Effects of convection-enhanced delivery of bevacizumab on survival of glioma-bearing animals

Abstract

<jats:sec> <jats:title>OBJECT</jats:title> <jats:p>Bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan (Camptosar [CPT-11]), is a promising treatment for recurrent glioblastoma. However, the intravenous (IV) administration of bevacizumab produces a number of systemic side effects, and the increase in survival it provides for patients with recurrent glioblastoma is still only a few months. Because bevacizumab is an antibody against VEGF, which is secreted into the extracellular milieu by glioma cells, the authors hypothesized that direct chronic intratumoral delivery techniques (i.e., convection-enhanced delivery [CED]) can be more effective than IV administration. To test this hypothesis, the authors compared outcomes for these routes of bevacizumab application with respect to animal survival, microvessel density (MVD), and inflammatory cell distribution.</jats:p></jats:sec> <jats:sec> <jats:title>METHODS</jats:title> <jats:p>Two human glioma cell lines, U87 and U251, were used as sources of intracranial tumor cells. The glioma cell lines were implanted into the brains of mice in an orthotopic xenograft mouse tumor model. After 7 days, the mice were treated with one of the following: 1) vehicle, 2) CED bevacizumab, 3) IV bevacizumab, 4) intraperitoneal (IP) irinotecan, 5) CED bevacizumab plus IP irinotecan, or 6) IV bevacizumab plus IP irinotecan. Alzet micro-osmotic pumps were used to introduce bevacizumab directly into the tumor. Survival was monitored. Excised tumor tissue samples were immunostained to measure MVD and inflammatory cell and growth factor levels.</jats:p></jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>The results demonstrate that mice treated with CED of bevacizumab alone or in combination with irinotecan survived longer than those treated systemically; CED-treated animals survived 30% longer than IV-treated animals. In combination studies, CED bevacizumab plus CPT-11 increased survival by more than 90%, whereas IV bevacizumab plus CPT-11 increased survival by 40%. Furthermore, CED bevacizumab-treated tissues exhibited decreased MVD compared with that of IV-treated tissues. In additional studies, the infiltration of macrophages and dendritic cells into CED-treated animals were increased compared with those in IV-treated animals, suggesting a highly active inflammatory response taking place in CED-treated mice.</jats:p></jats:sec> <jats:sec> <jats:title>CONCLUSIONS</jats:title> <jats:p>The administration of bevacizumab via CED increases survival over that of treatment with IV bevacizumab. Thus, CED of bevacizumab alone or in combination with chemotherapy can be an effective protocol for treating gliomas.</jats:p></jats:sec>

Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies

“…This result supports further developing CED by showing that current glioblastoma treatments could be more effective via CED. 80 Other studies published in 2015 assessed the efficacy of CED of agents used to systemically treat glioblastoma such as irinotecan, carboplatin, and cetuximab delivered via nanoparticles and liposomes to allow gradual release after CED. 1,26,43 These preclinical studies have improved CED techniques and identified agents to infuse via CED, information that has given rise to the multiple clinical trials in patients described below.…”

Brain Interstitial Fluid Drainage Alterations in Glioma-Bearing Rats

“…Theoretically CED can maximize the brain concentration of the treatment drug with minimal systemic exposure and toxicity [15]. It has been found that the concentration of the drug injected into the brain by CED can reach more than a thousand times that following traditional drug administration, and the region in which the drug is applied can be relatively vast [16][17][18][19]. However, the use of CED has been limited in clinical practice because of the difficulty in monitoring and controlling the concentration and distribution of the injected drugs [20].…”

“…Direct drug delivery is one of several methods that may be used to circumvent this restriction, but limitations in the ability to monitor drugs distributed in the ISF system have prevent this technique from being reliable and reproducible. Moreover, the parameters required for direct local drug administration (e.g., delivery pressure, time, and frequency) are mostly acquired through experience [4].…”

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

“…A phase III trial where CED was used to administrate interleukin-13 bound to Pseudomonas exotoxin to GBM patients did not show a significant improvement compared to Gliadel wafers [409]. Nevertheless, other preclinical studies have shown promising results [410], and continuous efforts have been made to improve the efficiency of CED, including works in catheter technology and optimal positioning [406]. Recently, a chronic CED administration system was used to infuse the topoisomerase inhibitor topotecan in a pig model for up to 32 days without toxicity [411].…”