Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation.

Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types. However, an incomplete understanding of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality. In particular, the impact of antiangiogenic therapy on tumor blood flow and oxygenation status (i.e., the role of vessel pruning versus normalization) remains controversial. This controversy has become critical as multiple phase III trials of anti-VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma (nGBM) patients and several other cancers. Here, we shed light on mechanisms of nGBM response to cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, using MRI techniques and blood biomarkers in prospective phase II clinical trials of cediranib with chemoradiation vs. chemoradiation alone in nGBM patients. We demonstrate that improved perfusion occurs only in a subset of patients in cediranib-containing regimens, and is associated with improved overall survival in these nGBM patients. Moreover, an increase in perfusion is associated with improved tumor oxygenation status as well as with pharmacodynamic biomarkers, such as changes in plasma placenta growth factor and sVEGFR2. Finally, treatment resistance was associated with elevated plasma IL-8 and sVEGFR1 posttherapy. In conclusion, tumor perfusion changes after antiangiogenic therapy may distinguish responders vs. nonresponders early in the course of this expensive and potentially toxic form of therapy, and these results may provide new insight into the selection of glioblastoma patients most likely to benefit from anti-VEGF treatments.

Low incidence of pseudoprogression by imaging in newly diagnosed glioblastoma patients treated with cediranib in combination with chemoradiation.

BACKGROUND: Chemoradiation (CRT) can significantly modify the radiographic appearance of malignant gliomas, especially within the immediate post-CRT period. Pseudoprogression (PsP) is an increasingly recognized phenomenon in this setting, and is thought to be secondary to increased permeability as a byproduct of the complex process of radiation-induced tissue injury, possibly enhanced by temozolomide. We sought to determine whether the addition of a vascular endothelial growth factor (VEGF) signaling inhibitor (cediranib) to conventional CRT had an impact on the frequency of PsP, by comparing two groups of patients with newly diagnosed glioblastoma before, during, and after CRT. METHODS: All patients underwent serial magnetic resonance imaging as part of institutional review board-approved clinical studies. Eleven patients in the control group received only chemoradiation, whereas 29 patients in the study group received chemoradiation and cediranib until disease progression or toxicity. Response assessment was defined according to Response Assessment in Neuro-Oncology criteria, and patients with enlarging lesions were classified into true tumor progressions (TTP) or PsP, based on serial radiographic follow-up. RESULTS: Two patients in the study group (7%) showed signs of apparent early tumor progression, and both were subsequently classified as TTP. Six patients in the control group (54%) showed signs of apparent early tumor progression, and three were subsequently classified as TTP and three as PsP. The frequency of PsP was significantly higher in the control group. CONCLUSION: Administration of a VEGF inhibitor during and after CRT modifies the expression of PsP by imaging.

Imaging of Activated T Cells as an Early Predictor of Immune Response to Anti-PD-1 Therapy.

Compelling evidence points to immune cell infiltration as a critical component of successful immunotherapy. However, there are currently no clinically available, noninvasive methods capable of evaluating immune contexture prior to or during immunotherapy. In this study, we evaluate a T-cell-specific PET agent, [18F]F-AraG, as an imaging biomarker predictive of response to checkpoint inhibitor therapy. We determined the specificity of the tracer for activated T cells in vitro and in a virally induced model of rhabdomyosarcoma. Of all immune cells tested, activated human CD8+ effector cells showed the highest accumulation of [18F]F-AraG. Isolation of lymphocytes from the rhabdomyosarcoma tumors showed that more than 80% of the intratumoral signal came from accumulation of [18F]F-AraG in immune cells, primarily CD8+ and CD4+. Longitudinal monitoring of MC38 tumor-bearing mice undergoing anti-PD-1 treatment revealed differences in signal between PD-1 and isotype antibody-treated mice early into treatment. The differences in [18F]F-AraG signal were also apparent between responders and nonresponders to anti-PD-1 therapy. Importantly, we found that the signal in the tumor-draining lymph nodes provides key information about response to anti-PD-1 therapy. Overall, [18F]F-AraG has potential to serve as a much needed immunomonitoring clinical tool for timely evaluation of immunotherapy. SIGNIFICANCE: These findings reveal differences in T-cell activation between responders and nonresponders early into anti-PD-1 treatment, which may impact many facets of immuno-oncology, including patient selection, management, and development of novel combinatorial approaches.

Early response of prostate carcinoma xenografts to docetaxel chemotherapy monitored with diffusion MRI.

For many anticancer therapies, it would be desirable to accurately monitor and quantify tumor response early in the treatment regimen. This would allow oncologists to continue effective therapies or discontinue ineffective therapies early in the course of treatment, and hence, reduce morbidity. This is especially true for second-line therapies, which have reduced response rates and increased toxicities. Previous works by others and ourselves have shown that water mobility, measured by diffusion-weighted magnetic resonance imaging (DW-MRI), increases early in tumors destined to respond to therapies. In the current communication, we further characterize the utility of DW-MRI to predict response of prostate cancer xenografts to docetaxel in SCID mice in a preclinical setting. The current data illustrate that tumor volumes and secreted prostate-specific antigen both respond strongly to docetaxel in a dose-responsive manner, and the apparent diffusion coefficient of water (ADC(w)) increases significantly by 2 days even at the lowest doses (10 mg/kg). The ADCw data were parsed by histogram analyses. Our results indicate that DW-MRI can be used for early detection of prostate carcinoma xenograft response to docetaxel chemotherapy.

Bevacizumab treatment for meningiomas in NF2: a retrospective analysis of 15 patients.

Bevacizumab treatment can result in tumor shrinkage of progressive vestibular schwannomas in some neurofibromatosis 2 (NF2) patients but its effect on meningiomas has not been defined. To determine the clinical activity of bevacizumab against NF2-related meningiomas, we measured changes in volume of meningiomas in NF2 patients who received bevacizumab for treatment of progressive vestibular schwannomas. A radiographic response was defined as a 20% decrease in tumor size by volumetric MRI analysis. In addition, we determined the expression pattern of growth factors associated with tumor angiogenesis in paraffin-embedded tissues from 26 unrelated meningiomas. A total of 48 meningiomas in 15 NF2 patients were included in this study with a median follow up time of 18 months. A volumetric radiographic response was seen in 29% of the meningiomas (14/48). Tumor shrinkage was not durable: the median duration of response was 3.7 months and the median time to progression was 15 months. There was no significant correlation between pre-treatment growth rate and meningioma response in regression models. Tissue analysis showed no correlation between tumor microvascular density and expression of VEGF pathway components. This data suggests that, in contrast to schwannomas, activation of VEGF pathway is not the primary driver of angiogenesis in meningiomas. Our results suggest that a minority of NF2-associated meningiomas shrink during bevacizumab therapy and that these responses were of short duration. These results are comparable to previous studies of bevacizumab in sporadic meningiomas.

Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy.

Measurement of vessel caliber by magnetic resonance imaging (MRI) is a valuable technique for in vivo monitoring of hemodynamic status and vascular development, especially in the brain. Here, we introduce a new paradigm in MRI termed vessel architectural imaging (VAI) that exploits an overlooked temporal shift in the magnetic resonance signal, forming the basis for vessel caliber estimation, and show how this phenomenon can reveal new information on vessel type and function not assessed by any other noninvasive imaging technique. We also show how this biomarker can provide new biological insights into the treatment of patients with cancer. As an example, we demonstrate using VAI that anti-angiogenic therapy can improve microcirculation and oxygen saturation and reduce vessel calibers in patients with recurrent glioblastomas and, more crucially, that patients with these responses have prolonged survival. Thus, VAI has the potential to identify patients who would benefit from therapies.

Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients.

OBJECTIVE: Early studies suggest that bevacizumab treatment can result in tumor shrinkage and hearing improvement for some patients with neurofibromatosis type 2 (NF2). The aim of this study was to report extended follow-up in a larger cohort of similarly treated patients. STUDY DESIGN: Retrospective study. SETTING: Tertiary referral center PATIENTS: Thirty-one consecutive NF2 patients who received bevacizumab for progressive vestibular schwannomas. MAIN OUTCOME MEASURE: Hearing improvement, defined as an improvement in word recognition score above the 95% critical difference compared with baseline, and radiographic response, defined as a 20% or greater decrease in tumor volume compared with baseline. RESULTS: The median age was 26 years (range, 12-73 yr). The median volumetric tumor growth rate before treatment was 64% per year. At the time of analysis, the median duration of treatment was 14 months (range, 6-41 mo) with a total of 47 patient-years of follow-up. A hearing response occurred in 57% (13/23) of evaluable patients and a radiographic response in 55% (17/31) of target vestibular schwannomas. The median time to response was 3 months for both end points. The only clinical or radiographic feature at baseline that correlated with change in tumor volume at 3 months was the mean apparent diffusion coefficient value, a radiologic marker of edema (p = 0.036). Ninety percent of patients had stable or improved hearing after 1 year of treatment and 61% at 3 years; 88% of patients had stable or decreased tumor size after 1 year of treatment and 54% at 3 years. Overall, treatment was well tolerated. CONCLUSION: Bevacizumab treatment was followed by hearing improvement and tumor shrinkage in more than 50% of progressive vestibular schwannomas in NF2 patients. Stable or improved hearing was retained in the majority of patients.

Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion.

The abnormal vasculature of the tumor microenvironment supports progression and resistance to treatment. Judicious application of antiangiogenic therapy may normalize the structure and function of the tumor vasculature, promoting improved blood perfusion. However, direct clinical evidence is lacking for improvements in blood perfusion after antiangiogenic therapy. In this study, we used MRI to assess tumor blood perfusion in 30 recurrent glioblastoma patients who were undergoing treatment with cediranib, a pan-VEGF receptor tyrosine kinase inhibitor. Tumor blood perfusion increased durably for more than 1 month in 7 of 30 patients, in whom it was associated with longer survival. Together, our findings offer direct clinical evidence in support of the hypothesis that vascular normalization can increase tumor perfusion and help improve patient survival.

3D Slicer as an image computing platform for the Quantitative Imaging Network.

Quantitative analysis has tremendous but mostly unrealized potential in healthcare to support objective and accurate interpretation of the clinical imaging. In 2008, the National Cancer Institute began building the Quantitative Imaging Network (QIN) initiative with the goal of advancing quantitative imaging in the context of personalized therapy and evaluation of treatment response. Computerized analysis is an important component contributing to reproducibility and efficiency of the quantitative imaging techniques. The success of quantitative imaging is contingent on robust analysis methods and software tools to bring these methods from bench to bedside. 3D Slicer is a free open-source software application for medical image computing. As a clinical research tool, 3D Slicer is similar to a radiology workstation that supports versatile visualizations but also provides advanced functionality such as automated segmentation and registration for a variety of application domains. Unlike a typical radiology workstation, 3D Slicer is free and is not tied to specific hardware. As a programming platform, 3D Slicer facilitates translation and evaluation of the new quantitative methods by allowing the biomedical researcher to focus on the implementation of the algorithm and providing abstractions for the common tasks of data communication, visualization and user interface development. Compared to other tools that provide aspects of this functionality, 3D Slicer is fully open source and can be readily extended and redistributed. In addition, 3D Slicer is designed to facilitate the development of new functionality in the form of 3D Slicer extensions. In this paper, we present an overview of 3D Slicer as a platform for prototyping, development and evaluation of image analysis tools for clinical research applications. To illustrate the utility of the platform in the scope of QIN, we discuss several use cases of 3D Slicer by the existing QIN teams, and we elaborate on the future directions that can further facilitate development and validation of imaging biomarkers using 3D Slicer.

Serial magnetic resonance spectroscopy reveals a direct metabolic effect of cediranib in glioblastoma.

Proton magnetic resonance spectroscopy is increasingly used in clinical studies of brain tumor to provide information about tissue metabolic profiles. In this study, we evaluated changes in the levels of metabolites predominant in recurrent glioblastoma multiforme (rGBM) to characterize the response of rGBM to antiangiogenic therapy. We examined 31 rGBM patients treated with daily doses of cediranib, acquiring serial chemical shift imaging data at specific time points during the treatment regimen. We defined spectra from three regions of interest (ROI)--enhancing tumor (ET), peritumoral tissue, and normal tissue on the contralateral side (cNT)--in post-contrast T1-weighted images, and normalized the concentrations of N-acetylaspartate (NAA) and choline (Cho) in each ROI to the concentration of creatine in cNT (norCre). We analyzed the ratios of these normalized metabolites (i.e., NAA/Cho, NAA/norCre, and Cho/norCre) by averaging all patients and categorizing two different survival groups. Relative to pretreatment values, NAA/Cho in ET was unchanged through day 28. However, after day 28, NAA/Cho significantly increased in relation to a significant increase in NAA/norCre and a decrease in Cho/norCre; interestingly, the observed trend was reversed after day 56, consistent with the clinical course of GBM recurrence. Notably, receiver operating characteristic analysis indicated that NAA/Cho in tumor shows a high prediction to 6-month overall survival. These metabolic changes in these rGBM patients strongly suggest a direct metabolic effect of cediranib and might also reflect an antitumor response to antiangiogenic treatment during the first 2 months of treatment. Further study is needed to confirm these findings.

Spectroscopic imaging with improved gradient modulated constant adiabaticity pulses on high-field clinical scanners.

The purpose of this work was to design and implement constant adiabaticity gradient modulated pulses that have improved slice profiles and reduced artifacts for spectroscopic imaging on 3T clinical scanners equipped with standard hardware. The newly proposed pulses were designed using the gradient offset independent adiabaticity (GOIA, Tannus and Garwood[13]) method using WURST modulation for RF and gradient waveforms. The GOIA-WURST pulses were compared with GOIA-HSn (GOIA based on nth-order hyperbolic secant) and FOCI (frequency offset corrected inversion) pulses of the same bandwidth and duration. Numerical simulations and experimental measurements in phantoms and healthy volunteers are presented. GOIA-WURST pulses provide improved slice profile that have less slice smearing for off-resonance frequencies compared to GOIA-HSn pulses. The peak RF amplitude of GOIA-WURST is much lower (40% less) than FOCI but slightly higher (14.9% more) to GOIA-HSn. The quality of spectra as shown by the analysis of lineshapes, eddy currents artifacts, subcutaneous lipid contamination and SNR is improved for GOIA-WURST. GOIA-WURST pulse tested in this work shows that reliable spectroscopic imaging could be obtained in routine clinical setup and might facilitate the use of clinical spectroscopy.

A "vascular normalization index" as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients.

Early imaging or blood biomarkers of tumor response are desperately needed to customize antiangiogenic therapy for cancer patients. Anti-vascular endothelial growth factor (VEGF) therapy can "normalize" brain tumor vasculature by decreasing vessel diameter and permeability, and thinning the abnormally thick basement membrane. We hypothesized that the extent of vascular normalization will be predictive of outcome of anti-VEGF therapy in glioblastoma. We used advanced magnetic resonance imaging methods to monitor vascular parameters and treatment response in 31 recurrent glioblastoma patients enrolled in a phase II trial of cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor. We evaluated the correlation between clinical outcome and magnetic resonance imaging-measured changes in vascular permeability/flow (i.e., K(trans)) and in microvessel volume, and the change of circulating collagen IV levels, all after a single dose of cediranib. Here, we show that evaluation of biomarkers as early as after one day of anti-VEGF therapy with cediranib is predictive of response in patients with recurrent glioblastoma. Changes in K(trans), microvessel volume, and circulating collagen IV correlated with duration of overall survival and/or progression-free survival (P < 0.05). When we combined these three parameters into a "vascular normalization index," we found that it closely associated with overall survival (rho = 0.54; P = 0.004) and progression-free survival (rho = 0.6; P = 0.001). The vascular normalization index described here should be validated in randomized clinical trials.

Imaging hemodynamics.

Microvascular permeability is a pharmacologic indicator of tumor response to therapy, and it is expected that this biomarker will evolve into a clinical surrogate endpoint and be integrated into protocols for determining patient response to antiangiogenic or antivascular therapies. This review discusses the physiological context of vessel permeability in an imaging setting, how it is affected by active and passive transport mechanisms, and how it is described mathematically for both theoretical and complex dynamic microvessel membranes. Many research groups have established dynamic-enhanced imaging protocols for estimating this important parameter. This review discusses those imaging modalities, the advantages and disadvantages of each, and how they compare in terms of their ability to deliver information about therapy-associated changes in microvessel permeability in humans. Finally, this review discusses future directions and improvements needed in these areas.

MRI-measured water mobility increases in response to chemotherapy via multiple cell-death mechanisms.

Numerous pre-clinical and clinical reports have demonstrated that the MRI-measured apparent diffusion coefficient of water (ADC) increases early in the response to a wide variety of anti-cancer therapies. It has been proposed that this increase in ADC generally results from an increase in the tumor extracellular volume fraction leading to a greater degree of unrestricted water motion. Furthermore, an increase in extracellular volume has been ascribed to the cell shrinkage that occurs early in the process of programmed cell death. However, other modes of death can be initiated soon after beginning therapy. These other modes of death include mitotic catastrophe and necrosis, and may also involve changes in the fraction of water with unrestricted motion. This work examines whether MRI-measured ADC is altered in response to therapies that induce cell death via non-apoptotic mechanisms and correlates ADC changes with cell death modalities regionally within the tumor. Apoptotic responses were limited to the tumor periphery in apoptosis-proficient tumors. Apoptosis was not observed in deficient tumors. Mitotic catastrophe was observed after treatment at the periphery and deeper into the tumor. Necrosis was the predominant response in the center of the tumor. ADC changes were moderate in the periphery and larger in the center. The results indicate that early and significant changes in ADC can occur in concert with mitotic catastrophe and lytic necrosis in the absence of apoptosis. Hence, changes in ADC may be a generalized measure of cytotoxic response to chemotherapy.