Caleb Roberts

Experimentally-derived functional form for a population-averaged high-temporal-resolution arterial input function for dynamic contrast-enhanced MRI

Rapid T1‐weighted 3D spoiled gradient‐echo (GRE) data sets were acquired in the abdomen of 23 cancer patients during a total of 113 separate visits to allow dynamic contrast‐enhanced MRI (DCE‐MRI) analysis of tumor microvasculature. The arterial input function (AIF) was measured in each patient at each visit using an automated AIF extraction method following a standardized bolus administration of gadodiamide. The AIFs for each patient were combined to obtain a mean AIF that is representative for any individual. The functional form of this general AIF may be useful for studies in which AIF measurements are not possible. Improvements in the reproducibility of DCE‐MRI model parameters (Ktrans, ve, and vp) were observed when this new, high‐temporal‐resolution population AIF was used, indicating the potential for increased sensitivity to therapy‐induced change. Magn Reson Med, 2006.

Dynamic contrast-enhanced MRI in clinical trials of antivascular therapies

About 100 early-phase clinical trials and investigator-led studies of targeted antivascular therapies—both anti-angiogenic and vascular-targeting agents—have reported data derived from T1-weighted dynamic contrast-enhanced (DCE)-MRI. However, the role of DCE-MRI for decision making during the drug-development process remains controversial. Despite well-documented guidelines on image acquisition and analysis, several key questions concerning the role of this technique in early-phase trial design remain unanswered. This Review describes studies of single-agent antivascular therapies, in which DCE-MRI parameters are incorporated as pharmacodynamic biomarkers. We discuss whether these parameters, such as volume transfer constant (Ktrans), are reproducible and reliable biomarkers of both drug efficacy and proof of concept, and whether they assist in dose selection and drug scheduling for subsequent phase II trials. Emerging evidence indicates that multiparametric analysis of DCE-MRI data offers greater insight into the mechanism of drug action than studies measuring a single parameter, such as Ktrans. We also provide an overview of current data and appraise the future directions of this technique in oncology trials. Finally, major hurdles in imaging biomarker development, validation and qualification that hinder a wide application of DCE-MRI techniques in clinical trials are addressed.

Phase I Evaluation of a Fully Human Anti–αv Integrin Monoclonal Antibody (CNTO 95) in Patients with Advanced Solid Tumors

Purpose: A fully human monoclonal antibody to anti–αv integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors. Experimental Design: In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [18F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months. Results: Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- and post-treatment lesion biopsies confirmed tumor cell αv integrin expression, as well as CNTO 95 penetration of the tumor and localization to tumor cells in association with reduced bcl-2 expression. A lesion in one patient (10.0 mg/kg) with stable ovarian carcinosarcoma was no longer detectable by FDG-PET by day 49. Exposure to CNTO 95 seemed to increase in a greater-than-dose-proportional manner; dose-dependent mean half-life ranged from 0.26 to 6.7 days. Conclusions: CNTO 95 was generally well tolerated. Six patients received extended therapy, including one patient with a prolonged response. Biopsy data confirmed tumor localization and pharmacodynamic activity.

Comparative study into the robustness of compartmental modeling and model-free analysis in DCE-MRI studies

To evaluate and compare the reproducibility of the preferred phenomenological parameter IAUC60 (initial area under the time‐concentration curve [IAUC] defined over the first 60 seconds postenhancement) with the preferred modeling parameter (Ktrans), as derived using two simple models, in abdominal and cerebral data collected in typical Phase I clinical trial conditions.

Quantifying Antivascular Effects of Monoclonal Antibodies to Vascular Endothelial Growth Factor: Insights from Imaging

Purpose: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti–vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials. Experimental Design: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab. Results: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P ≤ 0.005). Ultrasound imaging confirmed reduced tumor blood volume within the same time frame (P = 0.048). Consistent with the preclinical results, reductions in enhancing fraction and fractional plasma volume were detected in patient colorectal cancer metastases within 48 h after a single dose of bevacizumab that persisted throughout one cycle of therapy. These effects were followed by resolution of edema (P = 0.0023) and tumor shrinkage in 9 of 26 tumors at day 12. Conclusion: These data suggest that VEGF-specific inhibition induces rapid structural and functional effects with downstream significant antitumor activity within one cycle of therapy. This finding has important implications for the design of early-phase clinical trials that incorporate physiologic imaging. The study shows how animal data help interpret clinical imaging data, an important step toward the validation of image biomarkers of tumor structure and function. (Clin Cancer Res 2009;15(21):6674–82)Purpose Little is known concerning the onset, duration and magnitude of direct therapeutic effects of anti-VEGF therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early phase clinical trials.

Quantifying spatial heterogeneity in dynamic contrast-enhanced MRI parameter maps.

Dynamic contrast‐enhanced MRI is becoming a standard tool for imaging‐based trials of anti‐vascular/angiogenic agents in cancer. So far, however, biomarkers derived from DCE‐MRI parameter maps have largely neglected the fact that the maps have spatial structure and instead focussed on distributional summary statistics. Such statistics—e.g., biomarkers based on median values—neglect the spatial arrangement of parameters, which may carry important diagnostic and prognostic information. This article describes two types of heterogeneity biomarker that are sensitive to both parameter values and their spatial arrangement. Methods based on Rényi fractal dimensions and geometrical properties are developed, both of which attempt to describe the complexity of DCE‐MRI parameter maps. Experiments using simulated data show that the proposed biomarkers are sensitive to changes that distribution‐based summary statistics cannot detect and demonstrate that heterogeneity biomarkers could be applied in the drug trial setting. An experiment using 23 DCE‐MRI parameter maps of gliomas—a class of tumour that is graded on the basis of heterogeneity—shows that the proposed heterogeneity biomarkers are able to differentiate between low‐ and high‐grade tumours. Magn Reson Med, 2009.

Comparative study of methods for determining vascular permeability and blood volume in human gliomas

To characterize human gliomas using T1‐weighted dynamic contrast‐enhanced MRI (DCE‐MRI), and directly compare three pharmacokinetic analysis techniques: a conventional established technique and two novel techniques that aim to reduce erroneous overestimation of the volume transfer constant between plasma and the extravascular extracellular space (EES) (Ktrans) in areas of high blood volume.

Preliminary Study of Oxygen-Enhanced Longitudinal Relaxation in MRI: A Potential Novel Biomarker of Oxygenation Changes in Solid Tumors

PURPOSE There is considerable interest in developing non-invasive methods of mapping tumor hypoxia. Changes in tissue oxygen concentration produce proportional changes in the magnetic resonance imaging (MRI) longitudinal relaxation rate (R(1)). This technique has been used previously to evaluate oxygen delivery to healthy tissues and is distinct from blood oxygenation level-dependent (BOLD) imaging. Here we report application of this method to detect alteration in tumor oxygenation status. METHODS AND MATERIALS Ten patients with advanced cancer of the abdomen and pelvis underwent serial measurement of tumor R(1) while breathing medical air (21% oxygen) followed by 100% oxygen (oxygen-enhanced MRI). Gadolinium-based dynamic contrast-enhanced MRI was then performed to compare the spatial distribution of perfusion with that of oxygen-induced DeltaR(1). RESULTS DeltaR(1) showed significant increases of 0.021 to 0.058 s(-1) in eight patients with either locally recurrent tumor from cervical and hepatocellular carcinomas or metastases from ovarian and colorectal carcinomas. In general, there was congruency between perfusion and oxygen concentration. However, regional mismatch was observed in some tumor cores. Here, moderate gadolinium uptake (consistent with moderate perfusion) was associated with low area under the DeltaR(1) curve (consistent with minimal increase in oxygen concentration). CONCLUSIONS These results provide evidence that oxygen-enhanced longitudinal relaxation can monitor changes in tumor oxygen concentration. The technique shows promise in identifying hypoxic regions within tumors and may enable spatial mapping of change in tumor oxygen concentration.

Tracer kinetic model–driven registration for dynamic contrast-enhanced MRI time-series data

Dynamic contrast‐enhanced MRI (DCE‐MRI) time series data are subject to unavoidable physiological motion during acquisition (e.g., due to breathing) and this motion causes significant errors when fitting tracer kinetic models to the data, particularly with voxel‐by‐voxel fitting approaches. Motion correction is problematic, as contrast enhancement introduces new features into postcontrast images and conventional registration similarity measures cannot fully account for the increased image information content. A methodology is presented for tracer kinetic model–driven registration that addresses these problems by explicitly including a model of contrast enhancement in the registration process. The iterative registration procedure is focused on a tumor volume of interest (VOI), employing a three‐dimensional (3D) translational transformation that follows only tumor motion. The implementation accurately removes motion corruption in a DCE‐MRI software phantom and it is able to reduce model fitting errors and improve localization in 3D parameter maps in patient data sets that were selected for significant motion problems. Sufficient improvement was observed in the modeling results to salvage clinical trial DCE‐MRI data sets that would otherwise have to be rejected due to motion corruption. Magn Reson Med 58:1010–1019, 2007.

Comparison of normal tissue R1 and R *2 modulation by oxygen and carbogen

Magnetic resonance imaging has shown promise for evaluating tissue oxygenation. In this study differences in the tissue longitudinal relaxation rate (R1) and effective transverse relaxation rate (R  *2 ), induced by inhalation of pure oxygen and carbogen, were evaluated in 10 healthy subjects. Significant reductions in R1 were demonstrated following both oxygen and carbogen inhalation in the spleen (both P < 0.001), liver (P = 0.002 air vs. oxygen; P = 0.001 air vs. carbogen), skeletal muscle (both P < 0.001), and renal cortex (P = 0.005 air vs. oxygen; P = 0.008 air vs. carbogen). No significant change in R  *2 occurred following pure oxygen in any organ. However, a significant increase in R  *2 was observed in the spleen (P < 0.001), liver (P = 0.001), skeletal muscle (P = 0.026), and renal cortex (P = 0.001) following carbogen inhalation, an opposite effect to that observed in many studies of tumor pathophysiology. Changes in R1 and R  *2 were independent of the gas administration order in the spleen and skeletal muscle. These findings suggest that the R1 and R  *2 responses to hyperoxic gases are independent biomarkers of oxygen physiology. Magn Reson Med 61:75–83, 2009.