Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1alpha, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.

Glioblastoma multiforme (GBM) is the most malignant form of primary brain tumors known as gliomas. They proliferate and invade extensively and yield short life expectancies despite aggressive treatment. Response to treatment is usually measured in terms of survival of groups of patients treated similarly but this statistical approach misses the subgroups that may have responded to or may have been injured by treatment. Such statistics offer scant reassurance to individual patients who have suffered through these treatments. Furthermore, current imaging-based treatment response metrics in individual patients ignore patient-specific differences in tumor growth kinetics, which have been shown to vary widely across patients even within the same histological diagnosis and, unfortunately, these metrics have shown only minimal success in predicting patient outcome. We consider nine newly diagnosed GBM patients receiving diagnostic biopsy followed by standard of care external beam radiation therapy (XRT). We present and apply a patient-specific, biologically-based mathematical model for glioma growth that quantifies response to XRT in individual patients in vivo. The mathematical model uses net rates of proliferation and migration of malignant tumor cells to characterize the tumor’s growth and invasion along with the linear-quadratic model for the response to radiation therapy. Using only routinely available pre-treatment MRIs to inform the patient-specific bio-mathematical model simulations, we find that radiation response in these patients, quantified by both clinical and model-generated measures, could have been predicted prior to treatment with high accuracy. Specifically, we find the net proliferation rate is correlated with the radiation response parameter (r = 0.89, p = 0.0007), resulting in a predictive relationship that is tested with a leave-one-out cross validation technique. This relationship predicts the tumor size post therapy to within inter-observer tumor volume uncertainty. The results of this study suggest that a mathematical model can create a virtual in silico tumor with the same growth kinetics as a particular patient and can not only predict treatment response in individual patients in vivo but also provide a basis for evaluation of response in each patient to any given therapy.

Glioblastomas (GBMs) are the most aggressive primary brain tumors characterized by their rapid proliferation and diffuse infiltration of the brain tissue. Survival patterns in patients with GBM have been associated with a number of clinico-pathologic factors, including age and neurological status, yet a significant quantitative link to in vivo growth kinetics of each glioma has remained elusive. Exploiting a recently developed tool for quantifying glioma net proliferation and invasion rates in individual patients using routinely available magnetic resonance images (MRIs), we propose to link these patient-specific kinetic rates of biological aggressiveness to prognostic significance. Using our biologically-based mathematical model for glioma growth and invasion, examination of serial pre-treatment MRIs of 32 GBM patients allowed quantification of these rates for each patient’s tumor. Survival analyses revealed that even when controlling for standard clinical parameters (e.g., age, KPS) these model-defined parameters quantifying biologically aggressiveness (net proliferation and invasion rates) were significantly associated with prognosis. One hypothesis generated was that the ratio of the actual survival time after whatever therapies were employed to the duration of survival predicted (by the model) without any therapy would provide a “Therapeutic Response Index” (TRI) of the overall effectiveness of the therapies. The TRI may provided important information, not otherwise available, as to the effectiveness of the treatments in individual patients. To our knowledge, this is the first report indicating that dynamic insight from routinely obtained pre-treatment imaging may be quantitatively useful in characterizing survival of individual patients with GBM. Such a hybrid tool bridging mathematical modeling and clinical imaging may allow for statifying patients for clinical studies relative to their pretreatment biological aggressiveness.