In vivo mapping of the effects of radiotherapy on neovascular permeability using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI)

Abstract

3550 Background: Neoadjuvant therapy is an integral part of rectal cancer management. Prediction of response to radiotherapy (RT) is highly relevant for both further surgery and prognosis in these patients. In a rat colorectal cancer model, we studied the use of DCE-MRI with a new macromolecular rapid clearance contrast agent (P792) to visualize tumor vascular permeability as a surrogate marker for angiogenesis and evaluate the effect of RT. Methods: Male WAG/Rij rats were injected with 2x106 CC531 cells in the hind leg. Once the tumor reached a diameter of 1 cm, DCE-MRI with high temporal resolution was performed before and 5 days after 5x500 cGy of external RT. The DCE-MRI data were used to generate parametric tissue permeability maps of the endothelial transfer constant (Ktrans) according to the Tofts-Kermode two compartment mathematical model. Separate region of interest (ROI) analyses were performed of the entire tumor (T), periferal vascular rim (P) and tumor core (C). In order to differentiate permeability changes from flow and oxygenation effects of RT, fiber optic tissue pO2 and microcirculatory laser blood flow (LBF) histogram mapping was performed in each tumor before and after RT using a stepwise micromanipulator technique. Results: The biophysical properties of P792 allowed excellent discrimination between tumor and normal tissue. Mean Ktrans (ml/min/1000g tissue) value changes measured over all pixels in a ROI were as follows: T: 24.03 vs 5.47 (p<0.05); P: 29.7 vs 10.4 (p<0.05); and C: 8.65 vs 0.47 (p<0.05) before and after radiotherapy. Microcirculatory LBF (arbitrary units) decreased from 117.3 to 84.7 (p<0.001) after RT. All tumors were severely hypoxic with a mean tissue pO2 over a 4 mm trajectory of 3.5 mm Hg before and 5.6 mm Hg after RT (p<0.001). Conclusions: High temporal resolution DCE-MRI with P792 allows non-invasive imaging and quantification of neovascular permeability in this colorectal cancer model. Administration of RT significantly reduces permeability and microcirculatory flow. RT enhanced oxygenation, but all tumors remained severely hypoxic after radiotherapy. DCE-MRI could have an important role in therapy monitoring. No significant financial relationships to disclose.