Efficacy Of Convection-enhanced Delivery Research Articles

A Biphasic Fluid-Structure Interaction Model of Backflow During Infusion Into Agarose Gel.

The efficacy of convection-enhanced delivery as a technique to treat disorders of the central nervous system is limited by backflow, in which the infused fluid flows backwards along surface of the catheter rather than towards the targeted area. In order to improve treatment protocols, finite element models of backflow have been developed to understand the underlying physics. Garcia et al. (Journal of Computational and Nonlinear Dynamics, 8:011017, 2013) presented a finite element model that accounted for the flow in the annular gap that develops between the tissue and the outer surface of the catheter by using a layer of biphasic elements with a formula for the axial hydraulic conductivity to represent annular Poiseuille flow. In this study, we present a generalization of that model using fluid-FSI and biphasic-FSI elements that are recently available in FEBio. We demonstrate that our model of a 0.98-mm-radius catheter is able to reproduce experimental backflow lengths and maximum fluid pressures for infusions into a brain tissue surrogate and that it agrees well with the previous model by Garcia et al. (2013). The model predicts that the backflow length and the total amount of flow into the hemispherical region forward of the catheter tip is comparable for two different catheter sizes, albeit at a higher fluid pressure for the smaller catheter. This biphasic-FSI model has the potential to be extended to a stepped catheter geometry, which has been shown in experiments to be successful in controlling backflow.

SURG-24. REPEAT CONVECTION-ENHANCED DELIVERY FOR DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract INTRODUCTION While the safety and efficacy of convection-enhanced delivery (CED) have been studied in patients receiving single dose drug infusions, agents for oncologic therapy require repeated or chronic infusions to maintain therapeutic concentrations. Repeat/chronic CED infusions have rarely been described for oncologic purposes. We report on the safety and experience in a group of pediatric patients who received sequential CED into the brainstem for the treatment of diffuse intrinsic pontine glioma (DIPG). METHODS Patients were enrolled in a phase I single center clinical trial using 124I-8H9 monoclonal antibody (124I-Omburtamab, Y-mAbs Therapeutics) administered by CED (NCT01502917). Retrospective chart review was used to assess demographic data, CED infusion data, and post-operative neurologic and surgical outcomes. MRI scans were analyzed using iPlan® Flow software (Brainlab AG, Munich, Germany) for volumetric measurements. Target and catheter coordinates as well as radial, depth, and absolute error in MRI space were calculated with the Clearpoint imaging software (Clearpoint®, MRI Interventions Inc. Irvine, USA). RESULTS Seven patients underwent two or more sequential CED infusions. No patients experienced deficits Clinical Terminology Criteria for Adverse Events (CTCAE) grade 3 or greater. One patient had persistent grade 2 cranial nerve deficit after a second infusion. No patients experienced hemorrhage or stroke post-operatively. There was a statistically significant decrease in radial error (p= 0.005) and absolute tip error (p=0.008) for infusion two compared to the initial infusion. Sequential infusions did not result in significantly different distribution capacity between the first and second infusion (Vd:Vi ratio: 2.66 ± 0.35 versus 2.42 ± 0.75; p=0.45). CONCLUSIONS This series demonstrates the ability to safely perform sequential CED infusions into the pediatric brainstem. Past treatments did not negatively influence the procedural work flow, technical application of the targeting interface, or distribution capacity. This limited experience provides a foundation for using repeat CED for oncologic purposes.

Abstract B27: Toxicity of convection-enhanced delivery with doxorubicin to treat pediatric brain-tumors depends on anatomical location

Abstract Introduction and Aim: Diffuse Intrinsic Pontine Glioma (DIPG) and pediatric High Grade Glioma (pHGG) are primary pediatric brain tumors that have a very high mortality and morbidity. Especially tumors that are not (DIPG) or only partially (midline pHGG) eligible for surgical resection have a very poor prognosis. Systemic chemotherapy regimens have failed to deliver satisfactory results but convection enhanced delivery (CED) is a promising technique that delivers chemotherapeutics directly to the tumor. Determining the best agent to deliver via CED is a challenge. Doxorubicin has shown to be highly effective when delivered via CED in preclinical glioma models, and against pHGG and DIPG cells in vitro. Liposomal doxorubicin is thought to improve distribution, bio-availability and subsequent efficacy of CED in glioma models. This preclinical study aims to determine the feasibility of performing CED with free doxorubicin or pegylated liposomal doxorubicin (PLD) in the brainstem and thalamus, and to study the efficacy of PLD and free doxorubicin when treating preclinical DIPG and pHGG models. Methods: Preclinical CED was performed with 15μl doxorubicin in the brainstem and thalamus of 6-week-old nude mice. Maximal tolerated dose was determined by treating mice with doxorubicin concentrations ranging from 2 mg/ml to 0.02 mg/ml. The efficacy study was performed with the highest possible dose and using the orthotopic diffusely growing E98-FM-DIPG model in the brainstem. Mice (n=12) were treated at day 9 after injection of cells. Follow-up consisted of BLI measurements, and determination of body weight and clinical symptoms. Results: Maximal tolerated dose was 0.02 mg/ml in the brainstem and 0.2 mg/ml in the thalamus for both free doxorubicin and PLD. Clinical toxicity after CED with higher concentrations consisted of weight loss and neurological deficits including paresis and loss of balance. Symptoms occurred after three (free doxorubicin) or six days (PLD). E98FM-DIPG bearing mice treated with 0.02 mg/ml of free doxorubicin, or PL-doxorubicin via CED did not show any survival benefit compared to vehicle treated animals. 0.2 mg/ml has previously shown to be effective in treating preclinical glioma models. Conclusions: Local drug delivery of concentrations that are safe in the thalamus show severe toxicity when delivered to the brainstem. No therapeutic window existed for treating orthotopic brainstem tumors in mice. However, therapeutic concentrations could be reached in the thalamus. This data suggest that anatomical location of the tumor is of vital importance when considering the best drugs to deliver via CED. Citation Format: A. Charlotte P. Sewing, Susanna J.E. Veringa, Tonny Lagerweij, David P. Noske, Dannis G. van Vuurden, Gertjan J.L. Kaspers, Esther Hulleman. Toxicity of convection-enhanced delivery with doxorubicin to treat pediatric brain-tumors depends on anatomical location. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B27.

Convection Enhanced Delivery of Macromolecules for Brain Tumors

The blood brain barrier (BBB) poses a significant challenge for drug delivery of macromolecules into the brain. Convection-enhanced delivery (CED) circumvents the BBB through direct intracerebral infusion using a hydrostatic pressure gradient to transfer therapeutic compounds. The efficacy of CED is dependent on the distribution of the therapeutic agent to the targeted region. Here we present a review of convection enhanced delivery of macromolecules, emphasizing the role of tracers in enabling effective delivery anddiscuss current challenges in the field.

Imaging of Convection Enhanced Delivery of Toxins in Humans

Drug delivery of immunotoxins to brain tumors circumventing the blood brain barrier is a significant challenge. Convection-enhanced delivery (CED) circumvents the blood brain barrier through direct intracerebral application using a hydrostatic pressure gradient to percolate therapeutic compounds throughout the interstitial spaces of infiltrated brain and tumors. The efficacy of CED is determined through the distribution of the therapeutic agent to the targeted region. The vast majority of patients fail to receive a significant amount of coverage of the area at risk for tumor recurrence. Understanding this challenge, it is surprising that so little work has been done to monitor the delivery of therapeutic agents using this novel approach. Here we present a review of imaging in convection enhanced delivery monitoring of toxins in humans, and discuss future challenges in the field.

Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging

Many factors relating to the safety and efficacy of convection-enhanced delivery (CED) into intracranial tumors are poorly understood. To investigate these factors further and establish a more clinically relevant large animal model, with the potential to investigate CED in large, spontaneous tumors, the authors developed a magnetic resonance (MR) imaging-compatible system for CED of liposomal nanoparticles into the canine brain, incorporating real-time MR imaging. Additionally any possible toxicity of liposomes containing Gd and the chemotherapeutic agent irinotecan (CPT-11) was assessed following direct intraparenchymal delivery. Four healthy laboratory dogs were infused with liposomes containing Gd, rhodamine, or CPT-11. Convection-enhanced delivery was monitored in real time by sequential MR imaging, and the volumes of distribution were calculated from MR images and histological sections. Assessment of any toxicity was based on clinical and histopathological evaluation. Convection-enhanced delivery resulted in robust volumes of distribution in both gray and white matter, and real-time MR imaging allowed accurate calculation of volumes and pathways of distribution. Infusion variability was greatest in the gray matter, and was associated with leakage into ventricular or subarachnoid spaces. Complications were minimal and included mild transient proprioceptive deficits, focal hemorrhage in 1 dog, and focal, mild perivascular, nonsuppurative encephalitis in 1 dog. Convection-enhanced delivery of liposomal Gd/CPT-11 is associated with minimal adverse effects in a large animal model, and further assessment for use in clinical patients is warranted. Future studies investigating real-time monitored CED in spontaneous gliomas in canines are feasible and will provide a unique, clinically relevant large animal translational model for testing this and other therapeutic strategies.