

Background: Neoadjuvant chemoradiotherapy according to the Chemo- Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. However, the long-term benefits and harms remain unclear.We aimed to assess the long-term outcomes of this regimen. Materials and Methods: From 2004 through 2008, 366 patients were randomly assigned to either five weekly cycles of intravenous carboplatin (area under the curve of 2 mg/mL/min) and paclitaxel (50 mg/m2 bodysurface area) on days 1, 8,15, 22, and 29 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. Overall survival was estimated with the Kaplan-Meier method and compared with Cox regression analyses. The effect beyond 5 years of follow-up was assessed by using landmark analyses. Also, cause-specific mortality was estimated with cumulative incidence functions and compared with Cox regression. Results: The median follow-up was 147 months (IQR 134-157). Patients who received neoadjuvant chemoradiotherapy had better overall survival (HR 0.70, 95%CI 0.55-0.89), with 10-year overall survival of 38% (95%CI 31- 45) in the neoadjuvant chemoradiotherapy plus surgery arm and 25% (95% CI 19-32) in the surgery alone arm. Landmark analyses showed that the overall survival benefit that was gained in the first 5 years, persisted beyond 5 years. The risk of death from esophageal cancer was lower for patients who received neoadjuvant chemoradiotherapy plus surgery (HR 0.60, 95% CI 0.46-0.80), while death from other causes was comparable between both study arms (HR 1.17, 95%CI 0.68-1.99). Conclusions: The overall survival benefit of patients with locally advanced resectable esophageal or esophagogastric junctional cancer who received neoadjuvant chemoradiotherapy plus surgery according to the CROSS regimen persists for at least 10 years, compared with surgery alone.