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We have investigated the reproducibility of dynamic contrast enhanced imaging techniques in nine patients with cerebral glioma. Patients were imaged twice with a 2 day interval between scans. Maps were produced of the time taken to achieve 90% enhancement (T90), the maximal intensity change per time interval ratio (MITR), the volume transfer coefficient between plasma and the extravascular extracellular space (K(trans)) and the extravascular extracellular contrast distribution volume, v(e). Measurements of K(trans) greater than 1.2 min(-1) were used to exclude pixels where first pass perfusion effects dominated the measurement. Measures of the test-retest coefficient of variation (CoV) and intraclass correlation coefficients were used to assess reproducibility for measurements from a volume of interest containing enhancing tissue from the whole tumour. MITR showed poor reproducibility (mean CoV 17.9%, 95% confidence limits for group comparisons 20.2%). T90 showed good reproducibility (mean CoV 7.1%, 95% confidence limits for group comparisons 5.2%). Calculated values of K(trans) and v(e) also showed good reproducibility (mean CoV 7.7% and 6.2% respectively, 95% confidence limits for group comparisons 6.2% and 4.8%, respectively). We conclude that the measurements of K(trans) and v(e) derived from pharmacokinetic analysis are sufficiently reproducible to support their use as a biological markers in therapeutic trials.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), using gadopentetate dimeglumine, was used to monitor acute effects on tumour vascular permeability following inhibition of vascular endothelial growth factor-A (VEGF-A) signal transduction. Mice bearing PC-3 human prostate adenocarcinoma xenografts were treated with ZD6474, a VEGF receptor-2 (KDR) tyrosine kinase inhibitor. The pharmacokinetic parameter K trans was obtained, which reflects vascular permeability and perfusion. Mice were imaged immediately before, and following, acute treatment with ZD6474 (12.5 -100 mg kg À1 orally). Whole tumours were analysed to obtain mean K trans values, and a histogram approach was used to examine intratumour heterogeneity. Reproducibility of K trans measurements gave inter-and intra-animal coefficients of variation of 40 and 18%, respectively. Dose-related reductions in K trans were evident following acute ZD6474 treatment. A K trans reduction of approximately 30% (Po0.001) was evident with 50 and 100 mg kg À1 ZD6474, a reduction of 12.5% (Po0.05) at 25 mg kg À1 , and a reduction that did not reach statistical significance at 12.5 mg kg À1 . A correlation between this dose response and the growth inhibitory effect of ZD6474 following chronic treatment was also observed. The histogram analysis of the data indicated that ZD6474-induced a K trans reduction in both the most enhancing rim and the core of PC-3 tumours. Dynamic contrast-enhanced magnetic resonance imaging may have a role in assessing the acute effects of VEGF signalling inhibition, in clinical dose-ranging studies.

ZD6126 is a vascular targeting agent that disrupts the tubulin cytoskeleton of proliferating neo-endothelial cells. This leads to the selective destruction and congestion of tumour blood vessels in experimental tumours, resulting in extensive haemorrhagic necrosis. In this study, the dose-dependent activity of ZD6126 in rat GH3 prolactinomas and murine RIF-1 fibrosarcomas was assessed using two magnetic resonance imaging (MRI) methods. Dynamic contrast-enhanced (DCE) MRI, quantified by an initial area under the time -concentration product curve (IAUC) method, gives values related to tumour perfusion and vascular permeability. Multigradient recalled echo MRI measures the transverse relaxation rate T Ã 2 , which is sensitive to tissue (deoxyhaemoglobin). Tumour IAUC and R Ã 2 (¼ 1=T Ã 2 ) decreased post-treatment with ZD6126 in a dose-dependent manner. In the rat model, lower doses of ZD6126 reduced the IAUC close to zero within restricted areas of the tumour, typically in the centre, while the highest dose reduced the IAUC to zero over the majority of the tumour. A decrease in both MRI end points was associated with the induction of massive central tumour necrosis measured histologically, which increased in a dose-dependent manner. Magnetic resonance imaging may be of value in evaluation of the acute clinical effects of ZD6126 in solid tumours. In particular, measurement of IAUC by DCE MRI should provide an unambiguous measure of biological activity of antivascular therapies for clinical trial.

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