Prof. Jimmy SO National University of Singapore Singapore Link to biosketch

Abstract

Peritoneal metastasis (PM) is common and confers dismal prognosis. Conventional treatment is systemic chemotherapy but its effect is limited by chemoresistance and toxicity. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is the latest technique of peritoneal directed chemotherapy. Preclinical and early clinical studies have demonstrated its advantages which include (1) better distribution within the peritoneal cavity, (2) deeper penetration of chemotherapy into the tumors, (3) less systemic toxicity and (4) direct assessment of tumor response through laparoscopy. The surgical technique and PIPAC application are now standardized. The most used drugs in PIPAC are platinum (cisplatin and oxaliplatin) and doxorubicin. Our centre performed a dose escalation study of PIPAC with Oxaliplatin for patients with PM. Results showed that it was safe and there was a linear pharmacokinetics in the serum. The maximal tolerable dose of PIPAC oxaliplatin was 120mg/m². The recommended phase 2 dose of a combination of cisplatin and doxorubicin is 10.5mg/m² and 2.1mg/m² respectively. In terms of clinical efficacy, many retrospective and some prospective studies on PM from various primaries were published with encouraging results. For gastric cancer (GC) with unresectable PM, a recent French study showed an overall survival of 19 months, while 14% of patients became resectable and underwent debulking surgery. Two randomized phase 2 studies for GCPM are on-going. For ovarian cancer, a RCT comparing PIPAC with IV chemotherapy from India was recently reported. The objective response was better in PIPAC than IV (67% vs 23%) and G3-4 toxicity was lower in PIPAC than IV (10% vs 34%).

There are several novel approaches in PIPAC. We have started a first-in-human phase 1 study combining PIPAC with immunotherapy (Nivolumab) and the early results are encouraging. In addition, we performed a study on animal using PIPAC Paclitaxel and a clinical trial has been initiated. Nanoparticles (NPs) are attractive as drug delivery vehicles to sustain, target and enhance delivery of chemotherapeutics to tumor cells. A Belgium study reported favourable result using PIPAC with Nab-paclitaxel. Other groups are studying oncolytic viruses and clinical trials using PIPAC with oncolytic virus are on-going. A promising method to further enhance the distribution and penetration of intraperitoneal aerosols is the application of an external electrostatic field. The electrostatic generator is commercially available and we will apply this technique in our new clinical trial. Lastly, devices to deliver hyperthermic PIPAC were also developed, clinical results are awaiting. In summary, PIPAC is a promising technique to deliver intraperitoneal cytotoxic agents for cancer. It can also be used as platform to assess cancer longitudinally to unlock the molecular mechanisms of peritoneal carcinomatosis.