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Dynamic contrast enhanced MRI contrast agent kinetics in malignant tumors are typically complex, requiring multicompartment tumor models for adequate description. For consistent comparisons among tumors or among successive studies of the same tumor, we propose to estimate the total contrast agent-accessible volume fraction of tumor, including blood plasma, v(pe), and an average transfer rate constant across all tumor compartments, K(trans.av), by fitting a three-compartment tumor model and then calculating the area under the tumor impulse-response function (= v(pe)) and the ratio area under the tumor impulse response function over mean residence time in tumor (= K(trans.av)). If the duration of dynamic contrast enhanced MRI was too short to extrapolate the tumor impulse-response function to infinity with any confidence, then conditional parameters v(pe)(*) and K(trans.av*) should be calculated from the available incomplete impulse response function. Median decreases of 33% were found for both v(pe)(*) and K(trans.av*) in glioblastoma patients (n = 16) 24 hours after the administration of bevacizumab (P < 0.001). Median total contrast-enhancing tumor volume was reduced by 18% (P < 0.0001). The combined changes of tumor volume, v(pe)(*), and K(trans.av*) suggest a reduction of true v(pe), possibly accompanied by a reduction of true K(trans.av). The proposed method provides estimates of a scale and a shape parameter to describe contrast agent kinetics of varying complexity in a uniform way.

Here, we describe an automated nonparametric method for evaluating gadolinium-diethylene triamine pentaacetic acid (GdDTPA) kinetics, based on dynamic contrast-enhanced–MRI scans of glioblastoma patients taken before and after treatment with bevacizumab; no specific model or equation structure is assumed or used. Tumor and venous blood concentration-time profiles are smoothed, using a robust algorithm that removes artifacts due to patient motion, and then deconvolved, yielding an impulse response function. In addition to smoothing, robustness of the deconvolution operation is assured by excluding data that occur prior to the plasma peak; an exhaustive analysis was performed to demonstrate that exclusion of the prepeak plasma data does not significantly affect results. All analysis steps are executed by a single R script that requires blood and tumor curves as the sole input. Statistical moment analysis of the Impulse response function yields the area under the curve (AUC) and mean residence time (MRT). Comparison of deconvolution results to fitted Tofts model parameters suggests that AUC and AUC of the Impulse response function closely approximate fractional clearance from plasma to tissue (K trans ) and fractional interstitial volume (ve). Intervisit variability is shown to be comparable when using the deconvolution method (11%[ AUC ] and 13%[AUC]) compared to the Tofts model (14%[K trans ] and 24%[ve]). AUC and AUC both exhibit a statistically significant decrease (P < 0.005) 1 day after administration of bevacizumab. Magn Reson Med 63:1366–1375, 2010. © 2010 Wiley-Liss, Inc.

Effective cancer chemotherapy depends on the delivery of therapeutic drugs to cancer cells at cytotoxic concentrations. However, physiologic barriers, such as variable vessel permeability, high interstitial fluid pressure, and heterogeneous perfusion, make it difficult to achieve that goal. Efforts to improve drug delivery have been limited by the lack of noninvasive tools to evaluate intratumoral drug concentration and distribution. Here we demonstrate that tumor drug concentration can be measured in vivo using T1-weighted MRI, following systemic administration of liposomes containing both drug (doxorubicin (DOX)) and contrast agent (manganese (Mn)). Mn and DOX concentrations were calculated using T1 relaxation times and Mn:DOX loading ratios, as previously described. Two independent validations by high-performance liquid chromatography (HPLC) and histologic fluorescence in a rat fibrosarcoma (FSA) model indicate a concordant linear relationship between DOX concentrations determined using T1 and those measured invasively. This method of imaging exhibits potential for real-time evaluation of chemotherapeutic protocols and prediction of tumor response on an individual patient basis. Magn Reson Med 56: 1011–1018, 2006. © 2006 Wiley-Liss, Inc.