The use of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to study tumour angiogenesis in the management of metastatic cancer
Introduction: Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) may act as a biomarker for successful cancer therapy. This thesis demonstrates an imaging technique developed to be simple and reproducible. PTK787/ZK222584 (PTK/ZK) is an inhibitor of vascular endothelial growth factor mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast enhancement parameters of metastatic disease using DCE-MRI in advanced cancer patients treated in two dose escalating phase I studies using once and twice-daily dosing schedules. Patients and Methods: A theoretical analysis was performed to optimise sequence parameters. MRI phantom and clinical studies were performed to establish the validity and reproducibility of the technique. The clinical studies of PTK/ZK were performed with centralised DCE-MRI analysis. DCE-MRI was performed at baseline, day 2, and at the end of the 28-day cycle (EC1). Doses of oral PTK/ZK ranged from 50 to 2000 mg per day. Tumour permeability and vascularity were assessed by calculating the bi-directional transfer constant (Ktrans). Results: This technique can accurately measure R1 within the expected range of tumour enhancement. The reproducibility study showed a coefficient of variation (CoV) of 16% for Ktrans if tumours of diameter less than 3cm were excluded. A significant correlation was shown between changes in Ktrans and PTK/ZK oral dose, plasma levels and efficacy at both day 2 and ECI. Visual assessment of the DCE-MRI scans demonstrated similar results but with weaker correlations to dose and efficacy. Conclusion: The clinical findings suggest that DCE-MRI is sufficiently sensitive and reproducible to act as a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitors, such as PTK/ZK.