J Neurosurg 113 301 309 2010 Poor drug distribution as a possible explanation for the results of the PRECISE trial Clinical article JOHN H SAMPSON M D PH D M H SC 1 2 4 GARY ARCHER PH D 1 4 CHRISTOPH PEDAIN PH D 5 EVA WEMBACHER SCHR DER 5 MANFRED WESTPHAL M D PH D 6 SANDEEP KUNWAR M D PH D 7 MICHAEL A VOGELBAUM M D PH D 8 APRIL COAN M P H 3 4 JAMES E HERNDON II PH D 3 4 RAGHU RAGHAVAN PH D 9 MARTIN L BRADY PH D 9 DAVID A REARDON M D 1 ALLAN H FRIEDMAN M D 1 4 HENRY S FRIEDMAN M D 1 4 M INMACULADA RODR GUEZ PONCE PH D 5 SUSAN M CHANG M D 10 STEPHAN MITTERMEYER 5 DAVID CROTEAU M D 11 RAJ K PURI M D PH D 12 AND THE PRECISE TRIAL INVESTIGATORS Division of Neurosurgery Department of Surgery 2Department of Pathology 3Cancer Center Biostatistics Unit and 4Preston Robert Tisch Brain Tumor Center Duke University Durham North Carolina 5BrainLAB AG Feldkirchen 6Klinik und Poliklinik f r Neurochirurgie Hamburg Germany 7California Center for Pituitary Disorders at University of California at San Francisco 10University of California at San Francisco California 8Cleveland Clinic Cleveland Ohio 11Neopharm Inc Lake Bluff Illinois 9 Therataxis LLC Baltimore and 12Center for Biologics Evaluation and Research Food and Drug Administration Rockville Maryland 1 Object Convection enhanced delivery CED is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS Despite this promise Phase III clinical trials employing CED have failed to meet clinical end points Although this may be due to inactive agents or a failure to rigorously validate drug targets the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial Methods Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses BrainLAB iPlan Flow software was used to estimate the expected drug distribution Results Only 49 8 of catheters met all positioning criteria Still catheter positioning score hazard ratio 0 93 p 0 043 and the number of optimally positioned catheters hazard ratio 0 72 p 0 038 had a signi cant effect on progression free survival Estimated coverage of relevant target volumes was low however with only 20 1 of the 2 cm penumbra surrounding the resection cavity covered on average Although tumor location and resection cavity volume had no effect on coverage volume estimations of drug delivery to relevant target volumes did correlate well with catheter score p 0 003 and optimally positioned catheters had larger coverage volumes p 0 002 Only overall survival p 0 006 was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score Conclusions The potential ef cacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the ef cacy of drugs delivered by CED DOI 10 3171 2009 11 JNS091052 KEY WORDS brain neoplasm interleukin 13 planning software C ONVECTION ENHANCED delivery is a novel intracerebral drug delivery technique with considerable promise for delivering high concentrations of potent therapeutic agents throughout the CNS 1 9 Despite Abbreviations used in this paper CB cintredekin besudotox CED convection enhanced delivery DT diffusion tensor GBM glioblastoma multiforme HR hazard ratio IL interleukin KPS Karnofsky Performance Scale OS overall survival PFS progression free survival J Neurosurg Volume 113 August 2010 drug delivery system convection enhanced delivery this promise Phase III clinical trials employing CED with direct intracerebral infusion for neoplastic7 9 13 15 19 20 and neurodegenerative2 10 12 conditions have failed to meet clinical end points Although this may be due to inactive agents or a failure to rigorously validate drug targets 4 we have previously demonstrated that target tissue anatomy and patient speci c physiology as they relate to catheter positioning play a major role in drug distribution using this technique 16 18 Unlike systemic delivery where extensive pharmacokinetic studies are carried out 301 J H Sampson et al in Phase II studies before Phase III studies are undertaken drug distribution by CED into the brain is dif cult to monitor This is because many of the agents administered by intracerebral CED have a high molecular weight or are used in such low concentrations and there are limited opportunities to monitor or predict drug distribution in the brain by CED Clearly failure to deliver drug to tumor in ltrated tissue might explain apparent failure of an active agent in these randomized clinical trials The PRECISE Phase III Randomized Evaluation of CED of IL13 PE38QQR with Survival Endpoint study NeoPharm Inc was a randomized Phase III trial that used CED for the intracerebral infusion of a Pseudomonas based exotoxin targeted to a uniquely expressed receptor for IL 13 IL 13R 2 S Kunwar et al presented at the annual meeting of the Society for Neuro Oncology Dallas Texas November 15 18 2007 The survival of patients with recurrent GBM treated with this targeted toxin CB cintredekin besudotox IL13 PE38QQR was compared with the survival of patients treated with local implantation of carmustine impregnated wafers Gliadel The study did not show a signi cant difference in OS between the study groups The extensive MR imaging data collected within the trial provides a valuable resource for exploring factors that may be critical to the therapeutic success of this agent especially drug delivery The iPlan Flow BrainLAB AG software uses data derived from DT MR imaging to predict the drug distribution within the brain from CED Prior work using radiolabeled albumin as a validated surrogate tracer11 for drug distribution16 18 has allowed retrospective validation of this software which was not available for use during the PRECISE trial This software was used in the present analysis to estimate drug distribution in the PRECISE trial and to assess the hypothesis that inadequate drug distribution may have played a role in the suboptimal results obtained in that trial which failed to meet its primary end point The data presented here demonstrate that catheter
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