In situ distribution of metallic platinum in tumor tissues after intraperitoneal platinum chemotherapy assessed by digital synchrotron-abetted x-ray fluorescence microscopy.

Abstract

e13067 Background: Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) and catheter-administered intraperitoneal chemotherapy (CAIPEC) are used to treat peritoneal surface-spreading malignancies, including Malignant Peritoneal Mesothelioma (MPM), to maximize local drug concentrations. Previous HIPEC studies showed tissue penetration of cisplatin ~5mm from the peritoneal surface; biodistribution of CAIPEC has not been reported. Methods: Our protocol for MPM includes initial debulking surgery with HIPEC (41°C over 1 hour, drug is then removed), 6 cycles of CAIPEC (room temperature, indefinite dwell-time), and a second debulking surgery with HIPEC. To compare tissue drug penetrations in HIPEC versus CAIPEC, on an IRB-approved protocol we collected peritoneal tissue from 6 MPM patients receiving HIPEC at initial (n=2; both cisplatin) or second surgery (n=4; 2 cisplatin and 2 oxaliplatin) for digital image localization of in situ Pt by synchrotron-abetted (Brookhaven National Laboratory, Upton NY) x-ray fluorescence microscopy at a resolution of 10 microns. Results: Overall Pt levels were highest at second surgery post-HIPEC (median=26.1ppm, range: 2.2-113.4), lowest at initial surgery post-HIPEC (median=5.2ppm, range=4.7-5.8), and intermediate at second surgery pre-HIPEC (median=16.0ppm, range=5.6-21.8). Every sample had higher Pt at the peritoneal surface; also highest at second surgery post-HIPEC (median=40.4ppm, range=4.4-219.7), lowest at initial surgery post-HIPEC (median=11.3ppm, range=8.4-14.2), and intermediate at second surgery pre-HIPEC (median=25.9ppm, range=8.4-29.9). At second surgery, each sample’s overall Pt level was higher than contemporaneous plasma Pt, pre-HIPEC (median=0.27ppm, range=0.08-0.33) and post-HIPEC (median=1.86ppm, range=0.84-2.87). Conclusions: Both CAIPEC and HIPEC effect tissue drug accumulation, greatest at the peritoneal surface. The proportion of peritoneal surface Pt was lowest in second surgery pre-HIPEC samples, suggesting more homogeneous and/or extensive drug distribution in CAIPEC than HIPEC, likely due to longer dwell-time.