Accurate, repeatable, and geometrically precise diffusion-weighted imaging on a 0.35 T magnetic resonance imaging-guided linear accelerator.

Background and purpose: Diffusion weighted imaging (DWI) allows for the interrogation of tissue cellularity, which is a surrogate for cellular proliferation. Previous attempts to incorporate DWI into the workflow of a 0.35 T MR-linac (MRL) have lacked quantitative accuracy. In this study, accuracy, repeatability, and geometric precision of apparent diffusion coefficient (ADC) maps produced using an echo planar imaging (EPI)-based DWI protocol on the MRL system is illustrated, and in vivo potential for longitudinal patient imaging is demonstrated. Materials and methods: Accuracy and repeatability were assessed by measuring ADC values in a diffusion phantom at three timepoints and comparing to reference ADC values. System-dependent geometric distortion was quantified by measuring the distance between 93 pairs of phantom features on ADC maps acquired on a 0.35 T MRL and a 3.0 T diagnostic scanner and comparing to spatially precise CT images. Additionally, for five sarcoma patients receiving radiotherapy on the MRL, same-day in vivo ADC maps were acquired on both systems, one of which at multiple timepoints. Results: Phantom ADC quantification was accurate on the 0.35 T MRL with significant discrepancies only seen at high ADC. Average geometric distortions were 0.35 (±0.02) mm and 0.85 (±0.02) mm in the central slice and 0.66 (±0.04) mm and 2.14 (±0.07) mm at 5.4 cm off-center for the MRL and diagnostic system, respectively. In the sarcoma patients, a mean pretreatment ADC of 910x10-6 (±100x10-6) mm2/s was measured on the MRL. Conclusions: The acquisition of accurate, repeatable, and geometrically precise ADC maps is possible at 0.35 T with an EPI approach.

Treatment of Central Nervous System Tumors on Combination MR-Linear Accelerators: Review of Current Practice and Future Directions.

Magnetic resonance imaging (MRI) provides excellent visualization of central nervous system (CNS) tumors due to its superior soft tissue contrast. Magnetic resonance-guided radiotherapy (MRgRT) has historically been limited to use in the initial treatment planning stage due to cost and feasibility. MRI-guided linear accelerators (MRLs) allow clinicians to visualize tumors and organs at risk (OARs) directly before and during treatment, a process known as online MRgRT. This novel system permits adaptive treatment planning based on anatomical changes to ensure accurate dose delivery to the tumor while minimizing unnecessary toxicity to healthy tissue. These advancements are critical to treatment adaptation in the brain and spinal cord, where both preliminary MRI and daily CT guidance have typically had limited benefit. In this narrative review, we investigate the application of online MRgRT in the treatment of various CNS malignancies and any relevant ongoing clinical trials. Imaging of glioblastoma patients has shown significant changes in the gross tumor volume over a standard course of chemoradiotherapy. The use of adaptive online MRgRT in these patients demonstrated reduced target volumes with cavity shrinkage and a resulting reduction in radiation dose to uninvolved tissue. Dosimetric feasibility studies have shown MRL-guided stereotactic radiotherapy (SRT) for intracranial and spine tumors to have potential dosimetric advantages and reduced morbidity compared with conventional linear accelerators. Similarly, dosimetric feasibility studies have shown promise in hippocampal avoidance whole brain radiotherapy (HA-WBRT). Next, we explore the potential of MRL-based multiparametric MRI (mpMRI) and genomically informed radiotherapy to treat CNS disease with cutting-edge precision. Lastly, we explore the challenges of treating CNS malignancies and special limitations MRL systems face.

Stereotactic Magnetic Resonance-Guided Adaptive and Non-Adaptive Radiotherapy on Combination MR-Linear Accelerators: Current Practice and Future Directions.

Stereotactic body radiotherapy (SBRT) is an effective radiation therapy technique that has allowed for shorter treatment courses, as compared to conventionally dosed radiation therapy. As its name implies, SBRT relies on daily image guidance to ensure that each fraction targets a tumor, instead of healthy tissue. Magnetic resonance imaging (MRI) offers improved soft-tissue visualization, allowing for better tumor and normal tissue delineation. MR-guided RT (MRgRT) has traditionally been defined by the use of offline MRI to aid in defining the RT volumes during the initial planning stages in order to ensure accurate tumor targeting while sparing critical normal tissues. However, the ViewRay MRIdian and Elekta Unity have improved upon and revolutionized the MRgRT by creating a combined MRI and linear accelerator (MRL), allowing MRgRT to incorporate online MRI in RT. MRL-based MR-guided SBRT (MRgSBRT) represents a novel solution to deliver higher doses to larger volumes of gross disease, regardless of the proximity of at-risk organs due to the (1) superior soft-tissue visualization for patient positioning, (2) real-time continuous intrafraction assessment of internal structures, and (3) daily online adaptive replanning. Stereotactic MR-guided adaptive radiation therapy (SMART) has enabled the safe delivery of ablative doses to tumors adjacent to radiosensitive tissues throughout the body. Although it is still a relatively new RT technique, SMART has demonstrated significant opportunities to improve disease control and reduce toxicity. In this review, we included the current clinical applications and the active prospective trials related to SMART. We highlighted the most impactful clinical studies at various tumor sites. In addition, we explored how MRL-based multiparametric MRI could potentially synergize with SMART to significantly change the current treatment paradigm and to improve personalized cancer care.

Real-time, volumetric imaging of radiation dose delivery deep into the liver during cancer treatment.

Ionizing radiation acoustic imaging (iRAI) allows online monitoring of radiation's interactions with tissues during radiation therapy, providing real-time, adaptive feedback for cancer treatments. We describe an iRAI volumetric imaging system that enables mapping of the three-dimensional (3D) radiation dose distribution in a complex clinical radiotherapy treatment. The method relies on a two-dimensional matrix array transducer and a matching multi-channel preamplifier board. The feasibility of imaging temporal 3D dose accumulation was first validated in a tissue-mimicking phantom. Next, semiquantitative iRAI relative dose measurements were verified in vivo in a rabbit model. Finally, real-time visualization of the 3D radiation dose delivered to a patient with liver metastases was accomplished with a clinical linear accelerator. These studies demonstrate the potential of iRAI to monitor and quantify the 3D radiation dose deposition during treatment, potentially improving radiotherapy treatment efficacy using real-time adaptive treatment.

Image guidance for FLASH radiotherapy.

FLASH radiotherapy (FLASH-RT) is an emerging ultra-high dose (>40 Gy/s) delivery that promises to improve the therapeutic potential by limiting toxicities compared to conventional RT while maintaining similar tumor eradication efficacy. Image guidance is an essential component of modern RT that should be harnessed to meet the special emerging needs of FLASH-RT and its associated high risks in planning and delivering of such ultra-high doses in short period of times. Hence, this contribution will elaborate on the imaging requirements and possible solutions in the entire chain of FLASH-RT treatment, from the planning, through the setup and delivery with online in vivo imaging and dosimetry, up to the assessment of biological mechanisms and treatment response. In patient setup and delivery, higher temporal sampling than in conventional RT should ensure that the short treatment is delivered precisely to the targeted region. Additionally, conventional imaging tools such as cone-beam computed tomography will continue to play an important role in improving patient setup prior to delivery, while techniques based on magnetic resonance imaging or positron emission tomography may be extremely valuable for either linear accelerator (Linac) or particle FLASH therapy, to monitor and track anatomical changes during delivery. In either planning or assessing outcomes, quantitative functional imaging could supplement conventional imaging for more accurate utilization of the biological window of the FLASH effect, selecting for or verifying things such as tissue oxygen and existing or transient hypoxia on the relevant timescales of FLASH-RT delivery. Perhaps most importantly at this time, these tools might help improve the understanding of the biological mechanisms of FLASH-RT response in tumor and normal tissues. The high dose deposition of FLASH provides an opportunity to utilize pulse-to-pulse imaging tools such as Cherenkov or radiation acoustic emission imaging. These could provide individual pulse mapping or assessing the 3D dose delivery superficially or at tissue depth, respectively. In summary, the most promising components of modern RT should be used for safer application of FLASH-RT, and new promising developments could be advanced to cope with its novel demands but also exploit new opportunities in connection with the unique nature of pulsed delivery at unprecedented dose rates, opening a new era of biological image guidance and ultrafast, pulse-based in vivo dosimetry.

A simulation study of ionizing radiation acoustic imaging (iRAI) as a real-time dosimetric technique for ultra-high dose rate radiotherapy (UHDR-RT).

PURPOSE: Electron-based ultra-high dose rate radiation therapy (UHDR-RT), also known as Flash-RT, has shown the ability to improve the therapeutic index in comparison to conventional radiotherapy (CONV-RT) through increased sparing of normal tissue. However, the extremely high dose rates in UHDR-RT have raised the need for accurate real-time dosimetry tools. This work aims to demonstrate the potential of the emerging technology of Ionized Radiation Acoustic Imaging (iRAI) through simulation studies and investigate its characteristics as a promising relative in vivo dosimetric tool for UHDR-RT. METHODS: The detection of induced acoustic waves following a single UHDR pulse of a modified 6 MeV 21EX Varian Clinac in a uniform porcine gelatin phantom that is brain-tissue equivalent was simulated for an ideal ultrasound transducer. The full 3D dose distributions in the phantom for a 1 × 1 cm2 field were simulated using EGSnrc (BEAMnrc∖DOSXYZnrc) Monte Carlo (MC) codes. The relative dosimetry simulations were verified with dose experimental measurements using Gafchromic films. The spatial dose distribution was converted into an initial pressure source spatial distribution using the medium-dependent dose-pressure relation. The MATLAB-based toolbox k-Wave was then used to model the propagation of acoustic waves through the phantom and perform time-reversal (TR)-based imaging reconstruction. The effect of the various linear accelerator (linac) operating parameters, including linac pulse duration and pulse repetition rate (frequency), were investigated as well. RESULTS: The MC dose simulation results agreed with the film measurement results, specifically at the central beam region up to 80% dose within approximately 5% relative error for the central profile region and a local relative error of <6% for percentage dose depth. IRAI-based FWHM of the radiation beam was within approximately 3 mm relative to the MC-simulated beam FWHM at the beam entrance. The real-time pressure signal change agreed with the dose changes proving the capability of the iRAI for predicting the beam position. IRAI was tested through 3D simulations of its response to be based on the temporal changes in the linac operating parameters on a dose per pulse basis as expected theoretically from the pressure-dose proportionality. The pressure signal amplitude obtained through 2D simulations was proportional to the dose per pulse. The instantaneous pressure signal amplitude decreases as the linac pulse duration increases, as predicted from the pressure wave generation equations, such that the shorter the linac pulse the higher the signal and the better the temporal (spatial) resolutions of iRAI. The effect of the longer linac pulse duration on the spatial resolution of the 3D constructed iRAI images was corrected for linac pulse deconvolution. This correction has improved the passing rate of the 1%/1 mm gamma test criteria, between the pressure-constructed and dosimetric beam characteristics, to as high as 98%. CONCLUSIONS: A full simulation workflow was developed for testing the effectiveness of iRAI as a promising relative dosimetry tool for UHDR-RT radiation therapy. IRAI has shown the advantage of 3D dose mapping through the dose signal linearity and, hence, has the potential to be a useful dosimeter at depth dose measurement and beam localization and, hence, potentially for in vivo dosimetry in UHDR-RT.

Application of radiochromic gel dosimetry to commissioning of a megavoltage research linear accelerator for small-field animal irradiation studies.

PURPOSE: To develop and implement an efficient and accurate commissioning procedure for small-field static beam animal irradiation studies on an MV research linear accelerator (Linatron-M9) using radiochromic gel dosimetry. MATERIALS: The research linear accelerator (Linatron-M9) is a 9 MV linac with a static fixed collimator opening of 5.08 cm diameter. Lead collimators were manually placed to create smaller fields of 2 × 2 cm2 , 1 × 1 cm2 , and 0.5 × 0.5 cm2 . Relative dosimetry measurements were performed, including profiles, percent depth dose (PDD) curves, beam divergence, and relative output factors using various dosimetry tools, including a small volume ionization chamber (A14), GAFCHROMIC™ EBT3 film, and Clearview gel dosimeters. The gel dosimeter was used to provide a 3D volumetric reference of the irradiated fields. The Linatron profiles and relative output factors were extracted at a reference depth of 2 cm with the output factor measured relative to the 2 × 2 cm2 reference field. Absolute dosimetry was performed using A14 ionization chamber measurements, which were verified using a national standards laboratory remote dosimetry service. RESULTS: Absolute dosimetry measurements were confirmed within 1.4% (k = 2, 95% confidence = 5%). The relative output factor of the small fields measured with films and gels agreed with a maximum relative percent error difference between the two methods of 1.1 % for the 1 × 1 cm2 field and 4.3 % for the 0.5 × 0.5 cm2 field. These relative errors were primarily due to the variability in the collimator positioning. The measured beam profiles demonstrated excellent agreement for beam size (measured as FWHM), within approximately 0.8 mm (or less). Film measurements were more accurate in the penumbra region due to the film's finer resolution compared with the gel dosimeter. Following the van Dyk criteria, the PDD values of the film and gel measurements agree within 11% in the buildup region starting from 0.5 cm depth and within 2.6 % beyond maximum dose and into the fall-off region for depths up to 5 cm. The 2D beam profile isodose lines agree within 0.5 mm in all regions for the 0.5 × 0.5 cm2 and the 1 × 1 cm2 fields and within 1 mm for the larger field of 2 × 2 cm2 . The 2D PDD curves agree within approximately 2% of the maximum in the typical therapy region (1-4 cm) for the 1 × 1 cm2 and 2 × 2 cm2 and within 5% for the 0.5 × 0.5 cm2 field. CONCLUSION: This work provides a commissioning process to measure the beam characteristics of a fixed beam MV accelerator with detailed dosimetric evaluation for its implementation in megavoltage small animal irradiation studies. Radiochromic gel dosimeters are efficient small-field relative dosimetry tools providing 3D dose measurements allowing for full representation of dose, dosimeter misalignment corrections and high reproducibility with low inter-dosimeter variability. Overall, radiochromic gels are valuable for fast, full relative dosimetry commissioning in comparison to films for application in high-energy small-field animal irradiation studies.

An ionizing radiation acoustic imaging (iRAI) technique for real-time dosimetric measurements for FLASH radiotherapy.

PURPOSE: FLASH radiotherapy (FLASH-RT) is a novel irradiation modality with ultra-high dose rates (>40 Gy/s) that have shown tremendous promise for its ability to enhance normal tissue sparing while maintaining comparable tumor cell eradication toconventional radiotherapy (CONV-RT). Due to its extremely high dose rates, clinical translation of FLASH-RT is hampered by risky delivery and current limitations in dosimetric devices, which cannot accurately measure, in real time, dose at deeper tissue. This work aims to investigate ionizing radiation acoustic imaging (iRAI) as a promising image-guidance modality for real-time deep tissue dose measurements during FLASH-RT. The underlying hypothesis is that iRAI can enable mapping of dose deposition with respect to surrounding tissue with a single linear accelerator (linac) pulse precision in real time. In this work, the relationship between iRAI signal response and deposited dose was investigated as well as the feasibility of using a proof-of-concept dual-modality imaging system of ultrasound and iRAI for treatment beam co-localization with respect to underlying anatomy. METHODS: Two experimental setups were used to study the feasibility of iRAI for FLASH-RT using 6 MeV electrons from a modified Varian Clinac. First, experiments were conducted using a single element focused transducer to take a series of point measurements in a gelatin phantom, which was compared with independent dose measurements using GAFchromic film. Secondly, an ultrasound and iRAI dual-modality imaging system utilizing a phased array transducer was used to take coregistered two-dimensional (2D) iRAI signal amplitude images as well as ultrasound B-mode images, to map the dose deposition with respect to surrounding anatomy in an ex vivo rabbit liver model with a single linac pulse precision. RESULTS: Using a single element transducer, iRAI measurements showed a highly linear relationship between the iRAI signal amplitude and the linac dose per pulse (r2  = 0.9998) with a repeatability precision of 1% and a dose resolution error <2.5% in a homogenous phantom when compared to GAFchromic film dose measurements. These phantom results were used to develop a calibration curve between the iRAI signal response and the delivered dose per pulse. Subsequently, a normalized depth dose curve was generated that agreed with film measurements with an RMSE of 0.0243, using correction factors to account for deviations in measurement conditions with respect to calibration. Experiments on the ex-vivo rabbit liver model demonstrated that a 2D iRAI image could be generated successfully from a single linac pulse, which was fused with the B-mode ultrasound image to provide information about the beam position with respect to surrounding anatomy in real time. CONCLUSION: This work demonstrates the potential of using iRAI for real-time deep tissue dosimetry in FLASH-RT. Our results show that iRAI signals are linear with dose and can accurately map the delivered radiation dose with respect to soft tissue anatomy. With its ability to measure dose for individual linac pulses at any location within surrounding soft tissue while identifying where that dose is being delivered anatomically in real time, iRAI can be an indispensable tool to enable safe and efficient clinical translation of FLASH-RT.

Dual-Modality X-Ray-Induced Radiation Acoustic and Ultrasound Imaging for Real-Time Monitoring of Radiotherapy.

Objective. The goal is to increase the precision of radiation delivery during radiotherapy by tracking the movements of the tumor and other surrounding normal tissues due to respiratory and other body motions. Introduction. This work presents the recent advancement of X-ray-induced radiation acoustic imaging (xRAI) technology and the evaluation of its feasibility for real-time monitoring of geometric and morphological misalignments of the X-ray field with respect to the target tissue by combining xRAI with established ultrasound (US) imaging, thereby improving radiotherapy tumor eradication and limiting treatment side effects. Methods. An integrated xRAI and B-mode US dual-modality system was established based on a clinic-ready research US platform. The performance of this dual-modality imaging system was evaluated via experiments on phantoms and ex vivo and in vivo rabbit liver models. Results. This system can alternatively switch between the xRAI and the US modes, with spatial resolutions of 1.1 mm and 0.37 mm, respectively. 300 times signal averaging was required for xRAI to reach a satisfactory signal-to-noise ratio, and a frame rate of 1.1 Hz was achieved with a clinical linear accelerator. The US imaging frame rate was 22 Hz, which is sufficient for real-time monitoring of the displacement of the target due to internal body motion. Conclusion. Our developed xRAI, in combination with US imaging, allows for mapping of the dose deposition in biological samples in vivo, in real-time, during radiotherapy. Impact Statement. The US-based image-guided radiotherapy system presented in this work holds great potential for personalized cancer treatment and better outcomes.

Silicon Photomultipliers for Deep Tissue Cerenkov Emission Detection During External Beam Radiotherapy.

Cerenkov Emission (CE) during external beam radiation therapy (EBRT) from a linear accelerator (Linac) has been demonstrated as a useful tool for radiotherapy quality assurance and potentially other applications for online tracking of tumors during treatment delivery. However, some of the current challenges that are impacting the potential of CE are related to the limited detection sensitivity and the lack of flexible tools to fit into an already complex treatment delivery environment. Silicon photomultiplier (SiPM) solid-state devices are new promising tools for low light detection due to their extreme sensitivity that mirrors photomultiplier tubes and yet have a form factor that is similar to silicon photodiodes, allowing for improved flexibility in device design that may help in the process of wider clinical applicability. In this work, we assess the feasibility of using SiPMs to detect CE during EBRT from a Linac and contrast their performance with commercially available silicon photodiodes (PDs). We demonstrate the feasibility of the SiPM based probes for standard dosimetry measurements. We also demonstrate that CE optical signals can be detected from tissue depths about five times greater than that for standard probes based on PDs, making our SiPM probe an enabling technology of CE measurements, particularly for deep tissue applications.

Toward in vivo dosimetry in external beam radiotherapy using x-ray acoustic computed tomography: A soft-tissue phantom study validation.

PURPOSE: To study, using phantoms made from biological tissues, the feasibility and practical challenges of monitoring the position of the radiation beam and the deposited dose by x-ray acoustic computed tomography (XACT) during external beam radiotherapy delivery. MATERIAL AND METHODS: A prototype XACT system with a single immersion ultrasound transducer, which was positioned around the target sample driven by a motor-controlled rotation stage, was used to acquire the x-ray acoustic (XA) signals produced by a medical linear accelerator (Linac) to form an XACT image of the irradiated phantom. To investigate the feasibility of XACT in tracking the position of radiation dose, a large piece of veal liver with embedded fat tissue was imaged and beam misalignments were measured. Next, we explored the sensitivity of XACT in monitoring and quantifying the delivered dose, in which a block of porcine gel was embedded with equally spaced lard cylinders and imaged. The doses on the lard cylinders modulated by physical wedges were quantified from the XACT image and were verified by comparison to measurements from radiochromic films as the gold standard. Then, to simulate how XACT can perform in a targeted tissue in the human body, a porcine gel phantom with lard cylinders covered by different materials (bone, muscle, and air gap, respectively) was also imaged. RESULTS: The reconstructed XACT images of the phantoms show congruence with the boundaries of the beam field and the interfaces between the different tissue materials. The beam displacement from the target was tracked properly by the reconstructed XACT images. An intensity difference as small as 2.9% in delivered dose region can be measured from XACT images P = 0.02. The intensities of XACT images were highly correlated to the film measurements with an R2 better than 0.986. The expected variances of dose delivered to different target regions as a result of the difference in attenuation were successfully captured by the XACT images. CONCLUSIONS: This study validated the feasibility of XACT in accurately obtaining relative dose maps of tissue-mimicking phantoms. XACT offers a practical method for verifying the beam position against the target and quantifying the relative dose delivered to the target during external beam radiotherapy.