Assessing blood-brain and blood-tumor barrier opening using Gd-DTPA uptake during the course of radiotherapy treatment of high grade gliomas

Abstract

Despite the best available current therapy including surgery, conventional radiotherapy and chemotherapy, the median survival for glioblastoma remains less than one year. One potential reason for the ineffectiveness of chemotherapy is that few drugs can pass the endothelial junctions that make up the blood-brain-barrier (BBB) or blood-tumor-barrier (BTB) to reach tumor cells. Previous studies suggest that radiation could act to increase vascular permeability and, thus, to increase efficient drug delivery to tumors. Selective disruption of BTB vs BBB could provide an optimal time window for chemotherapy. Gd-DTP, a MRI contrast agent, does not pass through normal BBB into tissue, and an increase in the agent uptake in tissue can suggest BBB/BTB opening. The objective of this study is to assess BBB and/or BTB opening using Gd-DTPA uptake and MR imaging during the course of Radiotherapy treatment of high-grade gliomas. Between December 2000 and February 2004, 14 patients with Grade III or IV supratentorial malignant gliomas underwent 3DCRT with a median dose of 70 Gy. All patients underwent T1-weighted pre- and post-contrast, T2-weighted, FLAIR, and diffusion-weighted MR imaging before RT, at weeks 1–2 and 3–4 during RT, and 1 month, 3 months, and 6 months after the completion of RT in a prospective, internal review board approved, clinical study. Gross tumor volume (GTV) was defined using post-operative T1-weighted post-contrast and/or FLAIR MRI. All MRIs were registered to a treatment planning CT scan using a mutual information algorithm. Via this alignment process, the total accumulated planned radiation dose was also co-registered with the MRIs. Changes in Gd-DTPA uptake over the course of RT and within the first 6 months of the completion of RT were assessed using a ratio of post- to pre-contrast T1-weighted images (a Gd-DTPA uptake index). Voxels that had a change greater than two standard deviations above the mean (established from a region receiving <10Gy) were delineated, and analyzed with respect to their GTVs and the dose they received. The onset of increased Gd-DTPA uptake occurs at Week 1 during the course of RT (p < 0.0005, Students t test), and the increase reaches a maximum or plateau between Week 3 during RT and 1 month after the completion of RT. Fifty-five percent of the voxels that exhibit an increase in the Gd-DTPA uptake index are in brain regions that received total accumulated dose > 60Gy, 7% in the regions that received doses between 50 Gy and 60Gy, and the remaining 38% were distributed in regions that received doses less than 50 Gy. After one month past the completion of RT, the elevated Gd-DTPA uptake indices begin to subside gradually. In the regions that received doses >60Gy, voxels showing an elevated Gd-DTPA uptake index include, but are not limited to, those within the tumor core and near tumor periphery. Ten percent of the voxels in the brain region that received >60 Gy showed significantly increased Gd-DTPA uptake, in contrast to only 2% or less of the voxels in the regions that received dose less than 60 Gy. MR contrast imaging reveals increases in Gd-DTPA uptake in the high dose brain region during the course of RT, suggesting opening of the BBB and/or the BTB. This finding supports the use of highly conformal high-dose of radiation when concurrent chemotherapy is administered, and has implication regarding the timing of chemotherapy relative to radiotherapy