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

Publication ,  Journal Article
Sampson, JH; Archer, G; Pedain, C; Wembacher-Schröder, E; Westphal, M; Kunwar, S; Vogelbaum, MA; Coan, A; Herndon, JE; Raghavan, R; Brady, ML ...
Published in: J Neurosurg
August 2010

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.

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Published In

J Neurosurg

DOI

EISSN

1933-0693

Publication Date

August 2010

Volume

113

Issue

2

Start / End Page

301 / 309

Location

United States

Related Subject Headings

  • Treatment Failure
  • Tissue Distribution
  • Software
  • Retrospective Studies
  • Randomized Controlled Trials as Topic
  • Proportional Hazards Models
  • Neurology & Neurosurgery
  • Kaplan-Meier Estimate
  • Interleukin-13
  • Humans
 

Citation

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Sampson, J. H., Archer, G., Pedain, C., Wembacher-Schröder, E., Westphal, M., Kunwar, S., … PRECISE Trial Investigators. (2010). Poor drug distribution as a possible explanation for the results of the PRECISE trial. J Neurosurg, 113(2), 301–309. https://doi.org/10.3171/2009.11.JNS091052
Sampson, John H., Gary Archer, Christoph Pedain, Eva Wembacher-Schröder, Manfred Westphal, Sandeep Kunwar, Michael A. Vogelbaum, et al. “Poor drug distribution as a possible explanation for the results of the PRECISE trial.J Neurosurg 113, no. 2 (August 2010): 301–9. https://doi.org/10.3171/2009.11.JNS091052.
Sampson JH, Archer G, Pedain C, Wembacher-Schröder E, Westphal M, Kunwar S, et al. Poor drug distribution as a possible explanation for the results of the PRECISE trial. J Neurosurg. 2010 Aug;113(2):301–9.
Sampson, John H., et al. “Poor drug distribution as a possible explanation for the results of the PRECISE trial.J Neurosurg, vol. 113, no. 2, Aug. 2010, pp. 301–09. Pubmed, doi:10.3171/2009.11.JNS091052.
Sampson JH, Archer G, Pedain C, Wembacher-Schröder E, Westphal M, Kunwar S, Vogelbaum MA, Coan A, Herndon JE, Raghavan R, Brady ML, Reardon DA, Friedman AH, Friedman HS, Rodríguez-Ponce MI, Chang SM, Mittermeyer S, Croteau D, Puri RK, PRECISE Trial Investigators. Poor drug distribution as a possible explanation for the results of the PRECISE trial. J Neurosurg. 2010 Aug;113(2):301–309.

Published In

J Neurosurg

DOI

EISSN

1933-0693

Publication Date

August 2010

Volume

113

Issue

2

Start / End Page

301 / 309

Location

United States

Related Subject Headings

  • Treatment Failure
  • Tissue Distribution
  • Software
  • Retrospective Studies
  • Randomized Controlled Trials as Topic
  • Proportional Hazards Models
  • Neurology & Neurosurgery
  • Kaplan-Meier Estimate
  • Interleukin-13
  • Humans