Advanced magnetic resonance imaging methods for planning and monitoring radiation therapy in patients with high-grade glioma

Abstract

This review explores how the integration of advanced imaging methods with high-quality anatomical images significantly improves the characterization, target definition, assessment of response to therapy, and overall management of patients with high-grade glioma. Metrics derived from diffusion-, perfusion-, and susceptibility-weighted magnetic resonance imaging in conjunction with magnetic resonance spectroscopic imaging, allows us to characterize regions of edema, hypoxia, increased cellularity, and necrosis within heterogeneous tumor and surrounding brain tissue. Quantification of such measures may provide a more reliable initial representation of tumor delineation and response to therapy than changes in the contrast-enhancing or T2 lesion alone and have a significant effect on targeting resection, planning radiation, and assessing treatment effectiveness. In the long term, implementation of these imaging methodologies can also aid in the identification of recurrent tumor and its differentiation from treatment-related confounds and facilitate the detection of radiationinduced vascular injury in otherwise normal-appearing brain tissue.

Figure 1

Anatomic, diffusion, perfusion, and metabolic images from a patient with a suspected GBM obtained prior to surgical resection. The post-Gadolinium T1-weighted image shows a relatively small region of enhancement, but the T2-weighted FLAIR image is much larger and very heterogeneous. The normalized blood volume image (nCBV) and apparent diffusion coefficient (ADC) have a number of foci with abnormal intensity. The CNI color overlay is scaled on a range of 1-15 with a cut-off of 2 standard deviations above normal. The lactate color overlay shows a single focus if increased intensity.

Figure 2

Anatomic and metabolic imaging from four serial examinations of a patient with a GBM being treated with RT, temozolomide and enzastaurin. A.) T1-weighted post-Gadolinium images (top) and T2-weighted FLAIR images (bottom). The post-RT exam shows increases in the CE and T2 lesions, which subsequently reduce again, indicating that these changes were due to pseudoprogression. B.) Metabolic imaging data. The CNI overlays have a cut-off at a value of 2 and are all on the same color scale. The extent of the region of abnormal CNI is much larger than the anatomic lesion and decreases with time and intensity, which indicates that the tumor is responding to therapy during this period.

Figure 3

Coronal T1-weighted post-Gadolinium images and T2-weighted FLAIR images from the pre-RT and post-RT exams showing a relatively small CE lesion, which reduced significantly during treatment. The T2 lesion is much larger and extends inferior to the CE region. The sagittal color overlays of the CNI maps, which are on the same scale as those shown in Figure 3, indicate that the T2 lesion has CNI values of 6 or greater, are relatively stable during the first 9 months, and then begin to expand along the corpus callosum. There was no enhancement at this time but the patient was assessed as having progressed based upon an increase in the T2 lesion. Tumor recurrence was confirmed by subsequent surgical resection.

Figure 4

Anatomic (T2 FLAIR and T1 post-Gad), SWI, and diffusion (ADC) images of 2 patients with glioblastomas treated with RT, temozolomide, and enzastaurin. The patient in the top row who did not respond to this therapeutic regime and progressed only 3 months after initiating treatment had less %SWI signal hypointensity within the CE lesion at baseline and an increase in ADC after the completion of RT, while the patient in the bottom row who responded to the therapy had a larger percentage of SWI hypointense signal within the CE lesion, similar ADC values pre- and post-RT, and did not show signs of tumor progression until after a year from initiating therapy. The volumes of T2 hyperintensity and CE lesion similarly decreased at 2 months for both patients.

Figure 5

Formation of radiation-induced microbleeds. A.) A representative patient with a grade 3 oligodendroglioma who received RT and temozolomide post-surgical resection of their tumor. 9 new microbleeds formed between 3 and 4 years post-RT (green circles denote newly-formed microbleeds). B.) Another irradiated grade 3 glioma 9 years post-RT (left) compared to a low grade glioma who did not develop any microbleeds 6 years after receiving temozolomide (right). C.) A representative patient with a grade 4 glioma who received RT, temozolomide, and enzastaurin post-surgical resection of their tumor. Fewer microbleeds are present in this patient at both 3 and 4 years post-RT compared to the patient in A. D.) Plot of microbleed counts over different time periods showing the retardation of microbleed formation with the administration of an anti-angiogenic agent.

Figure 6

Microbleed dependence on dose. Radiation dosimetry contour lines overlaid on 7T susceptibility-weighted images. A.) Increases in microbleed density in higher dose regions. At 2 years post-RT (top), more microbleeds form within high-dose regions (red), while by 4 years post-RT (bottom), microbleeds begin to appear in lower dose regions as well (green and blue). B.) Two examples where dose influences microbleed location. When the dosimetry is not well localized (bottom), by 4 years post-RT microbleeds can often appear outside of the T2-hyperintensity lesion and into the contralateral hemisphere. Even though both patients have similar microbleed counts, when a significant portion of posterior contralateral brain tissue received greater than 15Gy dosimetry, microbleeds extended into the contralateral hemisphere.