Convection Enhanced Delivery of carmustine in diffuse intrinsic pontine glioma

Abstract

s ingediend voor het Amsterdam Kindersymposium 2013 113 Convection Enhanced Delivery of carmustine in diffuse intrinsic pontine glioma S.E.M. Veldhuijzen van Zanten (1), M.H.A. Jansen (1), D.G. van Vuurden (1,2), E. Hulleman (1,2), T. Lagerweij (2), S. Idema (3), D. P. Noske (2,3), N.I. Wolf (4), N.H. Hendrikse (5), W.P. Vandertop (3), G.J.L. Kaspers (1) (1) Department of Pediatrics, hematology oncology, VU medical center, Amsterdam (2) Neuro-oncology Research Group, VUmc Cancer Center Amsterdam (3) Neurosurgical Center Amsterdam (4) Department of Pediatrics, neurology, VU medical center, Amsterdam (5) Department of Clinical Pharmacology and Pharmacy, VU medical center, Amsterdam INTRODUCTION DIPG patients have a dismal prognosis with a median overall survival of nine months. Typically, surgical resection is not possible, radiotherapy has only temporary eff ect and systemic chemotherapeutics fail. Convection Enhanced Delivery (CED) provides high local drug concentrations and equal drug distribution directly at the tumor site through micro-catheters via a pressure gradient. In a murine CED-model, we injected DIPG with carmustine, a highly-active nitrosourea compound, and found a signifi cantly prolonged survival with no severe toxicity. Based on these preclinical data, and on studies in adults showing the safety of the procedure, we developed a clinical study in children with DIPG. METHODS Patients will be included at time of progression after initial radiotherapy. Catheters will be placed based on iPlan Flow simulations. Two cohorts of three patients will receive escalating concentrations of carmustine up to 50% of the maximum tolerated adult dose. Infusion-volume and infusion-rate will be determined by tumor-volume (maximum 7 ml). Co-infusion of gadolinium enables observation of distribution by MRI. Maximum infusion-duration will be 41 hours, during which a patient will be awake and observed intensively. Primary endpoints of this study are safety and feasibility. CONCLUSION Preclinical data has shown carmustine-CED to be safe and eff ective in DIPG mouse models. With this clinical study we intend to show safety and feasibility of carmustine administration via CED in patients with DIPG. This technique improves treatment options, and hopefully the dismal prognosis of patients in the future. Abstract fi gure: 3-dimensional simulation of CED in a child with DIPG (iPlan Flow BrainLAB AG). The tumor volume is orange-shaped. The red tract shows the safest route for catheter placement. In green, the spherically-shaped distribution volume of the therapeutic agent (based on MRI-DTI images). In this simulation the total infused volume was approximately 3-4 ml and the infusion rate was set to 3.0 μl/min. With expanding infusion volume and time, it is possible to distribute the therapeutic agent over the total tumor volume, resulting in high concentrations of the cytotoxic agent directly at the site of action.fi gure: 3-dimensional simulation of CED in a child with DIPG (iPlan Flow BrainLAB AG). The tumor volume is orange-shaped. The red tract shows the safest route for catheter placement. In green, the spherically-shaped distribution volume of the therapeutic agent (based on MRI-DTI images). In this simulation the total infused volume was approximately 3-4 ml and the infusion rate was set to 3.0 μl/min. With expanding infusion volume and time, it is possible to distribute the therapeutic agent over the total tumor volume, resulting in high concentrations of the cytotoxic agent directly at the site of action.