Original ArticleMagnetic Resonance Imaging–Based Assessment of Gadolinium-Conjugated Diethylenetriamine Penta-Acetic Acid Test-Infusion in Detecting Dysfunction of Convection-Enhanced Delivery Catheters
Introduction
Delivery of therapeutic agents into the brain has been an ongoing challenge for many years. The systemic delivery of drugs to the brain is limited by the presence of the blood–brain barrier, which only allows the selective entrance of molecules on the basis of size, solubility, and electrical charge. To circumvent the blood–brain barrier, more direct approaches to the brain parenchyma and cerebrospinal fluid (CSF) have been explored. Many of these techniques depend on the potential of the therapeutic agent to diffuse into the brain tissue, which results in a very limited area of distribution up to a few millimeters. Other challenges encountered in diffusion-based delivery techniques are how to selectively direct the agents to the target region and how to maintain constant and pharmacologically effective drug concentrations at the desired site in the brain. Clinical attempts to deliver potentially promising drugs have thus far been disappointing as the result of poor drug efficacy and serious side effects.1
In contrast to techniques that rely on diffusion, convection-enhanced delivery (CED) uses a constant pressure gradient, rather than a concentration gradient, established at the tip of an infusion catheter by a pump creating a bulk flow, which pushes the drug into the extracellular space. CED allows the distribution of therapeutic agents, like small molecules, macromolecules, and also larger particles such as viral vectors, into the brain in relatively large volumes with a steep concentration drop at the advancing margin of the bulk flow.2
In a phase 1 trial conducted at our institute, CED was used to deliver the Delta-24-RGD adenovirus, a genetically engineered conditionally replication-competent virus, in patients with recurrent glioblastoma multiforme (GBM). Visualizing infusions in real-time has proven to be an essential component of CED trials, allowing minimization of inappropriate infusion, such as leakage to the CSF spaces and thus reduction of the potential for adverse effects.3 Because strict safety requirements did not allow for real-time monitoring in this trial, virus-infusion was preceded by a test-infusion of gadolinium-conjugated diethylenetriamine penta-acetic acid (Gd-DTPA).
In this study, we evaluated whether the infusion of Gd-DTPA before the start of the drug infusion could provide sufficient information on CED catheter function. Therefore, we studied which magnetic resonance imaging (MRI) sequences could be used best to evaluate low concentrations of Gd-DTPA in tumor, brain tissue, and CSF. Furthermore we analyzed the results of gadolinium test-infusion through 50 catheters in a human clinical trial.
Section snippets
Patients and Treatment
Patients in this study were enrolled in the dose-escalation part of a larger phase 1 multicenter, dose-finding trial, in which a conditionally replication-competent adenovirus (DELTA-24-RGD) is administered by CED to patients with recurrent GBM. The trial was registered at http://clinicaltrials.gov (NCT01582516). Between June 2010 and October 2012, 13 adults with a recurrence of a histologically proven GBM and a Karnofsky performance status rating ≥70% were enrolled at the Erasmus MC–University
Results
In total 51 catheters were placed in 13 patients. One catheter could not be placed because of persistent bleeding at the entry point. On the basis of the postoperative CT scan, one catheter was excluded for test-infusion, because the catheter tip was located in the lateral ventricle. Thus, 50 catheters were amenable for analysis regarding results of test-infusion. Thirteen of the 50 catheters were planned and placed peritumorally. On the basis of the preoperative MRI, 37 of the 50 catheters
Discussion
The results of this study show that test-infusion with Gd-DTPA allows for the detection of leaking catheters before CED of a drug, in this case Delta-24-RGD adenovirus. Gd-DTPA test infusion was well tolerated and did not lead to changes in neurologic status or Karnofsky Performance Score. Safety and efficacy of CED depends on several factors, such as the ability to accurately place the catheters and to avoid leakage of infusate into the CSF compartment.6 Avoiding infusate leakage could be of
Conclusion
In conclusion, our findings indicate that pre-CED treatment infusion of Gd-DTPA is an adequate and safe method to identify dysfunctional catheters. This setup is successful in determining whether the infused fluid shows early leakage into the subarachnoid or ventricular CSF space and allows for adjustments in the treatment and therefore to reduce the risk of systemic effects. In many cases air bubbles do occur around the catheter tip; however, in our study this finding was not correlated to
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Conflict of interest statement: Eva Wembacher is an employee of Brainlab. The other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.