Prospective Clinical and Pharmacological Evaluation of the Delcath System's Second-Generation (GEN2) Hemofiltration System in Patients Undergoing Percutaneous Hepatic Perfusion with Melphalan

Abstract

Introduction: Percutaneous hepatic perfusion (PHP) with melphalan is an effective treatment for patients with hepatic metastases, but associated with high rates of bone marrow depression. To reduce systemic toxicity, improvements have been made to the filtration system. In pre-clinical studies, the Delcath System's GEN2 filter was superior to the first-generation filters. In this clinical study, we analysed the pharmacokinetics and toxicity of PHP using the new GEN2 filter.

Methods and materials: Starting February 2014, two prospective phase II studies were initiated in patients with hepatic metastases from ocular melanoma or colorectal cancer. In 10 PHP procedures performed in the first 7 enrolled patients, blood samples were obtained to determine filter efficiency and systemic drug exposure. PHP was performed with melphalan 3 mg/kg with a maximum of 220 mg. Complications were assessed according to CTCAE v4.03. Response was assessed according to RECIST 1.1.

Results: Pharmacokinetic analysis of blood samples showed an overall filter efficiency of 86% (range 71.1-95.5%). The mean filter efficiency decreased from 95.4% 10 min after the start of melphalan infusion to 77.5% at the end of the procedure (p = 0.051). Bone marrow depression was seen after up to 80.0% of 10 procedures, but was self-limiting and mostly asymptomatic. No hypotension-related complications or procedure-related mortality occurred.

Conclusion: The GEN2 filter has a higher melphalan filter efficiency compared to the first-generation filters and a more consistent performance. PHP with the GEN2 filter appears to have an acceptable safety profile, but this needs further validation in larger studies.

Keywords: Cancer; Chemoembolisation; Colorectal cancer; Interventional oncology; Liver; Uveal melanoma.

Fig. 1

Schematic overview of PHP circuit. Indicated are the pharmacokinetic sampling points

Fig. 2

Filter efficiency per patient at different time points during the procedure. The mean filter efficiency was calculated at three time points during the 10 procedures. First at ten minutes after the start of the melphalan infusion, then at the end of the melphalan infusion, and at the end of the washout period

Fig. 3

Mean systemic concentration of melphalan of all patients over time. A mean concentration of systemic melphalan was calculated at different time points; for all ten procedures, the bars indicate the standard deviation (SD). The horizontal dotted line at 0.5 µg/ml indicates the detection limit of melphalan in plasma