Optimal Timing of Surgery Following Neoadjuvant Therapy for Surgical and Oncological Outcomes in Advanced Esophageal Squamous Cell Carcinoma: An Exploratory Analysis of JCOG1109

Abstract Background The optimal timing of surgery following neoadjuvant therapy in esophageal squamous cell carcinoma (ESCC) remains uncertain. This exploratory analysis aims to assess the impact of time to surgery (TTS) on perioperative and survival outcomes in patients with advanced ESCC enrolled in the phase III trial JCOG1109. Methods Patients who underwent esophagectomy following neoadjuvant chemotherapy or chemoradiotherapy were included. Within each treatment arm, patients were categorized into four TTS subgroups according to cohort quartiles. Perioperative complications, overall survival (OS), and progression-free survival (PFS) were evaluated. Results The median TTS was 35 (range, 16–81), 38 (17–109), and 41 (14–98) days for the cisplatin plus fluorouracil (CF), docetaxel, cisplatin plus fluorouracil, and CF with radiotherapy (CF-RT) arms, respectively. Baseline characteristics were comparable across the TTS subgroups. Operative time and overall complication rates showed no significant differences. In the CF-RT arm, a longer TTS was associated with increased blood loss (200, 210, 300, and 370 mL) and a trend toward a higher anastomotic leakage (6%, 7%, 14%, and 18%), as well as a trend toward poorer PFS and OS, particularly at more prolonged intervals. However, across all treatment arms, OS and PFS did not differ among the TTS subgroups, with multivariable analysis revealing no consistent associations between TTS and survival. Conclusions Time to surgery following neoadjuvant therapy did not significantly influence prognosis in advanced ESCC. Nonetheless, prolonged intervals after chemoradiotherapy may increase surgical complexity and leakage risk, in addition to elevating the potential for adverse prognostic effects associated with excessive delays.