The paradoxical effect of bevacizumab in the therapy of malignant gliomas

Abstract

One rationale behind the use of agents that inhibit vascular endothelial growth factor in the therapy of primary CNS malignancies is based upon the concept that normalization of tumor vasculature with a decrease in tumor interstitial pressure will improve access of cytoreductive drugs and improve radiotherapy efficacy due to increased oxygen delivery. However, several studies have raised the concern that these agents may both rapidly restore the low permeability characteristics of the blood-brain barrier and counteract the beneficial effect of pseudoprogression. The result may be decreased therapeutic efficacy while increasing infiltration by co-opting normal vessels. In this discussion, we examine both histologic and radiographic tumor progression in the context of antiangiogenic agents. Issues dealing with the safety of bevacizumab (Avastin®, Genentech, South San Francisco, CA) and its potential to decrease efficacy of standard radiochemotherapy when used to treat patients with newly diagnosed malignant glioma are emphasized.

Figure 1. Time course for change in time to peak tumor enhancement

Serial dynamic contrast enhancement MRI at 12 T using gadodiamide was performed in rats with intracerebral U87 human glioma that were treated with bevacizumab or dexamethasone. Stars indicate significant increase in time to peak enhancement. (From Varallyay et al. Figure reprinted with permission.)

Figure 2. Comparison of survival and tumor volumetrics

The survival time of rats with UW28 human glioblastoma intracerebral xenografts (days after tumor implantation) and the histologic tumor volumes (mm³) are shown for each rat in the untreated control group (squares) and the bevacizumab (BEV) plus carboplatin (Carbo) treatment group (circles). The line indicates the linear regression for each group. (From Jahnke et al. Figure reprinted with permission.)

Figure 3. Bevacizumab decreases enhancement of pseudoprogression

The top row shows serial postcontrast T1-weighted MRIs using gadoteridol (T1+Gd). Dynamic susceptibility contrast with Gd or ferumoxytol (Fe) were performed before and after radiochemotherapy (RCT) and bevacizumab (BEV). Red and orange indicate increased relative cerebral blood volume (rCBV). Bevacizumab decreases T1+Gd enhancement and rCBV of both true progression and pseudoprogression. (From Weinstein et al. Figure reprinted with permission.)

Figure 4. Bevacizumab decreases enhancement when given up-front for glioblastoma multiforme (GBM)

This patient received bevacizumab before standard radiochemotherapy for newly diagnosed GBM secondary to significant tumor volume increase and neurologic decline. (A) T1-weighted MRI before bevacizumab therapy. (B) Postcontrast T1-weighted MRI before bevacizumab therapy. (C) T1-weighted MRI 3 months after bevacizumab therapy. (D) Postcontrast T1-weighted MRI 3 months after bevacizumab therapy. Note the substantial decrease in tumor enhancement with gadoteridol after bevacizumab therapy (arrows) without concurrent reduction in tumor volume, mass effect, or midline shift.

Figure 5. Comparison of relative cerebral blood volume (rCBV) tumor progression and pseudoprogression

rCBV was obtained using both ferumoxytol and gadoteridol-based contrast agent. rCBV of 1.75 is a threshold to differentiate high- and low-grade gliomas. (A) Dynamic susceptibility contrast (DSC) MRI using ferumoxytol as a blood pool agent demonstrated rCBV >4.2 in the tumor progression group (Tumor) and rCBV <1.1 in the pseudoprogression (Pseudo) group. The mixed group indicates that ferumoxytol-rCBV was high but gadoteridol-rCBV was inconsistent. (B) DSC MRI using gadoteridol demonstrated rCBV <1.7 in the 3 patients in the tumor progression group and rCBV <1.2 in the pseudoprogression group. A one-way analysis of variance was performed to evaluate the difference in rCBV values between active tumor, pseudoprogression, and mixed response groups. The difference was highly statistically significant for ferumoxytol (p < 0.00001) and significant for gadoteridol (p = 0.01). (From Gahramanov et al. Figure reprinted with permission.) These findings suggest that ferumoxytol is a more reliable agent than gadoteridol to determine rCBV in high-grade gliomas.