Edward F. Jackson

Randomized Double-Blind Placebo-Controlled Trial of Bevacizumab Therapy for Radiation Necrosis of the Central Nervous System

PURPOSE To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain. METHODS AND MATERIALS A total of 14 patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system radiation necrosis. All patients were required to have radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs. Eligible patients had undergone irradiation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Patients were randomized to receive intravenous saline or bevacizumab at 3-week intervals. The magnetic resonance imaging findings 3 weeks after the second treatment and clinical signs and symptoms defined the response or progression. RESULTS The volumes of necrosis estimated on T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced magnetic resonance imaging scans demonstrated that although no patient receiving placebo responded (0 of 7), all bevacizumab-treated patients did so (5 of 5 randomized and 7 of 7 crossover) with decreases in T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. All bevacizumab-treated patients-and none of the placebo-treated patients-showed improvement in neurologic symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all four study doses, only 2 patients had experienced a recurrence of magnetic resonance imaging changes consistent with progressive radiation necrosis; one patient received a single additional dose of bevacizumab and the other patient received two doses. CONCLUSION The Class I evidence of bevacizumab efficacy from the present study in the treatment of central nervous system radiation necrosis justifies consideration of this treatment option for people with radiation necrosis secondary to the treatment of head-and-neck cancer and brain cancer.

Clinical InvestigationRandomized Double-Blind Placebo-Controlled Trial of Bevacizumab Therapy for Radiation Necrosis of the Central Nervous System

PURPOSE To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain. METHODS AND MATERIALS A total of 14 patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system radiation necrosis. All patients were required to have radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs. Eligible patients had undergone irradiation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Patients were randomized to receive intravenous saline or bevacizumab at 3-week intervals. The magnetic resonance imaging findings 3 weeks after the second treatment and clinical signs and symptoms defined the response or progression. RESULTS The volumes of necrosis estimated on T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced magnetic resonance imaging scans demonstrated that although no patient receiving placebo responded (0 of 7), all bevacizumab-treated patients did so (5 of 5 randomized and 7 of 7 crossover) with decreases in T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. All bevacizumab-treated patients-and none of the placebo-treated patients-showed improvement in neurologic symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all four study doses, only 2 patients had experienced a recurrence of magnetic resonance imaging changes consistent with progressive radiation necrosis; one patient received a single additional dose of bevacizumab and the other patient received two doses. CONCLUSION The Class I evidence of bevacizumab efficacy from the present study in the treatment of central nervous system radiation necrosis justifies consideration of this treatment option for people with radiation necrosis secondary to the treatment of head-and-neck cancer and brain cancer.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study

PURPOSE Identifying suitable markers of biologic activity is important when assessing novel compounds such as angiogenesis inhibitors to optimize the dose and schedule of therapy. Here we present the pharmacodynamic response to acute dosing of AG-013736 measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). PATIENTS AND METHODS Thirty-six patients with advanced solid tumors were treated with various doses of AG-013736. In addition to standard measures of objective disease response and pharmacokinetic analysis, DCE-MRI scans were acquired at baseline and repeated at cycle 1--day 2 after the scheduled morning dose of the AG-013736 in 26 patients. Indicators of a vascular response, such as the volume transfer constant (K(trans)) and initial area under the curve (IAUC), were calculated to assess the effect of treatment on tumor vascular function. RESULTS Evaluable vascular response data were obtained in 17 (65%) of 26 patients. A linear correlation was found in which the percentage change from baseline to day 2 in K(trans) and IAUC was inversely proportional to AG-013736 exposure. Using a conservative a priori assumption that a > or = 50% decrease in K(trans) was indicative of an objective vascular response, a 50% decrease in K(trans) was achieved and corresponded to a plasma AUC(0-24) of > 200 ng . h/mL. CONCLUSION A sufficient decrease in tumor vascular parameters was observed at a dose chosen for additional phase II testing by conventional toxicity criteria. In addition, the day 2 vascular response measured using DCE-MRI seems to be a useful indicator of drug pharmacology, and additional research is needed to determine if it is a suitable marker for predicting clinical activity.

Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors

PURPOSE AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors. PATIENTS AND METHODS Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg. Results Thirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum AMG 386 levels appeared to reach steady-state after four weekly doses, and there was minimal accumulation. No anti-AMG 386 neutralizing antibodies were detected. Reductions in volume transfer constant (K(trans); measured by dynamic contrast-enhanced magnetic resonance imaging) were observed in 10 patients (13 lesions) 48 hours to 8 weeks after treatment. One patient with refractory ovarian cancer achieved a confirmed partial response (ie, 32.5% reduction by Response Evaluation Criteria in Solid Tumors) and withdrew from the study with a partial response after 156 weeks of treatment; four patients experienced stable disease for at least 16 weeks. CONCLUSION Weekly AMG 386 appeared well tolerated, and its safety profile appeared distinct from that of vascular endothelial growth factor-axis inhibitors. AMG 386 also appeared to impact tumor vascularity and showed antitumor activity in this patient population.

Phase II Study of Aflibercept in Recurrent Malignant Glioma: A North American Brain Tumor Consortium Study

PURPOSE Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma. PATIENTS AND METHODS Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse. Aflibercept 4 mg/kg was administered intravenously on day 1 of every 2-week cycle. RESULTS The 6-month progression-free survival rate was 7.7% for the glioblastoma cohort and 25% for patients with anaplastic glioma. Overall radiographic response rate was 24% (18% for glioblastoma and 44% for anaplastic glioma). The median progression-free survival was 24 weeks for patients with anaplastic glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with glioblastoma (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. The main treatment-related National Cancer Institute Common Terminology Criteria grades 3 and 4 adverse events (38 total) included fatigue, hypertension, and lymphopenia. Two grade 4 CNS ischemias and one grade 4 systemic hemorrhage were reported. Aflibercept rapidly decreases permeability on dynamic contrast enhanced magnetic resonance imaging, and molecular analysis of baseline tumor tissue identified tumor-associated markers of response and resistance. CONCLUSION Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma.

Impact of intraoperative high-field magnetic resonance imaging guidance on glioma surgery: a prospective volumetric analysis.

OBJECTIVETo determine the impact of intraoperative magnetic resonance imaging (iMRI) on the decision to proceed with additional glioma resection during surgery and to maximize extent of resection (EOR). METHODSPatients who underwent craniotomy for glioma resection with high-field iMRI guidance were prospectively evaluated between September 2006 and August 2007. Volumetric analysis and EOR were assessed with iMRI, using postcontrast T1-weighted images for tumors showing contrast enhancement and T2-weighted images for nonenhancing tumors. RESULTSForty-six patients underwent resection using iMRI guidance, with iMRI being used to evaluate the EOR in 44 patients and for reregistration in 2 patients. Surgery was terminated after iMRI in 23 patients (52%) because gross total resection was achieved or because of residual tumor infiltration in an eloquent brain region. Twenty-one patients (47%) underwent additional resection of residual tumor after iMRI. For enhancing gliomas, the median EOR increased significantly from 84% (range, 59%–97%) to 99% (range, 85%–100%) with additional tumor removal after iMRI (P < 0.001). For nonenhancing gliomas, the median EOR increased (from 63% to 80%) with additional tumor removal after iMRI, but not significantly, owing to the small sample size (7 patients). Overall, the EOR increased from 76% (range, 35%–97%) to 96% (range, 48%–100%) (P < 0.001). Gross total resection was achieved after additional tumor removal after iMRI in 15 of 21 patients (71%). Overall, 29 patients (65%) experienced gross total resection, and in 15 (52%), this was achieved with the contribution of iMRI. CONCLUSIONHigh-field iMRI is a safe and reliable technique, and its use optimizes the extent of glioma resection.

Neuropsychological significance of areas of high signal intensity on brain MRIs of children with neurofibromatosis

Of children with neurofibromatosis (NF), 40% have a cognitive or learning impairment.Approximately 60% also have anomalous areas of high signal intensity on T2-weighted brain MRIs. The association of these hyperintensities and neuropsychological status is not fully understood. We administered a battery of neuropsychological tests and a standard clinical MRI to determine the impact of hyperintensity presence, number, and location on cognitive status in 84 children (8 to 16 years) with NF type 1. These children underwent standard clinical MRI using a GE 1.5-tesla scanner (except one child who was examined with a 1.0-tesla scanner). We conducted three types of analyses: Hyperintensity presence or absence.--Scores of children with (55%) and without hyperintensities (45%) were compared using t tests. No statistically significant differences between groups in intellectual functioning or any neuropsychological variable were found. Number of hyperintensities--The number of hyperintensity locations per child ranged from one to five (mean = 2.22). Pearson correlations revealed no significant association between the number of hyperintensities and neuropsychological performance. Location of hyperintensities--In four of the five locations studied, no statistically significant differences were found between scores of children with a hyperintensity in an area and those with one elsewhere. However, mean scores for IQ, Memory, Motor, Distractibility, and Attention domains for children with hyperintensities in the thalamus were significantly lower than scores for those with hyperintensities elsewhere. These results suggest that the simple presence or absence of hyperintensities, or their total number, is not as important as their anatomic location for detecting their relationship with neuropsychological status. Taking location into account, hyperintensities in the cerebral hemispheres, basal ganglia, brainstem, or cerebellum seem to have no impact on neuropsychological functioning, whereas hyperintensities in the thalamus do. NEUROLOGY 1996;46: 1660-1668

Brain volume in children with neurofibromatosis type 1: Relation to neuropsychological status

Objective: To determine characteristics of brain morphology in children and adolescents with neurofibromatosis type 1 and relate these characteristics to neuropsychological functioning. Background: Neurofibromatosis type 1 is associated with numerous CNS abnormalities and cognitive impairment. Abnormal high signal intensity visible on brain MRI, brain tumors, and macrocephaly are common. Research into links between neuroanatomic and cognitive features has been inconclusive. Methods: Fifty-two children and adolescents with neurofibromatosis type 1 were compared with 19 control subjects on several quantitative neuroanatomic and neuropsychological measures. Results: Total brain volume, especially gray matter, was significantly greater for neurofibromatosis type 1 subjects than the control subjects. Group differences in the ratio of gray matter to white matter were more prominent in younger than in older subjects. Volume of gray matter in the subjects with neurofibromatosis type 1 was related to their degree of learning disability. Corpus callosum size was significantly larger for subjects in the neurofibromatosis type 1 group, and diminished performance on measures of academic achievement and visual–spatial and motor skills were associated with greater regional corpus callosum size. Conclusions: Neuroanatomic morphology and the developmental pattern of gray matter and white matter in subjects with neurofibromatosis type 1 differed from in control subjects. Some of these differences are related to the neuropsychological status of the neurofibromatosis type 1 group. We propose that delayed developmental apoptosis results in macrocephaly and a delay in the development of appropriate neuronal connections in children with neurofibromatosis type 1. We further propose that these morphologic delays are related to the cognitive profile of neurofibromatosis type 1.

A phase I surrogate endpoint study of SU6668 in patients with solid tumors

Purpose. To evaluate the biologic effects of SU6668 in patients with solid tumors using comprehensive measures of pharmacokinetics (PK), functional imaging, and tissue correlative studies. Experimental design. Eligible patients with tumors accessible for core needle biopsy were treated with SU6668 at doses of 200 or 400 mg/m2/day. Functional computed tomography (CT) scan and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed at baseline and repeated 4 weeks and 12 weeks after treatment for analysis of tumor angiogenesis. The PK was analyzed using a high-performance liquid chromatography assay. Tumor specimens obtained via core needle biopsy at baseline and 4 weeks later were analyzed for the biologic effects of SU6668. Results. Six of a total of seven patients received treatment for at least 3 months and underwent comprehensive correlative studies, including PK, imaging, and tissue biopsy. Functional CT showed that five of six patients had decreased blood flow in tumors in response to treatment, and DCE-MRI results indicated significant change of area under the signal intensity vs. time curve (AUC) and/or maximum slope (maximum rate of signal intensity change) in two of four patients evaluated with this technique. PK studies showed that the mean apparent oral clearance (Cloral) measured on day 1 was 6.3 ± 2.7 L/hr/m2, yielding a mean AUC of 16.6 ± 4.3 mg/L·hr. By day 22, the Cloral was 40% more than that observed on day 1. Conclusion. It is feasible to evaluate the biologic effects of antiangiogenic agents using comprehensive surrogate measures.

Accuracy and Reproducibility in Volumetric Analysis of Multiple Sclerosis Lesions

The accuracy and reproducibility of dual-contrast segmentation based on nonparametric feature map analysis have been investigated in a multicomponent gelatin phantom. The root mean square errors in volume ranged from 0.02 cm3 for small volumes to 3.8 cm3 for larger volumes, with a mean error of 0.97 cm3. Average inter- and intraobserver coefficients of variation were found to be <7% for all compartments. To evaluate the reproducibility of segmentation of clinical image data, volumes of total brain, CSF, and multiple sclerosis (MS) lesions were obtained from five image sets of MS patients. Inter- and intraobserver coefficients of variations were computed for the patient data and were found to be <5% for brain, 17% for CSF, and 20% for MS lesions. Such variations were found to be reduced by appropriate preprocessing of the images.