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Raghu Raghavan, Martin L. Brady, María Inmaculada Rodríguez-Ponce, Andreas Hartlep, Christoph Pedain and John H. Sampson

✓ Convection-enhanced delivery (CED) is the continuous injection under positive pressure of a fluid containing a therapeutic agent. This technique was proposed and introduced by researchers from the US National Institutes of Health (NIH) by the early 1990s to deliver drugs that would otherwise not cross the blood–brain barrier into the parenchyma and that would be too large to diffuse effectively over the required distances were they simply deposited into the tissue. Despite the many years that have elapsed, this technique remains experimental because of both the absence of approved drugs for intraparenchymal delivery and the difficulty of guaranteed delivery to delineated regions of the brain. During the first decade after the NIH researchers founded this analytical model of drug distribution, the results of several computer simulations that had been conducted according to more realistic assumptions were also published, revealing encouraging results. In the late 1990s, one of the authors of the present paper proposed the development of a computer model that would predict the distribution specific to a particular patient (brain) based on obtainable data from radiological images. Several key developments in imaging technology and, in particular, the relationships between image-obtained quantities and other parameters that enter models of the CED process have been required to implement this model. Note that delivery devices need further development.

In the present paper we review key features of CED as well as modeling of the procedure and indulge in informed speculation on optimizing the direct delivery of therapeutic agents into brain tissue.

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Editorial

Convection-enhanced delivery

John H. Sampson, Raghu Raghavan, Martin Brady, Allan H. Friedman and Darell Bigner

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John H. Sampson, Gary Archer, Christoph Pedain, Eva Wembacher-Schröder, Manfred Westphal, Sandeep Kunwar, Michael A. Vogelbaum, April Coan, James E. Herndon II, Raghu Raghavan, Martin L. Brady, David A. Reardon, Allan H. Friedman, Henry S. Friedman, M. Inmaculada Rodríguez-Ponce, Susan M. Chang, Stephan Mittermeyer, David Croteau, Raj K. Puri and PRECISE Trial Investigators

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.