Volumetric analysis of functional diffusion maps is a predictive imaging biomarker for cytotoxic and anti-angiogenic treatments in malignant gliomas

Translational Brain Tumor Research Program, Medical College of Wisconsin, Milwaukee, WI, USA.
Journal of Neuro-Oncology (Impact Factor: 3.07). 03/2011; 102(1):95-103. DOI: 10.1007/s11060-010-0293-7
Source: PubMed


Anti-angiogenic agents targeting brain tumor neovasculature may increase progression-free survival in patients with recurrent malignant gliomas. However, when these patients do recur it is not always apparent as an increase in enhancing tumor volume on MRI, which has been the standard of practice for following patients with brain tumors. Therefore alternative methods are needed to evaluate patients treated with these novel therapies. Furthermore, a method that can also provide useful information for the evaluation of conventional therapies would provide an important advantage for general applicability. Diffusion-weighted magnetic resonance imaging (DWI) has the potential to serve as a valuable biomarker for these purposes. In the current study, we explore the prognostic ability of functional diffusion maps (fDMs), which examine voxel-wise changes in the apparent diffusion coefficient (ADC) over time, applied to regions of fluid-attenuated inversion recovery (FLAIR) abnormalities in patients with malignant glioma, treated with either anti-angiogenic or cytotoxic therapies. Results indicate that the rate of change in fDMs is an early predictor of tumor progression, time to progression and overall survival for both treatments, suggesting the application of fDMs in FLAIR abnormal regions may be a significant advance in brain tumor biomarker technology.

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    • "Acquisition sequences for DWI are not completely standardized, but basic techniques are well known and available on systems from all major vendors. There is no established standard for measurement of ADC but recent reports promote voxel-based analysis and volumetric evaluation of ADC (vADC) which is well correlated with cellularity, as shown in gliomas [27,28]. This method also carries the advantages of being less operator-dependent and more reproducible than ROI-based techniques. "
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    ABSTRACT: Background: Metastatic colorectal cancer (mCRC) may present various behaviours that define different courses of tumor evolution. There is presently no available tool designed to assess tumor aggressiveness, despite the fact that this is considered to have a major impact on patient outcome. Methods/design: CORIOLAN is a single-arm prospective interventional non-therapeutic study aiming mainly to assess the natural tumor metabolic progression index (TMPI) measured by serial FDG PET-CT without any intercurrent antitumor therapy as a prognostic factor for overall survival (OS) in patients with mCRC.Secondary objectives of the study aim to test the TMPI as a prognostic marker for progression-free survival (PFS), to assess the prognostic value of baseline tumor FDG uptake on PFS and OS, to compare TMPI to classical clinico-biological assessment of prognosis, and to test the prognostic value on OS and PFS of MRI-based apparent diffusion coefficient (ADC) and variation of vADC using voxel-based diffusion maps.Additionally, this study intends to identify genomic and epigenetic factors that correlate with progression of tumors and the OS of patients with mCRC. Consequently, this analysis will provide information about the signaling pathways that determine the natural and therapy-free course of the disease. Finally, it would be of great interest to investigate whether in a population of patients with mCRC, for which at present no known effective therapy is available, tumor aggressiveness is related to elevated levels of circulating tumor cells (CTCs) and to patient outcome. Discussion: Tumor aggressiveness is one of the major determinants of patient outcome in advanced disease. Despite its importance, supported by findings reported in the literature of extreme outcomes for patients with mCRC treated with chemotherapy, no objective tool allows clinicians to base treatment decisions on this factor. The CORIOLAN study will characterize TMPI using FDG-PET-based metabolic imaging of patients with chemorefractory mCRC during a period of time without treatment. Results will be correlated to other assessment tools like DW-MRI, CTCs and circulating DNA, with the aim to provide usable tools in daily practice and in clinical studies in the future. Clinical trialsgov number: NCT01591590.
    BMC Cancer 05/2014; 14(1):385. DOI:10.1186/1471-2407-14-385 · 3.36 Impact Factor
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    • "Alternatively, individual pixel-to-pixel ADC comparisons may provide a more accurate description of tumor progression by accounting for regional heterogeneity. Several studies have investigated the value of functional diffusion maps (fDMs) in predicting tumor response in adult tumors, time to progression (TTP), and overall survival (OS) after cytotoxic or anti-angiogenic therapies.4,7,14,15 Typically, the 2 imaging biomarkers extracted from fDMs are relative volumes exhibiting a decrease16,17 and an increase4,18 in ADC. "
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    ABSTRACT: Background Assessment of treatment response by measuring tumor size is known to be a late and potentially confounded response index. Serial diffusion MRI has shown potential for allowing earlier and possibly more reliable response assessment in adult patients, with limited experience in clinical settings and in pediatric brain cancer. We present a retrospective study of clinical MRI data in children with high-grade brain tumors to assess and compare the values of several diffusion change metrics to predict treatment response.Methods Eighteen patients (age range, 1.9-20.6 years) with high-grade brain tumors and serial diffusion MRI (pre- and posttreatment interval range, 1-16 weeks posttreatment) were identified after obtaining parental consent. The following diffusion change metrics were compared with the clinical response status assessed at 6 months: (1) regional change in absolute and normalized apparent diffusivity coefficient (ADC), (2) voxel-based fractional volume of increased (fiADC) and decreased ADC (fdADC), and (3) a new metric based on the slope of the first principal component of functional diffusion maps (fDM).ResultsResponders (n = 12) differed significantly from nonresponders (n = 6) in all 3 diffusional change metrics demonstrating higher regional ADC increase, larger fiADC, and steeper slopes (P < .05). The slope method allowed the best response prediction (P < .01, η(2) = 0.78) with a classification accuracy of 83% for a slope of 58° using receiver operating characteristic (ROC) analysis.Conclusions We demonstrate that diffusion change metrics are suitable response predictors for high-grade pediatric tumors, even in the presence of variable clinical diffusion imaging protocols.
    Neuro-Oncology 04/2013; 15(8). DOI:10.1093/neuonc/not034 · 5.56 Impact Factor
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    • "The PI model can further incorporate differential motility of glioma cells through gray and white matter of the brain, providing predictions of diffuse tumor invasion through the regions of the brain that are specific to the patient's tumor (Figure 2). This simple model has served as a foundation for patient-specific MNO and provided numerous insights into clinical behaviors such as survival outcome (Pallud et al., 2006; Swanson et al., 2008b; Wang et al., 2009; Rockne et al., 2010), hypoxia development (Szeto et al., 2009b), response to surgical resection (Swanson et al., 2008b), chemo-and radiation therapies (Rockne et al., 2010), biological aggressiveness (Szeto et al., 2009a; Ellingson et al., 2010b), and to date is the single most applied patient-specific clinical scale model for glioma growth and response to therapy. Extensions to this model include consideration of anisotropic growth in white matter tracts (Jbabdi et al., 2005). "
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    ABSTRACT: Gliomas are notoriously aggressive, malignant brain tumors that have variable response to treatment. These patients often have poor prognosis, informed primarily by histopathology. Mathematical neuro-oncology (MNO) is a young and burgeoning field that leverages mathematical models to predict and quantify response to therapies. These mathematical models can form the basis of modern "precision medicine" approaches to tailor therapy in a patient-specific manner. Patient-specific models (PSMs) can be used to overcome imaging limitations, improve prognostic predictions, stratify patients, and assess treatment response in silico. The information gleaned from such models can aid in the construction and efficacy of clinical trials and treatment protocols, accelerating the pace of clinical research in the war on cancer. This review focuses on the growing translation of PSM to clinical neuro-oncology. It will also provide a forward-looking view on a new era of patient-specific MNO.
    Frontiers in Oncology 04/2013; 3:62. DOI:10.3389/fonc.2013.00062
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