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

John H. Sampson, Gary Archer, Christoph Pedain, Eva Wembacher-Schröder, Manfred Westphal, Sandeep Kunwar, Michael A. Vogelbaum, April Coan, James E. Herndon, Raghu Raghavan, Martin L. Brady, Davi D A Reardon, Allan H. Friedman, Henry S. Friedman, M. Inmaculada Rodríguez-Ponce, Susan M. Chang, Stephan Mittermeyer, Davi Croteau, Raj K. Puri, James MacDowell Markert & 58 others Michael Prados, Thomas Chen, Adam Mamelak, Timothy Cloughesy, John Yu, Kevin Lillehei, Joseph Piepmeier, Edward Pan, Frank Vrionis, H. Lee Moffitt, Jeffrey Olson, James Chandler, Nina Paleologos, Richard W. Byrne, Maciej Lesniak, Jon David Weingart, Peter Black, Tom Mikkelsen, Joon Uhm, Richard Bucholz, Lauren Abrey, Theodore H. Schwartz, Jeffrey Bruce, Anthony Asher, Stephen Tatter, Gene Barnett, Antonio E. Chiocca, Johnny B. Delashaw, Kevin Judy, Sunil Patel, Bruce Frankel, Fred Lang, Pamela New, Karen Fink, Randy L. Jensen, Mark Shaffrey, Lynne Taylor, Warren Boling, Behnam Badie, Abhijit Guha, Vivek Mehta, Mark Hamilton, David D. Eisenstat, Farhad Pirouzmand, David Macdonald, Rolando Del Maestro, Daryl Fourney, Maximilian Mehdorn, Roland Goldbrunner, Gabriele Schackert, Andreas Unterberg, Zvi Ram, Zvi Cohen, Zvi Rappaport, Jan Jacob Mooij, John G. Wolbers, Peter Warnke, Varnavas Papanastassiou

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)301-309
Number of pages9
JournalJournal of Neurosurgery
Volume113
Issue number2
DOIs
StatePublished - Aug 2010

Fingerprint

Convection
Catheters
Pharmaceutical Preparations
Software
Patient Positioning
Karnofsky Performance Status
Phase III Clinical Trials
Disease-Free Survival
Research Personnel
Survival
Neoplasms

Keywords

  • Brain neoplasm
  • Convection-enhanced delivery
  • Drug delivery system
  • Interleukin-13
  • Planning software

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

Cite this

Sampson, J. H., Archer, G., Pedain, C., Wembacher-Schröder, E., Westphal, M., Kunwar, S., ... Papanastassiou, V. (2010). Poor drug distribution as a possible explanation for the results of the PRECISE trial. Journal of Neurosurgery, 113(2), 301-309. https://doi.org/10.3171/2009.11.JNS091052

Poor drug distribution as a possible explanation for the results of the PRECISE trial. / Sampson, John H.; Archer, Gary; Pedain, Christoph; Wembacher-Schröder, Eva; Westphal, Manfred; Kunwar, Sandeep; Vogelbaum, Michael A.; Coan, April; Herndon, James E.; Raghavan, Raghu; Brady, Martin L.; Reardon, Davi D A; Friedman, Allan H.; Friedman, Henry S.; Rodríguez-Ponce, M. Inmaculada; Chang, Susan M.; Mittermeyer, Stephan; Croteau, Davi; Puri, Raj K.; Markert, James MacDowell; Prados, Michael; Chen, Thomas; Mamelak, Adam; Cloughesy, Timothy; Yu, John; Lillehei, Kevin; Piepmeier, Joseph; Pan, Edward; Vrionis, Frank; Moffitt, H. Lee; Olson, Jeffrey; Chandler, James; Paleologos, Nina; Byrne, Richard W.; Lesniak, Maciej; Weingart, Jon David; Black, Peter; Mikkelsen, Tom; Uhm, Joon; Bucholz, Richard; Abrey, Lauren; Schwartz, Theodore H.; Bruce, Jeffrey; Asher, Anthony; Tatter, Stephen; Barnett, Gene; Chiocca, Antonio E.; Delashaw, Johnny B.; Judy, Kevin; Patel, Sunil; Frankel, Bruce; Lang, Fred; New, Pamela; Fink, Karen; Jensen, Randy L.; Shaffrey, Mark; Taylor, Lynne; Boling, Warren; Badie, Behnam; Guha, Abhijit; Mehta, Vivek; Hamilton, Mark; Eisenstat, David D.; Pirouzmand, Farhad; Macdonald, David; Del Maestro, Rolando; Fourney, Daryl; Mehdorn, Maximilian; Goldbrunner, Roland; Schackert, Gabriele; Unterberg, Andreas; Ram, Zvi; Cohen, Zvi; Rappaport, Zvi; Mooij, Jan Jacob; Wolbers, John G.; Warnke, Peter; Papanastassiou, Varnavas.

In: Journal of Neurosurgery, Vol. 113, No. 2, 08.2010, p. 301-309.

Research output: Contribution to journalArticle

Sampson, JH, Archer, G, Pedain, C, Wembacher-Schröder, E, Westphal, M, Kunwar, S, Vogelbaum, MA, Coan, A, Herndon, JE, Raghavan, R, Brady, ML, Reardon, DDA, Friedman, AH, Friedman, HS, Rodríguez-Ponce, MI, Chang, SM, Mittermeyer, S, Croteau, D, Puri, RK, Markert, JM, Prados, M, Chen, T, Mamelak, A, Cloughesy, T, Yu, J, Lillehei, K, Piepmeier, J, Pan, E, Vrionis, F, Moffitt, HL, Olson, J, Chandler, J, Paleologos, N, Byrne, RW, Lesniak, M, Weingart, JD, Black, P, Mikkelsen, T, Uhm, J, Bucholz, R, Abrey, L, Schwartz, TH, Bruce, J, Asher, A, Tatter, S, Barnett, G, Chiocca, AE, Delashaw, JB, Judy, K, Patel, S, Frankel, B, Lang, F, New, P, Fink, K, Jensen, RL, Shaffrey, M, Taylor, L, Boling, W, Badie, B, Guha, A, Mehta, V, Hamilton, M, Eisenstat, DD, Pirouzmand, F, Macdonald, D, Del Maestro, R, Fourney, D, Mehdorn, M, Goldbrunner, R, Schackert, G, Unterberg, A, Ram, Z, Cohen, Z, Rappaport, Z, Mooij, JJ, Wolbers, JG, Warnke, P & Papanastassiou, V 2010, 'Poor drug distribution as a possible explanation for the results of the PRECISE trial', Journal of Neurosurgery, vol. 113, no. 2, pp. 301-309. 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. Journal of Neurosurgery. 2010 Aug;113(2):301-309. https://doi.org/10.3171/2009.11.JNS091052
Sampson, John H. ; Archer, Gary ; Pedain, Christoph ; Wembacher-Schröder, Eva ; Westphal, Manfred ; Kunwar, Sandeep ; Vogelbaum, Michael A. ; Coan, April ; Herndon, James E. ; Raghavan, Raghu ; Brady, Martin L. ; Reardon, Davi D A ; Friedman, Allan H. ; Friedman, Henry S. ; Rodríguez-Ponce, M. Inmaculada ; Chang, Susan M. ; Mittermeyer, Stephan ; Croteau, Davi ; Puri, Raj K. ; Markert, James MacDowell ; Prados, Michael ; Chen, Thomas ; Mamelak, Adam ; Cloughesy, Timothy ; Yu, John ; Lillehei, Kevin ; Piepmeier, Joseph ; Pan, Edward ; Vrionis, Frank ; Moffitt, H. Lee ; Olson, Jeffrey ; Chandler, James ; Paleologos, Nina ; Byrne, Richard W. ; Lesniak, Maciej ; Weingart, Jon David ; Black, Peter ; Mikkelsen, Tom ; Uhm, Joon ; Bucholz, Richard ; Abrey, Lauren ; Schwartz, Theodore H. ; Bruce, Jeffrey ; Asher, Anthony ; Tatter, Stephen ; Barnett, Gene ; Chiocca, Antonio E. ; Delashaw, Johnny B. ; Judy, Kevin ; Patel, Sunil ; Frankel, Bruce ; Lang, Fred ; New, Pamela ; Fink, Karen ; Jensen, Randy L. ; Shaffrey, Mark ; Taylor, Lynne ; Boling, Warren ; Badie, Behnam ; Guha, Abhijit ; Mehta, Vivek ; Hamilton, Mark ; Eisenstat, David D. ; Pirouzmand, Farhad ; Macdonald, David ; Del Maestro, Rolando ; Fourney, Daryl ; Mehdorn, Maximilian ; Goldbrunner, Roland ; Schackert, Gabriele ; Unterberg, Andreas ; Ram, Zvi ; Cohen, Zvi ; Rappaport, Zvi ; Mooij, Jan Jacob ; Wolbers, John G. ; Warnke, Peter ; Papanastassiou, Varnavas. / Poor drug distribution as a possible explanation for the results of the PRECISE trial. In: Journal of Neurosurgery. 2010 ; Vol. 113, No. 2. pp. 301-309.
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title = "Poor drug distribution as a possible explanation for the results of the PRECISE trial",
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.",
keywords = "Brain neoplasm, Convection-enhanced delivery, Drug delivery system, Interleukin-13, Planning software",
author = "Sampson, {John H.} and Gary Archer and Christoph Pedain and Eva Wembacher-Schr{\"o}der and Manfred Westphal and Sandeep Kunwar and Vogelbaum, {Michael A.} and April Coan and Herndon, {James E.} and Raghu Raghavan and Brady, {Martin L.} and Reardon, {Davi D A} and Friedman, {Allan H.} and Friedman, {Henry S.} and Rodr{\'i}guez-Ponce, {M. Inmaculada} and Chang, {Susan M.} and Stephan Mittermeyer and Davi Croteau and Puri, {Raj K.} and Markert, {James MacDowell} and Michael Prados and Thomas Chen and Adam Mamelak and Timothy Cloughesy and John Yu and Kevin Lillehei and Joseph Piepmeier and Edward Pan and Frank Vrionis and Moffitt, {H. Lee} and Jeffrey Olson and James Chandler and Nina Paleologos and Byrne, {Richard W.} and Maciej Lesniak and Weingart, {Jon David} and Peter Black and Tom Mikkelsen and Joon Uhm and Richard Bucholz and Lauren Abrey and Schwartz, {Theodore H.} and Jeffrey Bruce and Anthony Asher and Stephen Tatter and Gene Barnett and Chiocca, {Antonio E.} and Delashaw, {Johnny B.} and Kevin Judy and Sunil Patel and Bruce Frankel and Fred Lang and Pamela New and Karen Fink and Jensen, {Randy L.} and Mark Shaffrey and Lynne Taylor and Warren Boling and Behnam Badie and Abhijit Guha and Vivek Mehta and Mark Hamilton and Eisenstat, {David D.} and Farhad Pirouzmand and David Macdonald and {Del Maestro}, Rolando and Daryl Fourney and Maximilian Mehdorn and Roland Goldbrunner and Gabriele Schackert and Andreas Unterberg and Zvi Ram and Zvi Cohen and Zvi Rappaport and Mooij, {Jan Jacob} and Wolbers, {John G.} and Peter Warnke and Varnavas Papanastassiou",
year = "2010",
month = "8",
doi = "10.3171/2009.11.JNS091052",
language = "English (US)",
volume = "113",
pages = "301--309",
journal = "Journal of Neurosurgery",
issn = "0022-3085",
publisher = "American Association of Neurological Surgeons",
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TY - JOUR

T1 - Poor drug distribution as a possible explanation for the results of the PRECISE trial

AU - Sampson, John H.

AU - Archer, Gary

AU - Pedain, Christoph

AU - Wembacher-Schröder, Eva

AU - Westphal, Manfred

AU - Kunwar, Sandeep

AU - Vogelbaum, Michael A.

AU - Coan, April

AU - Herndon, James E.

AU - Raghavan, Raghu

AU - Brady, Martin L.

AU - Reardon, Davi D A

AU - Friedman, Allan H.

AU - Friedman, Henry S.

AU - Rodríguez-Ponce, M. Inmaculada

AU - Chang, Susan M.

AU - Mittermeyer, Stephan

AU - Croteau, Davi

AU - Puri, Raj K.

AU - Markert, James MacDowell

AU - Prados, Michael

AU - Chen, Thomas

AU - Mamelak, Adam

AU - Cloughesy, Timothy

AU - Yu, John

AU - Lillehei, Kevin

AU - Piepmeier, Joseph

AU - Pan, Edward

AU - Vrionis, Frank

AU - Moffitt, H. Lee

AU - Olson, Jeffrey

AU - Chandler, James

AU - Paleologos, Nina

AU - Byrne, Richard W.

AU - Lesniak, Maciej

AU - Weingart, Jon David

AU - Black, Peter

AU - Mikkelsen, Tom

AU - Uhm, Joon

AU - Bucholz, Richard

AU - Abrey, Lauren

AU - Schwartz, Theodore H.

AU - Bruce, Jeffrey

AU - Asher, Anthony

AU - Tatter, Stephen

AU - Barnett, Gene

AU - Chiocca, Antonio E.

AU - Delashaw, Johnny B.

AU - Judy, Kevin

AU - Patel, Sunil

AU - Frankel, Bruce

AU - Lang, Fred

AU - New, Pamela

AU - Fink, Karen

AU - Jensen, Randy L.

AU - Shaffrey, Mark

AU - Taylor, Lynne

AU - Boling, Warren

AU - Badie, Behnam

AU - Guha, Abhijit

AU - Mehta, Vivek

AU - Hamilton, Mark

AU - Eisenstat, David D.

AU - Pirouzmand, Farhad

AU - Macdonald, David

AU - Del Maestro, Rolando

AU - Fourney, Daryl

AU - Mehdorn, Maximilian

AU - Goldbrunner, Roland

AU - Schackert, Gabriele

AU - Unterberg, Andreas

AU - Ram, Zvi

AU - Cohen, Zvi

AU - Rappaport, Zvi

AU - Mooij, Jan Jacob

AU - Wolbers, John G.

AU - Warnke, Peter

AU - Papanastassiou, Varnavas

PY - 2010/8

Y1 - 2010/8

N2 - 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.

AB - 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.

KW - Brain neoplasm

KW - Convection-enhanced delivery

KW - Drug delivery system

KW - Interleukin-13

KW - Planning software

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