Detection of early response to temozolomide treatment in brain tumors using hyperpolarized 13C MR metabolic imaging

Abstract

Purpose: To demonstrate the feasibility of using DNP hyperpolarized [1-(13)C]-pyruvate to measure early response to temozolomide (TMZ) therapy using an orthotopic human glioblastoma xenograft model.

Materials and methods: Twenty athymic rats with intracranial implantation of human glioblastoma cells were divided into two groups: one group received an oral administration of 100 mg/kg TMZ (n = 10) and the control group received vehicle only (n = 10). (13)C 3D magnetic resonance spectroscopic imaging (MRSI) data were acquired following injection of 2.5 mL (100 mM) hyperpolarized [1-(13)C]-pyruvate using a 3T scanner prior to treatment (day D0), at D1 (days from treatment) or D2.

Results: Tumor metabolism as assessed by the ratio of lactate to pyruvate (Lac/Pyr) was significantly altered at D1 for the TMZ-treated group but tumor volume did not show a reduction until D5 to D7. The percent change in Lac/Pyr from baseline was statistically different between the two groups at D1 and D2 (P < 0.008), while percent tumor volume was not (P > 0.2).

Conclusion: The results from this study suggest that metabolic imaging with hyperpolarized [1-(13)C]-pyruvate may provide a unique tool that clinical neuro-oncologists can use in the future to monitor tumor response to therapy for patients with brain tumors.

Figure 1

Percent change in Lac/Pyr from baseline for the treated and control groups between 1 to 7 days following treatment. The ¹³C metabolism measured by this parameter showed a significant difference between the two groups at days 1 and 2 (*P < 0.008). The statistical test was confined to days 1 and 2 due to the lack of data at other timepoints.

Figure 2

Percent tumor volume change from baseline for the treated and control groups between 1 to 7 days following treatment. Both groups showed an increase in their tumor volume at days 1 and 2 (P > 0.2). The statistical test was confined to days 1 and 2 due to the lack of data at other timepoints.

Figure 3

An example of a treated rat, showing its T1 post-Gd images, ¹³C spectra zoomed-in around brain, and Lac/Pyr overlay map at D0 (pre-treatment), D1 (1 day after the initiation of treatment) and D2 scan. The lactate peak decreased shortly after the treatment, resulting in a drastic drop in Lac/Pyr.

Figure 4

An example of a control rat, showing its T1 post-Gd images, ¹³C spectra zoomed-in around brain and Lac/Pyr overlay map at D0 (pre-treatment), D1 (1 day after the treatment initiation) and D2 scan. The lactate peak continued to increase relatively to the pyruvate peak after the treatment, resulting in a steep increase in Lac/Pyr.

Figure 5

Immunohistochemical staining of caspase-3 for a control rat sacrificed at D2 (a, 20× magnification), a treated rat sacrificed at D2 (b, 20× magnification) and a treated rat sacrificed at D7 (c, 40× magnification).