Convection-enhanced delivery (CED) is a bulk flow-driven process. Its properties permit direct, homogeneous, targeted perfusion of CNS regions with putative therapeutics while bypassing the blood brain barrier. Development of surrogate imaging tracers that are co-infused during drug delivery now permit accurate, noninvasive real-time tracking of convective infusate flow in nervous system tissues. The potential advantages of CED in the CNS over other currently available drug delivery techniques, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation, have led to its application in research studies and clinical trials 1).
Delivery of drugs to malignant brain tumors is a very challenging task. Convection-enhanced delivery (CED) has been designed to overcome some of the difficulties so that pharmacological agents that would not normally cross the BBB can be used for treatment. Drugs are delivered through one to several catheters placed stereotactically directly within the tumor mass or around the tumor or the resection cavity. Several classes of drugs are amenable to this technology including standard chemotherapeutics or novel experimental targeted drugs. The first Phase III trial for CED-delivered, molecularly targeted cytotoxin in the treatment of recurrent glioblastoma multiforme has been accomplished and demonstrated objective clinical efficacy. The lessons learned from more than a decade of attempts at exploiting CED for brain cancer treatment weigh critically for its future clinical applications. The main issues center around the type of catheters used, number of catheters and their exact placement; pharmacological formulation of drugs, prescreening patients undergoing treatment and monitoring the distribution of drugs in tumors and the tumor-infiltrated brain. It is expected that optimizing CED will make this technology a permanent addition to clinical management of brain malignancies 2).
Further development of CED is ongoing, with novel catheter designs and imaging approaches that may allow CED to become a more effective therapeutic delivery technique 3).
Bond et al., are developing a novel method using convection-enhanced delivery to safely manipulate the extracellular space surrounding common anatomical targets for surgery. By altering the extracellular content of deep subcortical structures and their associated white matter tracts, the MRI visualization of the basal ganglia can be improved to better define the anatomy. This technique could greatly improve the accuracy and success of stereotactic surgery, potentially eliminating the reliance on awake surgery.
Observations were made in the clinical setting where vasogenic and cytotoxic edema improved the MRI visualization of the basal ganglia. These findings were replicated in the experimental setting using an FDA-approved intracerebral catheter that was stereotactically inserted into the thalamus or basal ganglia of 7 swine. Five swine were infused with normal saline, and 2 were infused with autologous CSF. Flow rates varied between 1 μl/min to 6 μl/min to achieve convective distributions. Concurrent MRI was performed at 15-minute intervals to monitor the volume of infusion and observe the imaging changes of the deep subcortical structures. The animals were then clinically observed, and necropsy was performed within 48 hours, 1 week, or 1 month for histological analysis. RESULTS In all animals, the white matter tracts became hyperintense on T2-weighted imaging as compared with basal ganglia nuclei, enabling better definition of the deep brain anatomy. The volume of distribution and infusion (Vd/Vi ratio) ranged from 2.5 to 4.5. There were no observed clinical effects from the infusions. Histological analysis demonstrated mild neuronal effects from saline infusions but no effects from CSF infusions. CONCLUSIONS This work provides the initial foundation for a novel approach to improve the visualization of deep brain anatomy during MRI-guided, stereotactic procedures. Convective infusions of CSF alter the extracellular fluid content of the brain for improved MRI without evidence of clinical or toxic effects 4).
In the brainstem, there are concerns regarding volumetric alterations following convection-enhanced delivery (CED). The relationship between distribution volume and infusion volume is predictably greater than one. Whether this translates into deformational changes and influences clinical management is unknown. As part of a trial using CED for diffuse intrinsic pontine glioma (DIPG), Bander et al. measured treatment-related volumetric alterations in the brainstem and ventricles.
Enrolled patients underwent a single infusion of radioimmunotherapy. Between 2012 and 2019, 23 patients with volumetric pre- and postoperative day 1 (POD1) and day 30 (POD30) MRI scans were analyzed using iPlan® Flow software for semiautomated volumetric measurements of the ventricles and pontine segment of the brainstem.
Children in the study had a mean age of 7.7 years (range 2-18 years). The mean infusion volume was 3.9 ± 1.7 ml (range 0.8-8.8 ml). Paired t-tests demonstrated a significant increase in pontine volume immediately following infusion (p < 0.0001), which trended back toward baseline by POD30 (p = 0.046; preoperative 27.6 ± 8.4 ml, POD1 30.2 ± 9.0 ml, POD30 29.5 ± 9.4 ml). Lateral ventricle volume increased (p = 0.02) and remained elevated on POD30 (p = 0.04; preoperative 23.5 ± 15.4 ml, POD1 26.3 ± 16.0, POD30 28.6 ± 21.2). Infusion volume had a weak, positive correlation with pontine and lateral ventricle volume change (r2 = 0.22 and 0.27, respectively). Four of the 23 patients had an increase in preoperative neurological deficits at POD30. No patients required shunt placement within 90 days.
CED infusion into the brainstem correlates with immediate but self-limited deformation changes in the pons. The persistence of increased ventricular volume and no need for CSF diversion post-CED are inconsistent with obstructive hydrocephalus. Defining the degree and time course of these deformational changes can assist in the interpretation of neuroimaging along the DIPG disease continuum when CED is incorporated into the treatment algorithm 5).