Wide variation in tissue, systemic, and drain fluid exposure after oxaliplatin-based HIPEC: results of the GUTOX study

Abstract

Purpose In this exploratory study, the effect of postprocedural flushing with crystalloids after oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) on platinum concentrations in peritoneal tissue, blood, and drain fluid was studied. Interpatient variability in oxaliplatin pharmacokinetics and the relation between platinum concentration in peritoneal fluid and platinum exposure in tissue and blood was explored. Methods Ten patients with peritoneal carcinomatosis of colorectal origin were treated with HIPEC including postprocedural flushing, followed by ten patients without flushing afterwards. Tissue, peritoneal fluid, blood, and drain fluid samples were collected for measurement of total and ultrafiltered platinum concentrations. Results Peritoneal tissue concentration and systemic ultrafiltered platinum exposure showed large inter individual variability, ranging from 65 to 1640 µg/g dry weight and 10.5 to 28.0 µg*h/ml, respectively. No effect of flushing was found on geometric mean platinum concentration in peritoneal tissue (348 vs. 356 µg/g dry weight), blood (14.8 vs. 18.1 µg*h/ml), or drain fluid (day 1: 7.6 vs. 7.7 µg/ml; day 2: 1.7 vs. 1.9 µg/ml). The platinum concentration in peritoneal fluid at the start of HIPEC differed twofold between patients and was positively correlated with systemic exposure (p = .04) and peak plasma concentration (p = .04). Conclusion In this exploratory study, no effect was found for postprocedural flushing on platinum concentrations in peritoneal tissue, blood, or drain fluid. BSA-based HIPEC procedure leads to large interpatient variability in platinum exposure in all compartments. The study was registered at ClinicalTrials.gov on 7 December 2017 under registration number NCT03364907.

Using HPLC for the determination of platinum drugs in biological matrixes after derivatization with diethyldithiocarbamate

“…Among other protocols that generally focus on the determination of platinum drugs in peritoneal fluid or lavage, there are two general approaches: (i) determination of total platinum content [17,51] and (ii) analysis of ultrafiltered samples [25,52,53]. We chose to use the total platinum assessment.…”

“…Bioanalysis involves three main objectives, namely the determination of (i) total platinum content, (ii) intact platinum drugs, and (iii) platinum-DNA adducts. Methods for the quantification of platinum drugs are often based on inductively coupled plasma mass spectrometry (ICP-MS) detection [17,[20][21][22][23], atomic absorption spectrometry, graphite furnace atomic absorption spectrometry [24], and flameless atomic absorption spectrometry [25,26]. In practice, ICP-MS remains the method of choice for the determination of platinum drugs suitable for the analysis of the total amount of a metal.…”