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

Clinical article

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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.

Article Information

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.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Diagram showing catheter scoring based on catheter positioning criteria as outlined in Tables 1 and 2.

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    Distribution of total catheter scores.

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    Kaplan-Meier curves showing PFS and OS for patients in the PRECISE trial that were randomized to receive catheter placement.

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    Kaplan-Meier curves showing PFS (left) and OS (right) for patients in the PRECISE trial who were randomized to receive catheter placement and designated as having optimally or suboptimally positioned catheters. After adjusting for age and KPS score, a small, but significant, effect of optimally positioned catheters was found on PFS (p = 0.038, HR = 0.72, 95% CI 0.52–0.98). Patients in the optimally positioned catheter groups had 2 or more catheters that were scored 1 or 2.

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    Screen shots showing simulations performed in iPlan Flow used to estimate drug delivery (green) and coverage of clinically relevant volumes on T2-weighted MR images. The plane of images is shown by intersecting blue lines. In this case, all 3 catheters were scored 2 out of 2. The 2-cm penumbra around the resection cavity is shown in orange. Drug coverage of this volume at the 10% isodose line is estimated to be 39.5%.

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    Correlation of total catheter score and estimated coverage of various clinically relevant target areas at risk for tumor recurrence. A significant correlation between catheter score and the coverage volumes was found for the 1-cm penumbra (r = 0.45, p = 0.0003, Spearman), 2-cm penumbra (r = 0.55, p < 0.0001), T2 edema (r = 0.57, p < 0.0001), and the combined area of the 2-cm penumbra and T2 edema (r = 0.59, p < 0.0001).

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    Comparison of estimated coverage of the combined area of T2 edema and the 2-cm penumbra around the resection cavity in patients with optimal or suboptimal catheter positioning. There was a significant difference in coverage volumes between those patients with optimally positioned catheters and those with suboptimally positioned catheters when assessing the 1-cm penumbra (p = 0.008), 2-cm penumbra (p = 0.002), T2 edema (p = 0.0003), or the combined area of the 2-cm penumbra and T2 edema (p = 0.0002, t-test).

  • View in gallery

    Kaplan-Meier curves showing PFS (left) and OS (right) for patients in the PRECISE trial who were randomized to receive catheter placement. Patients treated by experienced and inexperienced investigators are shown. Investigators were designated as experienced if they had performed catheter placement on 2 or more patients. The OS remained significantly longer for patients treated by experienced investigators after adjusting for age, KPS score, and tumor location (p = 0.0098, HR 0.63, 95% CI 0.44–0.89).

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