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.