Phase I study of hepatic arterial melphalan infusion and hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies

Abstract

Purpose: We conducted a phase I study of a 30-minute hepatic artery infusion of melphalan via a percutaneously placed catheter and hepatic venous hemofiltration using a double balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent through an activated charcoal filter and then to the systemic circulation. The purpose of the study was to demonstrate feasibility in an initial cohort and subsequently determine the maximum tolerated dose and dose-limiting toxicity of melphalan.

Patients and methods: The initial cohort (n = 12) was treated with 2.0 mg/kg of melphalan before dose escalation to 3.5 mg/kg (n = 16). Total hepatic drug delivery, systemic levels, and percent filter efficiency were determined. Patients were assessed for hepatic and systemic toxicity and response.

Results: A total of 74 treatments were administered to 28 patients. Twelve patients with primary and metastatic hepatic tumors received 30 treatments (mean, 2.5 per patient) at an initial melphalan dose of 2.0 mg/kg. At 3.5 mg/kg, a dose-limiting toxicity (neutropenia and/or thrombocytopenia) was observed in two of six patients. Transient grade 3/4 hepatic and systemic toxicity was seen after 19% and 66% of treatments, respectively. An overall radiographic response rate of 30% was observed in treated patients. In the 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses.

Conclusion: Delivery of melphalan via this system is feasible, with limited, manageable toxicity and evidence of substantial antitumor activity; 3 mg/kg is the maximum safe tolerated dose of melphalan administered via this technique.

Fig 1

(A) Diagram of the Delcath Catheter System (Delcath Inc, Stamford, CT): Melphalan is administered directly into the hepatic artery through a catheter placed percutaneously. Hepatic venous outflow is collected via a double balloon catheter in the retrohepatic inferior vena cava, and run through a pair of activated charcoal filters before return to the systemic circulation. (B) Depiction of the isolated retrohepatic inferior vena cava (IVC): Hepatic venous outflow is isolated by inflating two balloons in the IVC. (C) Fluoroscopic image of the isolated retrohepatic IVC segment obtained by retrograde injection of contrast through the interballoon fenestrations, to confirm the absence of systemic leak. This study is performed while caval flow is obstructed, and thus complete retrograde filling of both hepatic veins is not accomplished.

Fig 2

(A) Intrahepatic melphalan delivery. The pharmacokinetic profile of a single treatment demonstrates the rapid establishment of Cmax in the hepatic circulation, followed by a rapid washout phase. (B) Graphic representation of filter efficiency across multiple melphalan dosing cohorts. AUC, area under the concentration-time curve.

Fig 3

A 38-year-old man with metastatic ocular melanoma treated with four Delcath hepatic perfusions with melphalan. A complete response was observed for 10 months, at which time new hepatic metastases were noted. The patient underwent a second series of four treatments with a similar response and no cumulative toxicity. PHP, percutaneous hepatic perfusion.