A Clinical Pharmacological Perspective on Intraperitoneal Chemotherapy

Abstract

Peritoneal metastases (PM), frequently observed in malignancies such as ovarian, colorectal, pancreatic, and gastric cancers, present a significant therapeutic challenge due to poor prognosis and limited effectiveness to systemic chemotherapy. The peritoneal-plasma barrier reduces effective drug transfer from plasma to the peritoneal cavity, reducing cytotoxic effects on PM. Intraperitoneal (IP) chemotherapy offers a locoregional approach, enabling high local drug concentrations that can enhance therapeutic efficacy while limiting systemic toxicity. The three major methods for IP administration-hyperthermic intraperitoneal chemotherapy (HIPEC), pressurized intraperitoneal aerosol chemotherapy (PIPAC), and catheter-based IP (CBIP) chemotherapy-each provide unique pharmacokinetic (PK) advantages for PM treatment. This review provides a comprehensive update on the pharmacological rationale of IP chemotherapy, focusing on drug characteristics that support extended IP retention and effective tumor targeting. The effects of administration variables are discussed, highlighting their role in optimizing IP drug exposure. Additionally, recent PK data on commonly used drugs in IP therapy, including platinum-based agents, taxanes, and novel nanoparticle formulations, will be evaluated. While PK rationale supports the administration of IP chemotherapy, further efficacy results from ongoing clinical trials are still awaited. Innovations in nanoparticle-based formulations and controlled-release systems offer substantial potential for improving both drug retention and targeted delivery, enhancing treatment precision and minimizing systemic toxicity. Continued exploration in these areas, along with optimization of IP administration protocols, is vital for advancing patient outcomes, refining therapeutic strategies, and maximizing the benefits of IP chemotherapy in clinical practice.

Fig. 1

Comparative overview of intraperitoneal chemotherapy (IP) modalities: HIPEC, CBIP chemotherapy, and PIPAC. HIPEC is a single intraoperative treatment using heated perfusate, often combined with cytoreductive surgery. CBIP chemotherapy involves repeated outpatient instillations and enables prolonged drug exposure. PIPAC is a minimally invasive laparoscopic approach delivering aerosolized chemotherapy under pressure, potentially enhancing distribution and tissue penetration. Drug suitability varies by method, with heat-stable, hydrophilic agents favored for HIPEC, while high molecular weight or slow-clearing agents such as paclitaxel and docetaxel are best suited for CBIP chemotherapy. PIPAC shows promise for certain nanoparticles, though clinical data are emerging. *Primarily applicable to patients with stage III ovarian cancer following neoadjuvant chemotherapy; not generally applicable to recurrent ovarian cancer or gastrointestinal malignancies. **Only patients with limited peritoneal disease that is deemed resectable are eligible for cytoreductive surgery combined with HIPEC

Fig. 2

Anatomy and structure of the peritoneum. The peritoneum forms the peritoneal–plasma barrier and lines the abdominopelvic cavity, covering the internal organs and abdominal wall. It consists of a single layer of mesothelial cells resting on a basement membrane, underlaid by five layers of connective tissue. This connective tissue contains interstitial cells, a matrix of collagen, hyaluronan, and proteoglycans, as well as pericytes, parenchymal cells, and blood capillaries

Fig. 3

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