Neoadjuvant therapy for gastric adenocarcinoma with signet ring cells: a systematic review and meta-analysis

Background and aim: Signet ring cell-containing gastric cancer constitutes an increasingly recognized subtype, particularly in Western countries, associated with younger age at initial diagnosis, more aggressive biological behavior, and poor survival. Although perioperative chemotherapy is the standard of treatment for locally advanced gastric cancer in Western populations, its therapeutic 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 and secondary postoperative outcomes in signet ring cell-containing gastric cancer. Methods: A systematic search of MEDLINE, Scopus, and Cochrane was conducted up to October 2025 according to PRISMA 2020 guidelines. Eligible studies included adult patients diagnosed 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%), as well as 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%). Conclusion: Neoadjuvant chemotherapy did not achieve a significantly greater overall survival over upfront surgery in signet-ring cell-containing gastric cancer. While perioperative chemotherapy remains the recommended therapeutic approach, its efficacy should be further explored in subtype-specific randomized controlled trials to provide evidence-based recommendations and inform clinical practice.