The serial assessment of tumor angiogenesis and hypoxia using multiparametric and multimodal imaging

Objectives We describe the development and application of a multimodal imaging protocol to serially assess the spatial and temporal correlation between hypoxia, as measured by FMISO-PET, and MRI derived markers of cellularity, blood flow, blood volume, mean transit time and vascular permeability in a 9L rat brain tumor model.

Methods Twenty rats were inoculated with 9L brain tumor cells and imaged at three time points using 3D anatomical MRI, diffusion weighted MRI, dynamic susceptibility contrast MRI, dynamic contrast enhanced MRI, microCT and dynamic FMISO-PET. All images were spatially registered and statistically analyzed.

Results Generally, tumors had blood flow and blood volume values that were spatially heterogeneous with tumor rim values peaking at three times that found in contralateral brain tissue and substantially lower values near the tumor core. The mean transit time values were less heterogeneous and consistently elevated as compared to contralateral brain tissue, potentially indicating reduced perfusion efficiency. Vascular permeability values were highest in the tumor rim and were also spatially heterogeneous. Not all tumors had FMISO-detectable hypoxia at the first time point but by the last imaging session the tumor hypoxic fractions ranged from 60% to 90%. Initial multiparametric analysis has suggested that tumors with low negative spatial correlations between the blood volume and cellularity maps have higher FMISO uptake possibly indicating a mismatch between nutrient supply and demand.

Conclusions The proposed multimodal and multiparametric imaging method has the potential to more thoroughly and non-invasively interrogate the relationship between the spatial and temporal development of tumor hypoxia and the angiogenic response. Ongoing studies include the use of the proposed approach to serially assess the efficacy of therapeutic agents designed to improve tumor perfusion efficiency and tissue oxygenation.

Research Support NIH K99-CA127599, NIH R00-CA127599, NIH 2R25-CA092043