Molecular signals associated with intraperitoneal chemotherapy resistance in gastric cancer with peritoneal metastasis

Gastric cancer remains a significant global health burden, ranking as the fifth most common malignancy and the fourth leading cause of cancer-related mortality worldwide. The prognosis is particularly dismal for patients with peritoneal metastasis (PM), a condition that affects up to 40% of surgical cohorts and is associated with a median survival time of merely 2 to 9 months. The standard systemic chemotherapy regimens, typically comprising fluoropyrimidines, platinum agents, or taxanes, have shown limited efficacy in PM due to the peritoneal-plasma barrier, which impedes the effective distribution of these cytotoxic agents into the peritoneal cavity.To overcome this therapeutic challenge, novel treatment modalities have been explored, including intraperitoneal (IP) chemotherapy. The PIPS-GC (Perioperative IntraPeritoneal and Systemic chemotherapy for Gastric Cancer) study group has pioneered a regimen combining IP paclitaxel with systemic S-1 and oxaliplatin (SOX) for patients with PM from gastric cancer. This approach leverages the pharmacokinetic advantages of IP paclitaxel, which maintains high local concentrations with modest systemic toxicity and demonstrates superior tissue penetration. The multicenter prospective PIPS-GC trial in Korea has progressed through phase I, establishing the maximum tolerated dose of IP paclitaxel, and phase II, which has shown promising survival benefits. With overall response rates exceeding 70% in various trials of IP paclitaxel, there is now a critical need to identify biomarkers that can predict treatment response and guide patient selection for this therapeutic approach.