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Background
Convection-enhanced delivery (CED) is a method of directly administering drugs into the brain in order to enhance the distribution of drugs throughout the brain parehcyma. It involves the stereotactic placement through cranial burr holes of several catheters into brain parenchyma and the subsequent infusion of antineoplastic agents or other therapeutic agents via a microinfusion pump.
This technique has been described in published pre-clinical and early clinical studies. Although CED has been primarily evaluated for administering anti-neoplastics, this technique can be used for administering a wide range of agents, such as for treatment of Alzheimer’s disease and epilepsy.
Standard methods of local delivery of most drugs into the brain, either by intravenous injection and passage through the blood brain barrier (BBB), or intra-ventricular injection, has relied on diffusion, which results in a non-homogenous distribution of most agents. Intravenous administration of drugs to the brain has been hampered by the BBB, which prevents the passage of large molecules. The BBB is characterized by tight junctions between vascular endothelial cells, which prevent or impede various naturally occurring and synthetic substances (including anti-cancer drugs) from entering the brain.
Blood brain barrier disruption (BBBD) techniques have been used in chemotherapy of brain tumors to disrupt the BBB, in order to increase the concentration of chemotherapy drugs delivered to the tumor and prolong the drug-tumor contact time. Chemotherapy may be administered in conjunction with mannitol to cause osmotic disruption of the BBB, or disruption may be attempted through other mechanisms with other substances.
Although BBBD techniques have been used for over 20 years, the efficacy of this technique has been questioned (ICSI, 2001; CMS, 2007), as the long-term effects of BBBD chemotherapy are unknown, and no randomized controlled trials have established the superiority of BBBD chemotherapy over conventional chemotherapy. In addition, BBBD with chemotherapy is associated with a higher risk of complications than conventional chemotherapy. Complications associated with BBBD include seizures, obtundation, focal neurologic deficits, cerebral herniation, strokes, death, as well as the side-effects related to the chemotherapeutic agents themselves. Based upon a review of the evidence, CMS has issued a National Coverage Determination that stated that the use of osmotic BBBD is not reasonable and necessary when it is used as part of a treatment regimen for brain tumors (CMS, 2007).
In contrast to techniques that rely on diffusion, CED uses a pressure gradient established at the tip of an infusion catheter to push a drug into the extra-cellular space. The intention is to distribute the drug more evenly, at higher concentrations, and over a larger area than when administered by diffusion alone.
Convection-enhanced delivery of anti-neoplastic agents may occur after craniotomy with tumor resection, once the patient is stable. A separate hospital admission (apart from admission for tumor resection) is expected for CED for catheter placement and infusion of the therapeutic agent by means of a microinfusion pump. Once the infusion is complete, the catheters are removed and the patient is discharged.
Novel, targeted anti-neoplastics are in development for brain tumors. However, their administration has been hampered by the BBB, which prevents passage of large molecules.
One such targeted anti-neoplastic that is administered by CED is cintredekin besudotox, a novel cytotoxin-based therapy that is being investigated for the treatment of recurrent glioblastoma multiforme (GBM). Cintredekin besudotox is a recombinant protein consisting of a single molecule composed of 2 parts: (i) interleukin-13, which binds to receptors on tumor cells; and (ii) pseudomonas exotoxin (PE), a cytotoxin, which causes destruction of the tumor cell once the molecule is absorbed. Interleukin-13 receptors are present in substantial numbers on malignant glioma cells, but only a minimal amount on healthy brain cells. Hence, cintredekin besudotox has the potential to target tumor cells, with minimal impact on surrounding normal brain tissue.
Because of its large size, cintredekin besudotox can not cross the BBB. In clinical studies, cintredekin besudotox has been administered by CED. Catheters are placed following tumor resection, in areas of microscopic tumor spread or at risk of tumor spread around the tumor resection cavity. Because of the need to achieve homogenous distribution of cintredekin besudotox throughout the tumor infiltrated tissue, the catheters can not be placed in any previous resection cavity.
Once the patient is stable, approximately 2 weeks following craniotomy with tumor resection, the patient is admitted for catheter placement and anti-neoplastic infusion. Catheters are strategically placed by neurosurgeons, taking into account the location of residual non-resectable tumor, brain anatomy, and fluid dynamics. Anywhere from 2 to 4 catheters are placed during a surgical procedure lasting several hours. Cintredekin besudotox is then slowly infused through the catheter directly into the brain over 96 hours.
Available phase I/II clinical studies of cintredekin besudotox suggest that this is a promising agent for treatment of recurrent glioblastoma multiforme. A phase III trial (PRECISE) is currently underway. Cintredekin besudotox has been granted fast-track development designation and orphan drug designation by the U.S. Food and Drug Administration (FDA), and may be approved by the FDA as early as 2007.
At present, the pharmacokinetics of CED are poorly understood (Sampson et al, 2006). More research is needed to determine the optimal catheter location to distribute a drug to target tumor cells within the tumor mass and in the infiltrated adjacent parenchyma. Optimal catheter design is being researched to minimize backflow, to maximize distribution in the brain, and to account for the need to maintain patient mobility.
Raghavan et al (2006) explained that, although CED has been under investigation since the early 1990’s, "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."
Sampson et al (2008) determined the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intra-cerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intra-cerebral infusion technique of CED. A total of 20 patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last 8 patients, co-infusion of (123)I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the co-infused (123)I-albumin. Two DLTs were seen, and both were neurological. Median survival after TP-38 was 28 weeks (95 % confidence interval: 26.5 to 102.8). Of the 15 patients treated with residual disease, 2 (13.3 %) demonstrated radiographical responses, including 1 patient with glioblastoma multiforme who had a nearly complete response and remains alive for over 260 weeks after therapy. Co-infusion of (123)I-albumin demonstrated that high concentrations of the infusate could be delivered over 4 cm from the catheter tip. However, only 3 of 16 (19 %) catheters produced intra-parenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intra-cerebral CED of TP-38 was well-tolerated and produced some durable radiographical responses at doses less than or equal to 100 ng/ml. The authors concluded that CED has significant potential for enhancing delivery of therapeutic macromolecules throughout the human brain. However, the potential efficacy of drugs delivered by this technique may be severely constrained by ineffective infusion in many patients.
Fiandaca and colleagues (2008) stated that CED of substances within the human brain is becoming a more frequent experimental treatment option in the management of brain tumors, and more recently in phase 1 trials for gene therapy in Parkinson's disease (PD). Benefits of this intracranial drug-transfer technology include a more efficient delivery of large volumes of therapeutic agent to the target region when compared with more standard delivery approaches (i.e., biopolymers, local infusion). These researchers developed a reflux-resistant infusion cannula that allows increased infusion rates to be used. They also described their efforts to visualize the CED process in vivo, using liposomal nanotechnology and real-time intra-operative MRI. In addition to carrying the MRI contrast agent, nanoliposomes also provide a standardized delivery vehicle for the convection of drugs to a specific brain-tissue volume. This technology provides an added level of assurance via visual confirmation of CED, allowing intra-operative alterations to the infusion if there is reflux or aberrant delivery. These investigators proposed that these specific modifications to the CED technology will improve efficacy by documenting and standardizing the treatment-volume delivery. Furthermore, they believe that this image-guided CED platform can be used in other translational neuroscience efforts, with eventual clinical application beyond neuro-oncology and PD.
In a review on novel drug delivery strategies in neuro-oncology, Bidros and Vogelbaum (2009) stated that an important impediment to finding effective treatments for malignant gliomas is the presence of the BBB, which serves to prevent delivery of potentially active therapeutic compounds. Multiple efforts are focused on developing strategies to effectively deliver active drugs to brain tumor cells. Convection-enhanced delivery and BBBD have emerged as leading investigational delivery techniques for the treatment of malignant brain tumors. Clinical trials using these methods have been completed, with mixed results, and several more are being initiated.
Bidros et al (2010) stated that CED has emerged as a leading investigational delivery technique for the treatment of brain tumors. Clinical trials utilizing these methods have been completed, with mixed results, and several more are being initiated. However, the potential effectiveness of drugs delivered by CED may be severely constrained by poor durg distribution.
Sampson et al (2010) retrospectively analyzed the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. 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. The authors concluded that potential effectiveness of drugs delivered by CED may be limited by ineffective delivery in many patients.
Buonerba et al (2011) stated that GBM is the most frequent and aggressive malignant glioma (MG), with a median survival time of 12 to15 months, despite current best treatment based on surgery, radiotherapy and systemic chemotherapy. Many potentially active therapeutic agents are not effective by systemic administration, because they are unable to cross the BBB. As intra-cerebral administration bypasses the BBB, it increases the number of drugs that can be successfully delivered to the brain, with the possibility of minor systemic toxicity and better effectiveness. These researchers summarized the results of the extensive clinical research conducted on intra-cerebral therapy. Biodegradable drug carriers, implantable subcutaneous reservoirs and CED represent the main techniques for intra-cerebral delivery, while conventional chemotherapy agents, radiolabeled antibodies and receptor-targeted toxins are the main classes of drugs for intra-cerebral therapy. At the present time, biodegradable carmustine wafers, commercialized as Gliadel, are the only FDA-approved treatment for intra-cerebral chemotherapy of MG, but intra-cavitary delivery of mitoxantrone and radiolabeled anti-tenascin antibodies via implantable reservoirs has yielded promising results in uncontrolled trials. The pressure-driven flow generated by CED can potentially distribute convected drugs over large volumes of the brain, independently on their intrinsic diffusivity. Nevertheless, prominent technical problems, like back-flow, are yet to be properly addressed and contributed to the disappointing results of 2 phase III trials that investigated CED of cintredekin besudotox and TransMid in patients with recurrent GBM.
In a prospective, dose-escalation phase Ib study, Bruce et al (2011) examined the safety profile of topotecan via CED in the treatment of recurrent MGs and assessed radiographical response and survival. Significant anti-tumor activity as described by radiographical changes and prolonged overall survival with minimal drug-associated toxicity was demonstrated. A MTD was established for future phase II studies. The authors concluded that topotecan by CED has significant anti-tumor activity at concentrations that are non-toxic to normal brain. The potential for use of this therapy as a generally effective treatment option for MGs will be tested in subsequent phase II and phase III trials.
Lam et al (2011) stated that CED is a promising neurosurgical technique for the delivery of potential therapeutic agents to the PD-affected striatum. Convection-enhanced delivery utilizes stereotactic insertion of a catheter to the striatum and continuous infusion to distribute agents in the brain parenchyma. Insufficient attention to the details of CED may have contributed to early failures of translating candidate therapeutic agents from the laboratory to PD patients. A literature review was performed to examine the factors that govern CED in the laboratory as well as translation in PD and these researchers found that although there have been significant developments in implant design, infusion parameters and infusate composition, there have not been enough comparative trials of different technologies. Further optimization of CED is needed before it can be applied in the clinical setting and this will require a step-by-step breakdown of the different elements of delivery for independent testing. The authors concluded that CED is a promising technique for delivering therapeutic agents to the striatum for the treatment of PD; but further refinements are necessary for successful clinical translation.
Barua et al (2012) examined if the peri-vascular distribution of solutes delivered by CED into the striatum of rats is affected by the molecular weight of the infused agent, by co-infusion of vasodilator, alteration of infusion rates or use of a ramping regime. These investigators also wanted to make a preliminary comparison of the distribution of solutes with that of nanoparticles. These researchers analysed the peri-vascular distribution of 4, 10, 20, 70, 150 kDa fluorescein-labelled dextran and fluorescent nanoparticles at 10 mins and 3 hrs following CED into rat striatum. They investigated the effect of local vasodilatation, slow infusion rates and ramping on the peri-vascular distribution of solutes. Co-localization with peri-vascular basement membranes and vascular endothelial cells was identified by immunohistochemistry. The uptake of infusates by peri-vascular macrophages was quantified using stereological methods. Widespread peri-vascular distribution and macrophage uptake of fluorescein-labelled dextran was visible 10 mins after cessation of CED irrespective of molecular weight. However, a significantly higher proportion of peri-vascular macrophages had taken up 4, 10 and 20 kDa fluorescein-labelled dextran than 150 kDa dextran (p < 0.05, ANOVA). Co-infusion with vasodilator, slow infusion rates and use of a ramping regime did not alter the peri-vascular distribution. Convection-enhanced delivery of fluorescent nanoparticles indicated that particles co-localize with peri-vascular basement membranes throughout the striatum but, unlike soluble dextrans, are not taken up by peri-vascular macrophages after 3 hrs. The authors concluded that the findings of this study suggested that widespread peri-vascular distribution and interaction with peri-vascular macrophages is likely to be an inevitable consequence of CED of solutes. The potential consequences of peri-vascular distribution of therapeutic agents, and in particular cytotoxic chemotherapies, delivered by CED must be carefully considered to ensure safe and effective translation to clinical trials.
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