Combined Intraperitoneal and Systemic Chemotherapy for Peritoneal Metastases: Drug Delivery Concepts, Pharmacokinetics, and Clinical Applications: A Narrative Review

<b>Background/Objectives:</b> Peritoneal metastases (PMs) remain difficult to treat because the peritoneum-plasma barrier limits drug penetration from the systemic circulation. Intraperitoneal chemotherapy (IPC), particularly repeated intraperitoneal (IP) administration via implantable ports, can achieve high local drug exposure with prolonged retention. This review summarizes the pharmacological rationale, clinical evidence, and future directions of catheter-based IPC, with emphasis on combined IP and systemic chemotherapy for ovarian, gastric, and pancreatic cancers. <b>Methods:</b> We narratively reviewed prospective clinical trials and key retrospective studies evaluating IPC and compared repeated catheter-based IPC with hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). Efficacy, safety, practice considerations, and opportunities for ascites-based monitoring were examined. <b>Results:</b> In ovarian cancer, several randomized trials demonstrated improved progression-free survival (PFS), and in selected trials, improved overall survival (OS) was demonstrated using IP plus intravenous (IV) therapy, although in the latter trials, toxicity and catheter-related complications limited treatment completion. A phase III Intraperitoneal Therapy for Ovarian Cancer with Carboplatin (iPocc) trial further showed significantly prolonged PFS with IP carboplatin and weekly paclitaxel, with non-catheter-related toxicity comparable to that of IV therapy. In gastric and pancreatic cancer, phase II studies reported symptomatic control, cytologic conversion, and higher rates of conversion surgery in selected patients, although confirmatory phase III data are limited. Device complications, including infection, obstruction, and leakage, occurred, but were manageable. <b>Conclusions:</b> Repeated catheter-based IPC is a feasible approach that enhances intraperitoneal drug delivery and complements IV chemotherapy. Future priorities include randomized trials, pharmacokinetic optimization, and biomarker-guided patient selection, supported by serial ascites assessment to refine indications and improve outcomes.