Poor drug distribution as a possible explanation for the results of the PRECISE trial

Author:

Sampson John H.123,Archer Gary13,Pedain Christoph4,Wembacher-Schröder Eva4,Westphal Manfred5,Kunwar Sandeep6,Vogelbaum Michael A.7,Coan April83,Herndon James E.83,Raghavan Raghu9,Brady Martin L.9,Reardon David A.1,Friedman Allan H.13,Friedman Henry S.13,Rodríguez-Ponce M. Inmaculada4,Chang Susan M.10,Mittermeyer Stephan4,Croteau David11,Puri Raj K.12,_ _

Affiliation:

1. Division of Neurosurgery, Department of Surgery,

2. Department of Pathology,

3. Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina;

4. BrainLAB AG, Feldkirchen;

5. Klinik und Poliklinik für Neurochirurgie, Hamburg, Germany;

6. California Center for Pituitary Disorders at University of California at San Francisco,

7. Cleveland Clinic, Cleveland, Ohio;

8. Cancer Center Biostatistics Unit, and

9. Therataxis, LLC, Baltimore; and

10. University of California at San Francisco, California;

11. Neopharm, Inc., Lake Bluff, Illinois;

12. Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland

Abstract

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 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 delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

Publisher

Journal of Neurosurgery Publishing Group (JNSPG)

Subject

Genetics,Animal Science and Zoology

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