A pilot study to reliably measure the tissue concentration of mitomycin C after hyperthermic intraperitoneal chemotherapy in patients with gastrointestinal malignancies.

Abstract

138 Background: HIPEC with MMC is a treatment for gastrointestinal cancers metastatic to the peritoneal cavity. The pharmacokinetics of MMC in plasma, peritoneal fluid, and urine are described. The amount of MMC in intraabdominal tissues after HIPEC are not well described. The aim of this study is to evaluate if MMC concentrated in tissue samples after HIPEC by high performance liquid chromatography (HPLC) from patients with gastrointestinal neoplasms. Methods: HIPEC was performed at 40°C with 40mg of MMC for 90 minutes, after which the peritoneal cavity was flushed, anastomoses created as needed, and the wound closed. Eligible patients were treated at a single institution, ≥18 years old, and underwent HIPEC with MMC. Samples were taken of the omentum, peritoneum, liver core biopsy, tumor, and mesenteric fat before and after HIPEC. All patients signed informed consent. Samples were frozen in liquid nitrogen, minced, and sonicated in 500µL of phosphate buffered saline. The homogenized samples were centrifuged, and the supernatant was analyzed by HPLC for MMC. The HPLC was performed using a Dionex Ultimate 3000. Analysis was performed with a Kinetex - 5µm Biphenyl 100A – 150 x 4.6mm column. MMC was detected with a Diode Array Detector 3000 with fixed UV at 365nm, 280nm, 254nm, and 210nm. The mobile phase used isocratic 40% acetonitrile and 60% water at 0.5 ml/min. The analysis volume was 10µL. Samples were blinded prior to analysis and analyzed in triplicate. Results: Thirteen patients were enrolled, 11 were female, the average age was 57 years (range: 30 – 85). Diagnoses were low-grade appendiceal mucinous neoplasm (7), high-grade appendiceal mucinous neoplasm (1), appendiceal adenocarcinoma (1), colon adenocarcinoma (1), colon mucinous adenocarcinoma (1), peritoneal mesothelioma (1), and small bowel mucinous adenocarcinoma (1). Complete tissue samples were available for 10 patients. Two patients had complete cytoreduction and did not have tumor for analysis after HIPEC. One patient refused liver biopsy. MMC was not detected in any sample prior to HIPEC. After HIPEC, MMC was most often detected in peritoneum (12 of 13 cases) and tumor (9 of 11). MMC was less often detected in omentum (5 of 13), mesenteric fat (2 of 13), or liver (1 of 12). Conclusions: MMC concentrated in 92% of peritoneal samples, 82% of tumor samples, and less often in liver tissue. MMC is hydrophilic which may contribute to the low detection rates in omentum and mesenteric fat. A reliable method to measure MMC concentration in normal and malignant tissues is novel and may have clinical implications. Our next steps are to expand the cohort of patients and evaluate whether tissue concentration is associated with clinical outcomes.