J Neurosurg / Volume 113 / August 2010 J Neurosurg 113:301–309, 2010301CONVECTION-ENHANCED delivery is a novel intra ce-rebral drug delivery technique with considerable promise for delivering high concentrations of po-tent therapeutic agents throughout the CNS.1,9 Despite 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 in-active agents or a failure to rigorously validate drug tar-gets,4 we have previously demonstrated that target tissue anatomy and patient-specific physiology as they relate to catheter positioning play a major role in drug distribu-tion using this technique.16–18 Unlike systemic delivery, where extensive pharmacokinetic studies are carried out Poor drug distribution as a possible explanation for the results of the PRECISE trialClinical articleJOHN 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-SCHRÖDER,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 DAV I D A. REARDON, M.D.,1 ALLAN H. FRIEDMAN, M.D.,1,4 HENRY S. FRIEDMAN, M.D.,1,4 M. INMACULADA RODRÍGUEZ-PONCE, PH.D.,5 SUSAN M. CHANG, M.D.,10 STEPHAN MITTERMEYER,5 DAV I D CROTEAU, M.D.,11 RAJ K. PURI, M.D., PH.D.,12 AND THE PRECISE TRIAL INVESTIGATORS 1Division 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 für 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; 9Therataxis, LLC, Baltimore; and 12Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland 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 employ-ing 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 significant 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 efficacy of drugs delivered by CED may be severely constrained by ineffective de-livery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED. (DOI: 10.3171/2009.11.JNS091052)KEY WORDS • brain neoplasm • drug delivery system • interleukin-13 • planning software • convection-enhanced delivery301Abbreviations 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. H. Sampson et al.302 J Neurosurg / Volume 113 / August 2010in Phase II studies before Phase III studies are undertak-en, drug distribution by CED into the brain is difficult 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 lim-ited opportunities to monitor or predict drug distribution in the brain by CED. Clearly, failure to deliver drug to tumor-infiltrated 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 Pseudomo-nas-based exotoxin targeted to a uniquely expressed re-ceptor for IL-13, IL-13Rα2 (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 significant difference in OS be-tween 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 dis-tribution within the brain from CED. Prior work using radiolabeled albumin as a validated surrogate tracer11 for drug
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