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

Loek A W De Jong,Nielka P Van Erp,Fortuné M K Elekonawo,Philip R De Reuver,David M Burger,Johannes H W De Wilt,Henk M W Verheul,Rob Ter Heine,Marie Lambert,Jan Marie De Gooyer,Andre J A Bremers,Etienne Chatelut

doi:10.1007/s00280-020-04107-y

Abstract

PurposeIn 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.MethodsTen 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.ResultsPeritoneal 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).ConclusionIn 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.

Highlights

Peritoneal metastasis of colorectal origin is identified in 5–10% of patients undergoing primary resection, and metachronous colorectal peritoneal metastasis occurs in 20–50% of patients during follow-up [1,2,3]
Substantial interpatient variability was demonstrated for platinum concentrations in both peritoneal tissue, blood, and drain fluid during and after hyperthermic intraperitoneal chemotherapy (HIPEC) procedure
Since platinum concentrations were prospectively collected in multiple compartments, including peritoneal fluid, peritoneal tissue, blood, and drain fluid, and this study provides insights in the further understanding of oxaliplatin distribution during HIPEC procedure

Summary

Introduction

Peritoneal metastasis of colorectal origin is identified in 5–10% of patients undergoing primary resection, and metachronous colorectal peritoneal metastasis occurs in 20–50% of patients during follow-up [1,2,3]. Despite the use of modern systemic chemotherapy regimens, patients with peritoneal metastasis of colorectal cancer have poor outcome with a median overall survival of 10–16 months [4, 5]. The rationale for HIPEC is to obtain high local drug concentrations and high penetration in tumour tissue with relatively low systemic exposure. In organoids derived from colorectal peritoneal metastases, a platinum concentration of 118–275 μg/ml in peritoneal fluid is required to eliminate 50% of tumour cells during 30-min HIPEC procedure [11]. These findings cannot be extrapolated to in vivo tumour nodules in patients, it provides insight in the importance of the drug concentration in peritoneal fluid. It seems reasonable to strive for the highest local tissue concentration while limiting systemic exposure to prevent toxicity to the patient and the treating personnel in the postoperative period.[13, 14]

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Results

Conclusion