Imaging Biomarkers In Clinical Trials Research Articles

A Review on the Use of Imaging Biomarkers in Oncology Clinical Trials: Quality Assurance Strategies for Technical Validation.

Imaging biomarkers (IBs) have been proposed in medical literature that exploit images in a quantitative way, going beyond the visual assessment by an imaging physician. These IBs can be used in the diagnosis, prognosis, and response assessment of several pathologies and are very often used for patient management pathways. In this respect, IBs to be used in clinical practice and clinical trials have a requirement to be precise, accurate, and reproducible. Due to limitations in imaging technology, an error can be associated with their value when considering the entire imaging chain, from data acquisition to data reconstruction and subsequent analysis. From this point of view, the use of IBs in clinical trials requires a broadening of the concept of quality assurance and this can be a challenge for the responsible medical physics experts (MPEs). Within this manuscript, we describe the concept of an IB, examine some examples of IBs currently employed in clinical practice/clinical trials and analyze the procedure that should be carried out to achieve better accuracy and reproducibility in their use. We anticipate that this narrative review, written by the components of the EFOMP working group on "the role of the MPEs in clinical trials"-imaging sub-group, can represent a valid reference material for MPEs approaching the subject.

Multivariate modeling of magnetic resonance biomarkers and clinical outcome measures for Duchenne muscular dystrophy clinical trials.

Although regulatory agencies encourage inclusion of imaging biomarkers in clinical trials for Duchenne muscular dystrophy (DMD), industry receives minimal guidance on how to use these biomarkers most beneficially in trials. This study aims to identify the optimal use of muscle fat fraction biomarkers in DMD clinical trials through a quantitative disease-drug-trial modeling and simulation approach. We simultaneously developed two multivariate models quantifying the longitudinal associations between 6-minute walk distance (6MWD) and fat fraction measures from vastus lateralis and soleus muscles. We leveraged the longitudinal individual-level data collected for 10 years through the ImagingDMD study. Age of the individuals at assessment was chosen as the time metric. After the longitudinal dynamic of each measure was modeled separately, the selected univariate models were combined using correlation parameters. Covariates, including baseline scores of the measures and steroid use, were assessed using the full model approach. The nonlinear mixed-effects modeling was performed in Monolix. The final models showed reasonable precision of the parameter estimates. Simulation-based diagnostics and fivefold cross-validation further showed the model's adequacy. The multivariate models will guide drug developers on using fat fraction assessment most efficiently using available data, including the widely used 6MWD. The models will provide valuable information about how individual characteristics alter disease trajectories. We will extend the multivariate models to incorporate trial design parameters and hypothetical drug effects to inform better clinical trial designs through simulation, which will facilitate the design of clinical trials that are both more inclusive and more conclusive using fat fraction biomarkers.

Integration of quantitative imaging biomarkers in clinical trials for MR-guided radiotherapy: Conceptual guidance for multicentre studies from the MR-Linac Consortium Imaging Biomarker Working Group

Quantitative imaging biomarkers (QIBs) derived from MRI techniques have the potential to be used for the personalised treatment of cancer patients. However, large-scale data are missing to validate their added value in clinical practice. Integrated MRI-guided radiotherapy (MRIgRT) systems, such as hybrid MRI-linear accelerators, have the unique advantage that MR images can be acquired during every treatment session. This means that high-frequency imaging of QIBs becomes feasible with reduced patient burden, logistical challenges, and costs compared to extra scan sessions. A wealth of valuable data will be collected before and during treatment, creating new opportunities to advance QIB research at large. The aim of this paper is to present a roadmap towards the clinical use of QIBs on MRIgRT systems. The most important need is to gather and understand how the QIBs collected during MRIgRT correlate with clinical outcomes. As the integrated MRI scanner differs from traditional MRI scanners, technical validation is an important aspect of this roadmap. We propose to integrate technical validation with clinical trials by the addition of a quality assurance procedure at the start of a trial, the acquisition of in vivo test-retest data to assess the repeatability, as well as a comparison between QIBs from MRIgRT systems and diagnostic MRI systems to assess the reproducibility. These data can be collected with limited extra time for the patient. With integration of technical validation in clinical trials, the results of these trials derived on MRIgRT systems will also be applicable for measurements on other MRI systems.

Longitudinal intracortical diffusivity changes in de-novo Parkinson's disease: A promising imaging biomarker

Cognitive impairment and dementia in Parkinson's disease (PD) are highly disabling non-motor symptoms with no effective treatment currently available. As cortical degeneration is thought to be involved in the development of these comorbidities, novel imaging biomarkers capable of detecting early cortical deterioration are needed. Recently, an increase in mean diffusivity (MD) within the cerebral cortex has been proposed as a highly sensitive imaging indicator of early microstructural cortical damage in neurodegenerative diseases. Using the Parkinson's Progression Markers Initiative (PPMI), we studied longitudinal changes in intracortical MD in recently-diagnosed and drug-naïve PD patients (n = 64). Compared to healthy controls (n = 20), de novo PD patients showed a higher one-year MD increase in frontal and occipital cortices (p < 0.05, corrected). These PD-specific MD changes correlated with changes in cognitive measures. Importantly, cortical MD increases were widespread in the PD group and loss of cortical thickness was only increased in a small parietal cluster. These results suggest that intracortical MD changes could be promising imaging biomarker in clinical trials targeting the prevention and treatment of early cortical degeneration in PD, but further research confirmation is needed.

Correlations between renal function and the total kidney volume measured on imaging for autosomal dominant polycystic kidney disease: A systematic review and meta-analysis

PurposeTo provide a systematic summary of total kidney volume (TKV) as an imaging biomarker in clinical trials for autosomal dominant polycystic kidney disease (ADPKD), focusing on the correlation between TKV and renal function. MethodsA computerized literature search was performed using MEDLINE and EMBASE databases for studies that evaluated the correlation between TKV and the glomerular filtration rate (GFR) and between the TKV growth rate and GFR decline rate. A meta-analysis was performed to generate the summary correlation coefficient (r). A qualitative review was performed to evaluate the characteristics of TKV as an imaging biomarker. ResultsEighteen articles including a total sample size of 2835 patients were retrieved. Meta-analysis revealed substantial correlations between TKV and GFR [r, −0.520; 95% confidence interval (CI), −0.60 to −0.43] and between the TKV growth rate and GFR decline rate [r, −0.320; 95% CI, −0.54 to −0.10]. The quantitative review revealed that baseline TKV can affect the TKV growth rate and GFR decline rate, such that patients with a higher baseline TKV showed faster TKV growth and GFR decline. There was significant variability in image acquisition and analysis methods. ConclusionThere were significant negative correlations between TKV and GFR as well as between TKV growth and GFR decline rates, suggesting that TKV imaging is a useful biomarker in clinical trials. However, standardization—or at least trial-specific standardization—of image acquisition and analysis techniques is required to use TKV as a reliable biomarker.

Humoral Mediators of Remote Ischemic Conditioning: Important Role of eNOS/NO/Nitrite.

Remote ischemic conditioning (RIC) is a powerful cardioprotectant and neuroprotectant. The mechanism of protection likely involves circulating, blood-borne mediators that transmit the signal from the periphery to the brain. The neuroprotective effect of RIC may be partially related to improvements in cerebral blood flow (CBF). Nitrite is a key circulating mediator of RIC and may be a mediator of increased CBF and also mediate cytoprotection through its effects on nitrosylation of mitochondrial proteins such as complex I. Measuring plasma nitrite may serve as an important blood biomarker, and measuring CBF by techniques such as MRI arterial spin labeling (ASL) may be an ideal surrogate imaging biomarker in clinical trials of RIC.

MRI measurements of vessel calibre in tumour xenografts: Comparison with vascular corrosion casting

Vessel size index (Rv, μm) has been proposed as a quantitative magnetic resonance imaging (MRI) derived imaging biomarker in oncology, for the non-invasive assessment of tumour blood vessel architecture and vascular targeted therapies. Appropriate pre-clinical evaluation of Rv in animal tumour models will improve the interpretation and guide the introduction of the biomarker into clinical studies. The objective of this study was to compare Rv measured in vivo with vessel size measurements from high-resolution X-ray computed tomography (μCT) of vascular corrosion casts measured post mortem from the same tumours, with and without vascular targeted therapy. MRI measurements were first acquired from subcutaneous SW1222 colorectal xenografts in mice following treatment with 0 (n=6), 30 (n=6) or 200mg/kg (n=3) of the vascular disrupting agent ZD6126. The mice were then immediately infused with a low viscosity resin and, following polymerisation and maceration of surrounding tissues, the resulting tumour vascular casts were dissected and subsequently imaged using an optimised μCT imaging approach. Vessel diameters were not measurable by μCT in the 200mg/kg group as the high dose of ZD6126 precluded delivery of the resin to the tumour vascular bed. The mean Rv for the three treatment groups was 24, 23 and 23.5μm respectively; the corresponding μCT measurements from corrosion casts from the 0 and 30mg/kg cohorts were 25 and 28μm. The strong association between the in vivo MRI and post mortem μCT values supports the use of Rv as an imaging biomarker in clinical trials of investigational vascular targeted therapies.

Use of FDG PET as an Imaging Biomarker in Clinical Trials of Alzheimer’s Disease

PET with the glucose analog FDG as a tracer is a mature and increasingly available clinical imaging technique that can improve the diagnostic accuracy for Alzheimer's disease, which is of particular value at an early stage of the disease when clinical symptoms are still mild and nonspecific. It can also monitor progression of Alzheimer's disease, and the findings are closely related to clinical symptoms. FDG PET, therefore, could also potentially be used as an imaging biomarker for selection of patients and assessment of outcome in clinical trials. Several published intervention studies indicate a good correspondence between clinical outcome and FDG PET findings, but study designs and methods used for data analysis vary widely. Recent developments towards standardization of largely user-independent methods for quantification of regional metabolic impairment on FDG PET scans will allow a new generation of studies that could provide the required evidence for full qualification of FDG PET as an imaging biomarker in clinical trials.

DW-MRI as a Biomarker to Compare Therapeutic Outcomes in Radiotherapy Regimens Incorporating Temozolomide or Gemcitabine in Glioblastoma

The effectiveness of the radiosensitizer gemcitabine (GEM) was evaluated in a mouse glioma along with the imaging biomarker diffusion-weighted magnetic resonance imaging (DW-MRI) for early detection of treatment effects. A genetically engineered murine GBM model [Ink4a-Arf−/− PtenloxP/loxP/Ntv-a RCAS/PDGF(+)/Cre(+)] was treated with gemcitabine (GEM), temozolomide (TMZ) +/− ionizing radiation (IR). Therapeutic efficacy was quantified by contrast-enhanced MRI and DW-MRI for growth rate and tumor cellularity, respectively. Mice treated with GEM, TMZ and radiation showed a significant reduction in growth rates as early as three days post-treatment initiation. Both combination treatments (GEM/IR and TMZ/IR) resulted in improved survival over single therapies. Tumor diffusion values increased prior to detectable changes in tumor volume growth rates following administration of therapies. Concomitant GEM/IR and TMZ/IR was active and well tolerated in this GBM model and similarly prolonged median survival of tumor bearing mice. DW-MRI provided early changes to radiosensitization treatment warranting evaluation of this imaging biomarker in clinical trials.

The Role of Magnetic Resonance Imaging Biomarkers in Clinical Trials of Treatment Response in Cancer

Current standard-of-care radiological methods for assessing the response of solid tumors to treatment are based on measuring changes in lesion size in a single dimension using high-resolution x-ray computed tomography (CT) or magnetic resonance imaging (MRI). Even if size measurements are adapted to record true volume changes more accurately, the effects of therapeutic drugs on tumor size may not occur for several cycles of treatment. Furthermore, current and future generations of anticancer drugs will be designed to affect highly specific cancer characteristics, and their effects may not be immediately cytotoxic. More sensitive and specific measures are required that can report on tumor status and treatment response early in the course of therapy. Several MRI techniques have matured to the point where they can offer quantitative information on tissue status and greater insight into specific biophysical and physiological characteristics of tumors. Here we review and provide illustrative examples of two MRI methods that have already been incorporated into clinical trials of treatment response in solid tumors: diffusion imaging and dynamic contrast-enhanced MRI. We also discuss the limitations and future research directions required for these techniques to gain greater acceptance and to have their maximum impact.

TU‐C‐BRC‐02: Infrastructure to Integrate Imaging in Clinical Trials

Imaging biomarkers are increasingly used as primary or secondary endpoints in therapeutic trials. There are many academic units, professional organizations, industry groups and federal agencies addressing one or more components or issues associated with imaging biomarkers, and communication and coordination of efforts has been minimal. The RSNA has organized an Imaging Biomarkers Roundtable to establish ongoing communication among these organizations, and to develop a roadmap of activities and goals.Validation of imaging methods as biomarkers is complicated by the variability within and between patients, by the human observer component, by the variability across imaging devices from different manufacturers, and by the need to standardize methods across institutions and centers. To understand the errors and reduce them where possible, the Quantitative Imaging Biomarkers Alliance (QIBA) has been formed. These and other efforts are active and productive. Accomplishments and future plans will be discussed.Learning Objectives:1. Understand efforts to integrate imaging biomarkers in clinical trials.2. Understand efforts to improve the accuracy and precision of imaging biomarkers.

Automatic Quantification of Joint Space Narrowing and Erosions in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic disease that affects and potentially destroys the joints of the appendicular skeleton. The precise and reproducible quantification of the progression of joint space narrowing and the erosive bone destructions caused by RA is crucial during treatment and in imaging biomarkers in clinical trials. Current manual scoring methods exhibit high interreader variability, even after intensive training, and thus, impede the efficient monitoring of the disease. We propose a fully automatic quantitative assessment of the radiographic changes that result from RA, to increase the accuracy, reproducibility, and speed of image interpretation. Initial joint location estimates are obtained by local linear mappings based on texture features. Bone contours are delineated by active shape models comprised of statistical models of bone shape and local texture. These models are refined by snakes which increase the accuracy and allow for a fitting of pathological deviations from the training population. The method then measures joint space widths and detects erosions on the bone contour. Joint space widths are measured with a coefficient of variation of 2%-7% for repeated measurements and erosion detection exhibits an area under the receiver operating characteristic (ROC) curve of 0.89. Model landmarks serve as a reference system along the contour. These landmarks enable the definition of joint regions and more specific follow-up monitoring. The automatic quantification allows for a remote analysis, relevant for multicenter clinical trials, and reduces the workload of clinical experts since parts of the process can be managed by nonexpert personnel.

Quantitative intravascular ultrasound elasticity imaging as an imaging biomarker in clinical trials

The composition and morphology of an atherosclerotic lesion are currently considered more important determinants of acute coronary ischemic syndromes that the degree of stenosis. When a lesion is unstable, it can rupture and cause an acute thrombotic reaction. An unstable plaque can be characterized by a lipid core that is covered by a thin fibrous cap, which has been locally weakened by inflammatory cells. Intravascular Ultrasound Palpography is an intravascular ultrasound based technique that is capable to measure the local strain in coronaries and atherosclerotic plaque. This strain is induced by varying intraluminal pressure. This lecture will show principles of the technology and how this technology is used in clinical trials. Results from a trial with traditional lipid lowering treatment (IBIS1) and from a trial on the efficacy of a new medication (IBIS2) will be presented. Furthermore the potential of Intravascular Ultrasound Modulography will be discussed. This work is financially supported by the Dutch Technology Foundation, The Dutch Heart Foundation and a research grants from Volcano Corporation and Glaxo Smith Kline