Quantitative metrics of net proliferation and invasion link biological aggressiveness assessed by MRI with hypoxia assessed by FMISO-PET in newly diagnosed glioblastomas

Abstract

Glioblastoma multiforme (GBM) are aggressive and uniformly fatal primary brain tumors characterized by their diffuse invasion of the normal-appearing parenchyma peripheral to the clinical imaging abnormality. Hypoxia, a hallmark of aggressive tumor behavior often noted in GBMs, has been associated with resistance to therapy, poorer survival, and more malignant tumor phenotypes. Based on the existence of a set of novel imaging techniques and modeling tools, our objective was to assess a hypothesized quantitative link between tumor growth kinetics [assessed via mathematical models and routine magnetic resonance imaging (MRI)] and the hypoxic burden of the tumor [assessed via positron emission tomography (PET) imaging]. Our biomathematical model for glioma kinetics describes the spatial and temporal evolution of a glioma in terms of concentration of malignant tumor cells. This model has already been proven useful as a novel tool to dynamically quantify the net rates of proliferation (rho) and invasion (D) of the glioma cells in individual patients. Estimates of these kinetic rates can be calculated from routinely available pretreatment MRI in vivo. Eleven adults with GBM were imaged preoperatively with (18)F-fluoromisonidazole (FMISO)-PET and serial gadolinium-enhanced T1- and T2-weighted MRIs to allow the estimation of patient-specific net rates of proliferation (rho) and invasion (D). Hypoxic volumes were quantified from each FMISO-PET scan following standard techniques. To control for tumor size variability, two measures of hypoxic burden were considered: relative hypoxia (RH), defined as the ratio of the hypoxic volume to the T2-defined tumor volume, and the mean intensity on FMISO-PET scaled to the blood activity of the tracer (mean T/B). Pearson correlations between RH and the net rate of cell proliferation (rho) reached significance (P < 0.04). Moreover, highly significant positive correlations were found between biological aggressiveness ratio (rho/D) and both RH (P < 0.00003) and the mean T/B (P < 0.0007).

Figure 1

A 55-yr-old woman with a temporal glioblastoma multiforme imaged pre-operatively on T1Gd MRI (A), T2 MRI (B), and FMISO-PET (C). MRI showed a contrast-enhancing tumor with a large necrotic center. A simulation of tumor expansion shown in (D) was generated by applying D and ρ measured from the serial MRI of a ring-shaped temporal glioblastoma, revealing a diffuse extent of disease peripheral to the imaging abnormality.

Figure 2

An illustration of the results of applying a range of T/B ratios to the FMISO PET image of a right frontal GBM (Patient #3) to generate visualizations of the HV regions suggesting T/B = 1.2 is a reasonable threshold to define a HV separate from imaging noise.

Figure 3

Plot of RH as measured at various T/B thresholds. Curves represent individual patients (N = 11), with the direction of the superimposed arrow denoting a general increase in ρ/D values.

Figure 4

Scatter plots of RH vs. ρ/D for all patients in this study (N = 11). RH was determined over a variety of T/B levels, ranging from 1.1 to 1.6 in increments of 0.1. A strong linear relationship between the variables is shown for all thresholds; correlations were statistically significant for all T/B levels considered.