Glioblastoma multiforme is a highly vascularized tumor with a high degree of angiogenesis resulting from high levels of vascular endothelial growth factor (VEGF). Bevacizumab is a humanized monoclonal antibody that binds to VEGF-A and inhibits endothelial cell proliferation, thus reducing tumor neovascularization. In principle, steady administration of antiangiogenic chemotherapy should impede vascular development and deprive a tumor of its nutrients, thus impeding its growth. However, these effects are mitigated by the reduction of vascular permeability by anti-VEGF medications, which transiently restores normalcy to the blood-brain barrier (BBB), thereby reducing further penetration of bevacizumab through the BBB and into brain parenchyma. This ultimately reduces the antiangiogenic efficacy of bevacizumab.
On the basis of previous studies of the ability of the BBB to be disrupted by focused ultrasound1 and to allow the passage of chemotherapeutic agents,2 Liu et al3 hypothesized that focused ultrasound could be used to temporarily disrupt the BBB and to allow consistent penetration of the BBB by bevacizumab. They divided their experiment into 2 parts. First, they assessed whether focused ultrasound generated BBB disruption sufficient enough to enhance bevacizumab penetration in healthy mice and to determine the appropriate focused ultrasound dose. They found that pressure levels of 0.4 MPa (an intermediate exposure) and 0.8 MPa (aggressive exposure) resulted in a 5.73-fold and 56.77-fold increase, respectively, in intraparenchymal bevacizumab concentrations compared with controls not exposed to focused ultrasound.
The second part of their experiment assessed the therapeutic efficacy of bevacizumab combined with focused ultrasound exposure in tumor-bearing mice. This part of the experiment had 4 subgroups: sham procedure (n = 7), focused ultrasound alone (n = 9), bevacizumab alone (dose of 50 mg·kg−1·wk−1 for 5 weeks, n = 6), and bevacizumab and focused ultrasound BBB opening (dose of 50 mg·kg−1·wk−1 immediately followed by 0.4-MPa focused ultrasound exposure, n = 12). They found that treatment with bevacizumab alone showed tumor-suppressive effects in the first 4 weeks of treatment but significant tumor progression thereafter. This group had a median survival of 46 days (P = .04). The combined bevacizumab and focused ultrasound treatment group had a median survival of 73 days (P = .001) with slower rates of tumor growth.
The findings of Liu et al suggest a potentially important role for focused ultrasound as an additional tool for the treatment of glioblastoma in patients receiving chemotherapy. Modulation of the intensity of the focused ultrasound can be used to destabilize the BBB and to allow agents of varying sizes to pass more readily. However, the authors failed to address the interesting ramifications of their findings with bevacizumab. Traditionally, bevacizumab has been viewed as an antiangiogenic with a mechanism of action that involves entry into the luminal side of endothelial cells with a consequent reduction in angiogenesis. Such a mechanism would not require increased BBB permeability. Interestingly, other investigators have suggested a tumor cell–specific antiapoptotic mechanism, which may explain the therapeutic effect observed by the investigators in this study. Nevertheless, as newer chemotherapeutic agents are developed and older ones revisited, it will be interesting to see the role that focused ultrasound plays in facilitating central nervous system penetration.
1. Hynynen K, McDannold N, Sheikov NA, Jolesz FA, Vykhodtseva N. Local and reversible blood-brain barrier disruption by non- invasive focused ultrasound at frequencies suitable for trans-skull sonications. Neuroimage. 2005;24(1):12–20.
2. Liu HL, Huang CY, Chen JY, Wang HY, Chen PY, Wei KC. Pharmacodynamic and therapeutic investigation of focused ultrasound-induced blood-brain barrier opening for enhanced temozolomide delivery in glioma treatment. PLoS One. 2014;9(12):e114311.
3. Liu HL, Hsu PH, Huang CW, et al. Focused ultrasound enhances central nervous system delivery of bevacizumab for malignant glioma treatment. Radiology. 2016;281(1):99–108.