Nanoparticle Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy.

More than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies.

Monte Carlo model of a prototype flat-panel detector for multi-energy applications in radiotherapy.

BACKGROUND: The incorporation of multi-energy capabilities into radiotherapy flat-panel detectors offers advantages including enhanced soft tissue visualization by reduction of signal from overlapping anatomy such as bone in 2D image projections; creation of virtual monoenergetic images for 3D contrast enhancement, metal artefact reduction and direct acquisition of relative electron density. A novel dual-layer on-board imager offering dual energy processing capabilities is being designed. As opposed to other dual-energy implementation techniques which require separate acquisition with two different x-ray spectra, the dual-layer detector design enables simultaneous acquisition of high and low energy images with a single exposure. A computational framework is required to optimize the design parameters and evaluate detector performance for specific clinical applications. PURPOSE: In this study, we report on the development of a Monte Carlo (MC) model of the imager including model validation. METHODS: The stack-up of the dual-layer imager (DLI) was implemented in GEANT4 Application for Tomographic Emission (GATE). The DLI model has an active area of 43×43 cm2 , with top and bottom Cesium Iodide (CsI) scintillators of 600 and 800 µm thickness, respectively. Measurement of spatial resolution and imaging of dedicated multi-material dual-energy (DE) phantoms were used to validate the model. The modulation transfer function (MTF) of the detector was calculated for a 120 kVp x-ray spectrum using a 0.5 mm thick tantalum edge rotated by 2.5o . For imaging validation, the DE phantom was imaged using a 140 kVp x-ray spectrum. For both validation simulations, corresponding measurements were done using an initial prototype of the imager. Agreement between simulations and measurement was assessed using normalized root mean square error (NRMSE) and 1D profile difference for the MTF and phantom images respectively. Further comparison between measurement and simulation was made using virtual monoenergetic images (VMIs) generated from basis material images derived using precomputed look-up tables. RESULTS: The MTF of the bottom layer of the dual-layer model shows values decreasing more quickly with spatial frequency, compared to the top layer, due to the thicker bottom scintillator thickness and scatter from the top layer. A comparison with measurement shows NRMSE of 0.013 and 0.015 as well as identical MTF50 of 0.8 mm1 and 1.0 mm1 for the top and bottom layer respectively. For the DE imaging of the DE-phantom, although a maximum deviation of 3.3% is observed for the 10 mm aluminum and Teflon inserts at the top layer, the agreement for all other inserts is less than 2.2% of the measured value at both layers. Material decomposition of simulated scatter-free DE images gives an average accuracy in PMMA and aluminum composition of 4.9% and 10.3% for 11-30 mm PMMA and 1-10 mm aluminum objects respectively. A comparison of decomposed values using scatter containing measured and simulated DE images shows good agreement within statistical uncertainty. CONCLUSION: Validation using both MTF and phantom imaging shows good agreement between simulation and measurements. With the present configuration of the digital prototype, the model can generate material decomposed images and virtual monoenergetic images.

Gold nanoparticle-aided brachytherapy with vascular dose painting: estimation of dose enhancement to the tumor endothelial cell nucleus.

PURPOSE: Theoretical microdosimetry at the subcellular level is employed in this study to estimate the dose enhancement to tumor endothelial cell nuclei, caused by radiation-induced photo/Auger electrons originating from gold nanoparticles (AuNPs) targeting the tumor endothelium, during brachytherapy. METHODS: A tumor vascular endothelial cell (EC) is modeled as a slab of 2 µm (thickness) × 10 µm (length) × 10 µm (width). The EC contains a nucleus of 5 µm diameter and thickness of 0.5-1 µm, corresponding to nucleus size 5%-10% of cellular volume, respectively. Analytic calculations based on the electron energy loss formula of Cole were carried out to estimate the dose enhancement to the nucleus caused by photo/Auger electrons from AuNPs attached to the exterior surface of the EC. The nucleus dose enhancement factor (nDEF), representing the ratio of the dose to the nucleus with and without the presence of gold nanoparticles was calculated for different AuNP local concentrations. The investigated concentration range considers the potential for significantly higher local concentration near the EC due to preferential accumulation of AuNP in the tumor vasculature. Four brachytherapy sources: I-125, Pd-103, Yb-169, and 50 kVp x-rays were investigated. RESULTS: For nucleus size of 10% of the cellular volume and AuNP concentrations ranging from 7 to 140 mg/g, brachytherapy sources Pd-103, I-125, 50 kVp, and Yb-169 yielded nDEF values of 5.6-73, 4.8-58.3, 4.7-56.6, and 3.2-25.8, respectively. Meanwhile, for nucleus size 5% of the cellular volume in the same concentration range, Pd-103, I-125, 50 kVp, and Yb-169 yielded nDEF values of 6.9-79.2, 5.1-63.2, 5.0-61.5, and 3.3-28.3, respectively. CONCLUSIONS: The results predict that a substantial dose boost to the nucleus of endothelial cells can be achieved by applying tumor vasculature-targeted AuNPs in combination with brachytherapy. Such vascular dose boosts could induce tumor vascular shutdown, prompting extensive tumor cell death.

Formulation of simvastatin within high density lipoprotein enables potent tumour radiosensitisation.

Preclinical, clinical and epidemiologic studies have established the potent anticancer and radiosensitisation effects of HMG-CoA reductase inhibitors (statins). However, the low bioavailability of oral statin formulations is a key barrier to achieving effective doses within tumour. To address this issue and ascertain the radiosensitisation potential of simvastatin, we developed a parenteral high density lipoprotein nanoparticle (HDL NP) formulation of this commonly used statin. A scalable method for the preparation of the simvastatin-HDL NPs was developed using a 3D printed microfluidic mixer. This enables the production of litre scale amounts of particles with minimal batch to batch variation. Simvastatin-HDL NPs enhanced the radiobiological response in 2D/3D head and neck squamous cell carcinoma (HNSCC) in vitro models. The simvastatin-HDL NPs radiosensitisation was comparable to that of 10 and 5 times higher doses of free drug in 2D and 3D cultures, respectively, which could be partially explained by more efficient cellular uptake of the statin in the nanoformulation as well as by the inherent biological activity of the HDL NPs on the cholesterol pathway. The radiosensitising potency of the simvastatin-HDL nanoformulation was validated in an immunocompetent MOC-1 HNSCC tumour bearing mouse model. This data supports the rationale of repurposing statins through reformulation within HDL NPs. Statins are safe and readily available molecules including as generic, and their use as radiosensitisers could lead to much needed effective and affordable approaches to improve treatment of solid tumours.

3-D fiducial motion tracking using limited MV projections in arc therapy.

PURPOSE: In-treatment fiducial tracking has recently received attention as a method for improving treatment accuracy, dose conformity, and sparing of healthy tissue. 3-D fiducial localization in arc-radiotherapy remains challenging due to the motion of targets and the complexity of arc deliveries. We propose a novel statistical method for estimating 3-D fiducial motion using limited 2-D megavoltage (MV) projections. METHODS: 3-D fiducial motion was estimated by a maximum a posteriori (MAP) approach to integrating information of fiducial projections with prior knowledge of target motion. To obtain the imaging geometries, short sequences of MV projections were selected in which fiducials were continuously visible. The MAP algorithm estimated the 3-D motion by maximizing the probability of displacement of fiducials in the sequences. Prior knowledge of target motion from a large statistical sample was built into the model to enhance the accuracy of estimation. In the case that a motion prior was unavailable, the algorithm can be simplified to the maximum likelihood (ML) approach. To compare tracking performance, a multiprojection geometric method was also presented by extending the typical two-project ion geometric estimation approach. The algorithms were evaluated using clinical prostate motion traces, and the performance was measured in quality indices and statistical evaluation. RESULTS: The results showed that the MAP method significantly outperforms the geometric method in all measures. In our simulations, the MAP method achieved an accuracy of less than 1 mm RMS error using only five continuous projections, whereas the geometric method required 15 projections to achieve a similar result. CONCLUSIONS: The approach presented can accurately estimate tumor motion using a limited number of continuous projections. The MAP motion estimation is superior to both the ML and geometric estimation methods.

Frequency-dependent optimal weighting approach for megavoltage multilayer imagers.

Multi-layer imaging (MLI) devices improve the detective quantum efficiency (DQE) while maintaining the spatial resolution of conventional mega-voltage (MV) x-ray detectors for applications in radiotherapy. To date, only MLIs with identical detector layers have been explored. However, it may be possible to instead use different scintillation materials in each layer to improve the final image quality. To this end, we developed and validated a method for optimally combining the individual images from each layer of MLI devices that are built with heterogeneous layers. Two configurations were modeled within the GATE Monte Carlo package by stacking different layers of a terbium doped gadolinium oxysulfide Gd2O2S:Tb (GOS) phosphor and a LKH-5 glass scintillator. Detector response was characterized in terms of the modulation transfer function (MTF), normalized noise power spectrum (NNPS) and DQE. Spatial frequency-dependent weighting factors were then analytically derived for each layer such that the total DQE of the summed combination image would be maximized across all spatial modes. The final image is obtained as the weighted sum of the sub-images from each layer. Optimal weighting factors that maximize the DQE were found to be the quotient of MTF and NNPS of each layer in the heterogeneous MLI detector. Results validated the improvement of the DQE across the entire frequency domain. For the LKH-5 slab configuration, DQE(0) increases between 2%-3% (absolute), while the corresponding improvement for the LKH-5 pixelated configuration was 7%. The performance of the weighting method was quantitatively evaluated with respect to spatial resolution, contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) of simulated planar images of phantoms at 2.5 and 6 MV. The line pair phantom acquisition exhibited a twofold increase in CNR and SNR, however MTF was degraded at spatial frequencies greater than 0.2 lp mm-1. For the Las Vegas phantom, the weighting improved the CNR by around 30% depending on the contrast region while the SNR values are higher by a factor of 2.5. These results indicate that the imaging performance of MLI systems can be enhanced using the proposed frequency-dependent weighting scheme. The CNR and SNR of the weighted combined image are improved across all spatial scales independent of the detector combination or photon beam energy.

AAPM Task Group 264: The safe clinical implementation of MLC tracking in radiotherapy.

The era of real-time radiotherapy is upon us. Robotic and gimbaled linac tracking are clinically established technologies with the clinical realization of couch tracking in development. Multileaf collimators (MLCs) are a standard equipment for most cancer radiotherapy systems, and therefore MLC tracking is a potentially widely available technology. MLC tracking has been the subject of theoretical and experimental research for decades and was first implemented for patient treatments in 2013. The AAPM Task Group 264 Safe Clinical Implementation of MLC Tracking in Radiotherapy Report was charged to proactively provide the broader radiation oncology community with (a) clinical implementation guidelines including hardware, software, and clinical indications for use, (b) commissioning and quality assurance recommendations based on early user experience, as well as guidelines on Failure Mode and Effects Analysis, and (c) a discussion of potential future developments. The deliverables from this report include: an explanation of MLC tracking and its historical development; terms and definitions relevant to MLC tracking; the clinical benefit of, clinical experience with and clinical implementation guidelines for MLC tracking; quality assurance guidelines, including example quality assurance worksheets; a clinical decision pathway, future outlook and overall recommendations.

Evaluation of the need for simultaneous orthogonal gated setup imaging.

Image-guided patient setup for respiratory-gated radiotherapy often relies on a pair of respiratory-gated orthogonal radiographs, acquired one after the other. This study quantifies the error due to changes in the internal/external correlation which may affect asynchronous (non-simultaneous) imaging. The dataset from eight patients includes internal and external coordinates acquired at 30Hz during multi-fraction SBRT treatments using the Mitsubishi RTRT system coupled with an external surrogate gating device. We performed a computational simulation of the position of an implanted fiducial marker in an asynchronous orthogonal image set. A comparison is made to the reference position, the actual 3D fiducial location at the initial time point, as would be obtainable by simultaneous orthogonal setup imaging at that time point. The time interval between the two simulated radiographic acquisitions was set to a minimum of 30, 60 or 90 seconds, based on our clinical experience. The setup position is derived from a combination of both the initial (AP) and the final (LR) simulated 2D images in the following way: LRsetup = LRinitial , SIsetup = SIinitial + (SIfinal - SIinitial)/2, APsetup = APfinal. The 3D error is then the magnitude of the vector from the initial (reference) position to the setup position. The calculation was done for every exhale phase in the data for which there was another one at least 30, 60 or 90 seconds later, at an amplitude within 0.5 mm from the first. A correlation between the time interval and the 3D error was also sought. The mean 3D error is found to be roughly equivalent for time intervals (tinterval) of 30, 60 and 90 seconds between the orthogonal simulated images (0.8 mm, 0.8 mm, 0.6 mm, respectively). The 3D error is less than 1, 2 and 3 mm for 77%, 89% and 98% of the data points, respectively. The actual time between simulated images turned out to be very close to tinterval, with 90% of the second simulated image acquisitions being completed within 38, 68 and 95 seconds of the first simulated image for tinterval of 30, 60 and 90 seconds, respectively. No correlation was found between the length of the time interval and the 3D error. When acquiring respiratory-gated radiographs for patient setup, only small errors should be expected if those images are not taken simultaneously.

Noninvasive imaging of tumor hypoxia after nanoparticle-mediated tumor vascular disruption.

We have previously demonstrated that endothelial targeting of gold nanoparticles followed by external beam irradiation can cause specific tumor vascular disruption in mouse models of cancer. The induced vascular damage may lead to changes in tumor physiology, including tumor hypoxia, thereby compromising future therapeutic interventions. In this study, we investigate the dynamic changes in tumor hypoxia mediated by targeted gold nanoparticles and clinical radiation therapy (RT). By using noninvasive whole-body fluorescence imaging, tumor hypoxia was measured at baseline, on day 2 and day 13, post-tumor vascular disruption. A 2.5-fold increase (P<0.05) in tumor hypoxia was measured two days after combined therapy, resolving by day 13. In addition, the combination of vascular-targeted gold nanoparticles and radiation therapy resulted in a significant (P<0.05) suppression of tumor growth. This is the first study to demonstrate the tumor hypoxic physiological response and recovery after delivery of vascular-targeted gold nanoparticles followed by clinical radiation therapy in a human non-small cell lung cancer athymic Foxn1nu mouse model.

GPU-accelerated Monte Carlo simulation of MV-CBCT.

Monte Carlo simulation (MCS) is one of the most accurate computation methods for dose calculation and image formation in radiation therapy. However, the high computational complexity and long execution time of MCS limits its broad use. In this paper, we present a novel strategy to accelerate MCS using a graphic processing unit (GPU), and we demonstrate the application in mega-voltage (MV) cone-beam computed tomography (CBCT) simulation. A new framework that generates a series of MV projections from a single simulation run is designed specifically for MV-CBCT acquisition. A Geant4-based GPU code for photon simulation is incorporated into the framework for the simulation of photon transport through a phantom volume. The FastEPID method, which accelerates the simulation of MV images, is modified and integrated into the framework. The proposed GPU-based simulation strategy was tested for its accuracy and efficiency in a Catphan 604 phantom and an anthropomorphic pelvis phantom with beam energies at 2.5 MV, 6 MV, and 6 MV FFF. In all cases, the proposed GPU-based simulation demonstrated great simulation accuracy and excellent agreement with measurement and CPU-based simulation in terms of reconstructed image qualities. The MV-CBCT simulation was accelerated by factors of roughly 900-2300 using an NVIDIA Tesla V100 GPU card against a 2.5 GHz AMD Opteron™ Processor 6380.

A rapid, accurate image simulation strategy for mega-voltage cone-beam computed tomography.

Intensive computation time is required to simulate images of electronic portal imaging device (EPID) using Monte Carlo (MC) technique, limiting the development of applications associated with EPID, such as mega-voltage cone-beam computed tomography (MV-CBCT). In this study, a fast, accurate simulation strategy for MV-CBCT utilizing the FastEPID technique has been developed and validated. During FastEPID simulation, photon detection was determined by pre-calculated photon energy deposition efficiency (η) and particle transport within the EPID was replaced with a pre-calculated optical photon spread function. This method is capable of reducing the time required for EPID image simulation by a factor of 90-140, without compromising image quality. MV-CBCT images reconstructed from the FastEPID simulated projections have been validated against measurement in terms of mean Hounsfield unit (HU), noise, and cupping artifact. These images were obtained with both a Catphan 604 phantom and an anthropomorphic pelvis phantom, under treatment beam energies of 2.5 MV, 6 MV, and 6 MV flattening filter free. The agreement between measurement and simulation was excellent in all cases. This novel strategy was capable of reducing the run time of a full scan simulation of MV-CBCT performed on a CPU cluster to a matter of hours, rather than weeks or months required by a conventional approach. Multiple applications associated with MV-CBCT (e.g. imager design optimization) are anticipated to gain from the implementation of this novel simulation strategy.

Author Correction: Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: Selective Priming of Tumor Blood Vessels by Radiation Therapy Enhances Nanodrug Delivery.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Characterizing a novel scintillating glass for application to megavoltage cone-beam computed tomography.

PURPOSE: The purpose of this study was to evaluate the performance of a prototype electric portal imaging device (EPID) with a high detective quantum efficiency (DQE) scintillator, LKH-5. Specifically, image quality in context of both planar and megavoltage (MV) cone-beam computed tomography (CBCT) is analyzed. METHODS: Planar image quality in terms of modulation transfer function (MTF), noise power spectrum (NPS), and DQE are measured and compared to an existing EPID (AS-1200) using the 6 MV beamline for a Varian TrueBeam linac. Imager performance is contextualized for three-dimensional (3D), MV-CBCT performance by measuring imager lag and analyzing the expected degradation of the DQE as a function of dose. Finally, comparisons between reconstructed images of the Catphan phantom in terms of qualitative quality and signal-difference-to-noise ratio (SDNR) are made for 6 MV images using both conventional and LKH-5 EPIDs as well as for the kilovoltage (kV) on-board imager (OBI). RESULTS: Analysis of the NPS reveals linearity at all measured doses using the prototype LKH-5 detector. While the first zero of the MTF is much lower for the LKH-5 detector than the conventional EPID (0.6 cycles/mm vs 1.6 cycles/mm), the normalized NPS (NNPS) multiplied by total quanta (qNNPS) of the LKH-5 detector is roughly a factor of seven to eight times lower, yielding a DQE(0) of approximately 8%. First, second, and third frame lag were measured at approximately 23%, 5%, and 1%, respectively, although no noticeable image artifacts were apparent in reconstructed volumes. Analysis of low-dose performance reveals that DQE(0) remains at 80% of its maximum value at a dose as low as 7.5 × 10-6  MU. For a 400 projection technique, this represents a total scan dose of 0.0030 MU, suggesting that if imaging doses are increased to a value typical of kV-CBCT scans (~2.7 cGy), the LKH-5 detector will retain quantum noise limited performance. Finally, comparing Catphan scans, the prototype detector exhibits much lower image noise than the conventional EPID, resulting in improved small object representation. Furthermore, SDNR of H2 O and polystyrene cylinders improved from -1.95 and 2.94 to -15 and 18.7, respectively. CONCLUSIONS: Imaging performance of the prototype LKH-5 detector was measured and analyzed for both planar and 3D contexts. Improving noise transfer of the detector results in concurrent improvement of DQE(0). For 3D imaging, temporal characteristics were adequate for artifact-free performance and at relevant doses, the detector retained quantum noise limited performance. Although quantitative MTF measurements suggest poorer resolution, small object representation of the prototype imager is qualitatively improved over the conventional detector due to the measured reduction in noise.

Selective Priming of Tumor Blood Vessels by Radiation Therapy Enhances Nanodrug Delivery.

Effective drug delivery is restricted by pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, poorly-permeable blood vessels limit the intratumoral permeation and penetration of chemo or nanotherapeutic drugs. New and clinically viable strategies are urgently sought to breach the neoplastic barriers that prevent effective drug delivery. Here, we present an original idea to boost drug delivery by selectively knocking down the tumor vascular barrier in a human pancreatic cancer model. Clinical radiation activates the tumor endothelial-targeted gold nanoparticles to induce a physical vascular damage due to the high photoelectric interactions. Active modulation of these tumor neovessels lead to distinct changes in tumor vascular permeability. Noninvasive MRI and fluorescence studies, using a short-circulating nanocarrier with MR-sensitive gadolinium and a long-circulating nanocarrier with fluorescence-sensitive nearinfrared dye, demonstrate more than two-fold increase in nanodrug delivery, post tumor vascular modulation. Functional changes in altered tumor blood vessels and its downstream parameters, particularly, changes in Ktrans (permeability), Kep (flux rate), and Ve (extracellular interstitial volume), reflect changes that relate to augmented drug delivery. The proposed dual-targeted therapy effectively invades the tumor vascular barrier and improve nanodrug delivery in a human pancreatic tumor model and it may also be applied to other nonresectable, intransigent tumors that barely respond to standard drug therapies.

A novel method for estimating SBRT delivered dose with beam's-eye-view images.

Stereotactic body radiation therapy is predicated on a high degree of targeting accuracy. However, inaccurate patient setup as well as intra-fractional motion can hinder the delivery of high doses preferentially to the target. To ensure that the coverage delivered to the patient is as planned, an image-guided verification system has been created to estimate the delivered dose retrospectively. This will not only aid the assessment of treatment techniques, but will also allow for more accurate dose response analysis. Patients with limited hepatic metastases from solid tumors were treated with SBRT. Implanted gold markers were used as target surrogates and a body frame and compression plate provided stereotactic localization and target immobilization, respectively. During treatment, an electronic portal imaging device (EPID), operating in cine mode, collected the exit dose. The sequences of images for each field were processed off-line using in-house software for registration and seed localization. The beam's-eye-view seed positions in the treatment images were compared to those in the DRR's to determine the target shifts in the imaging plane. These target shifts were then imported into the treatment planning software. Each original field was multiplied by the number of images taken during treatment. The calculated shift from each image was then applied to each of the new subfields. Summing all of these subfields together gives the dose distribution that was actually delivered to the patient. The dose-volume histograms for the planned and delivered distributions for four patients' complete treatments are shown. For two of the patients, underdosing due to a setup error or intra-fractional drift was not wholly resolved by subsequent fractions. For one of these patients two alternative corrective strategies have been applied, retrospectively, and the prescribed target coverage recovered for both. The delivered dose can be estimated using the information contained in cine EPID images acquired during irradiation. Calculating the dose actually delivered to the target will allow us to assess treatment procedures as well as more accurately report clinical results.

Gating based on internal/external signals with dynamic correlation updates.

Precise localization of mobile tumor positions in real time is critical to the success of gated radiotherapy. Tumor positions are usually derived from either internal or external surrogates. Fluoroscopic gating based on internal surrogates, such as implanted fiducial markers, is accurate however requiring a large amount of imaging dose. Gating based on external surrogates, such as patient abdominal surface motion, is non-invasive however less accurate due to the uncertainty in the correlation between tumor location and external surrogates. To address these complications, we propose to investigate an approach based on hybrid gating with dynamic internal/external correlation updates. In this approach, the external signal is acquired at high frequency (such as 30 Hz) while the internal signal is sparsely acquired (such as 0.5 Hz or less). The internal signal is used to validate and update the internal/external correlation during treatment. Tumor positions are derived from the external signal based on the newly updated correlation. Two dynamic correlation updating algorithms are introduced. One is based on the motion amplitude and the other is based on the motion phase. Nine patients with synchronized internal/external motion signals are simulated retrospectively to evaluate the effectiveness of hybrid gating. The influences of different clinical conditions on hybrid gating, such as the size of gating windows, the optimal timing for internal signal acquisition and the acquisition frequency are investigated. The results demonstrate that dynamically updating the internal/external correlation in or around the gating window will reduce false positive with relatively diminished treatment efficiency. This improvement will benefit patients with mobile tumors, especially greater for early stage lung cancers, for which the tumors are less attached or freely floating in the lung.

Feasibility of closed-MLC tracking using high sensitivity and multi-layer electronic portal imagers.

In radiation therapy, improvements in treatment conformality are often limited by movement of target tissue. To better treat the target, tumor tracking strategies involving beam's-eye-view (BEV) have been explored. However, localization surrogates like implanted fiducial markers may sometimes leave the field-of-view (FOV), as defined by the linear accelerator (LINAC) multi-leaf collimator (MLC). Radiation leakage through the MLC has been measured previously at approximately 1%-2%. High sensitivity prototype detectors imagers may improve the ability to visualize objects outside of the MLC FOV during treatment. The present study presents a proof-of-concept for tracking fiducial markers outside the MLC FOV by employing high sensitivity detectors using a high-efficiency, prototype scintillating glass called LKH-5 and also investigates the impact of multi-layer imager (MLI) architecture. It was found that by improving the detector efficiency, using either of these methods results in a reduction of dose required for fiducial marker visibility. Further, image correction by a rectangular median filter will improve fiducial marker representation in the MLC blocked images. Quantified by measuring the peak-to-sidelobe ratio (PSR) of the normalized cross correlation (NCC) between a template of the fiducial marker with the blocked MLC acquisition, visibility has been found at a threshold of roughly 5 for all configurations with a 3 × 3 cm2 ROI. For typical gadolinium oxysulfide (GOS) detectors in single and simulated 4-layer configurations, the minimum dose required for visualization was 20 and 10 MU, respectively. For LKH-5 detectors in single and simulated 4-layer configurations, this minimum dose was reduced to 4 and 2 MU, respectively. With a 6 MV flattening filter free (FFF) beam dose rate of 1400 MU min-1, the maximum detector frame rate while maintaining fiducial visibility is approximately 12 fps for a 4-layer LKH-5 configuration.