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

Clinical article

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  • 1 Division of Neurosurgery, Department of Surgery,
  • 2 Department of Pathology,
  • 3 Cancer Center Biostatistics Unit, and
  • 4 Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina;
  • 5 BrainLAB AG, Feldkirchen;
  • 6 Klinik und Poliklinik für Neurochirurgie, Hamburg, Germany;
  • 7 California Center for Pituitary Disorders at University of California at San Francisco,
  • 10 University of California at San Francisco, California;
  • 8 Cleveland Clinic, Cleveland, Ohio;
  • 11 Neopharm, Inc., Lake Bluff, Illinois;
  • 9 Therataxis, LLC, Baltimore; and
  • 12 Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland
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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.

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.

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Contributor Notes

Address correspondence to: John H. Sampson, M.D., Ph.D., M.H.Sc., Duke University Medical Center, Box 3050, Durham, North Carolina 27710. email: john.sampson@duke.edu.

Please include this information when citing this paper: published online December 18, 2009; DOI: 10.3171/2009.11.JNS091052.

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