Neoadjuvant Therapy for Gastric Adenocarcinoma with Signet Ring Cells: A Systematic Review and Meta-Analysis

Background: Signet ring cell-containing gastric cancer constitutes an increasingly recognized subtype. Although perioperative chemotherapy is the standard of treatment for locally advanced gastric cancer, its efficacy in signet ring cell-containing gastric adenocarcinomas remains controversial. This systematic review and meta-analysis aims to assess the impact of neoadjuvant chemotherapy compared to upfront surgery on overall survival. Methods: A systematic search of MEDLINE, Scopus, and Cochrane was conducted up to January 2026. Eligible studies included adult patients with signet ring cell-containing gastric cancer undergoing neoadjuvant chemotherapy followed by surgery compared to upfront gastrectomy. A random-effects meta-analysis was performed to pool hazard ratios for overall survival. Results: Six studies, including seven cohorts and 5.388 patients, were included. The pooled analysis demonstrated no significant difference in overall survival between neoadjuvant chemotherapy and upfront surgery (HR 0.96, 95% CI 0.68–1.34, I2 = 83.2%). Subgroup analyses by studies’ geographic origin and design revealed consistent results with no significant differences in overall survival among Western (HR 0.85, 95% CI 0.53–1.38, I² = 86.9%) or Eastern studies (HR 1.12, 95% CI 0.63–1.97, I² = 83%), and among different study designs (randomized controlled trial: HR 1.16, 95% CI 0.81–1.67; observational: HR 0.92, 95% CI 0.62–1.38, I² = 85.5%). Conclusions: Neoadjuvant chemotherapy was not associated with a significant improvement in overall survival compared with upfront surgery in signet-ring cell-containing gastric cancer. While perioperative chemotherapy remains the recommended therapeutic approach, further studies employing contemporary chemotherapy regimens are warranted to define its role in this distinct histological subtype.