Static MLC transmission simulation using two-dimensional ray tracing.

PURPOSE: We investigated the hypothesis that the transmission function of rounded end linearly traveling multileaf collimators (MLCs) is constant with position. This assumption is made by some MLC models used in clinical treatment planning systems (TPSs) and in the Varian MLC calibration convention. If not constant, this would have implications for treatment plan QA results. METHODS: A two-dimensional ray-tracing tool to generate transmission curves as a function of leaf position was created and validated. The curves for clinically available leaf tip positions (-20 to 20 cm) were analyzed to determine the location of the beam edge (half-attenuation X-ray [XR]) location, the beam edge broadening (BEB, 80%-20% width), as well as the leaf tip zone width. More generalized scenarios were then simulated to elucidate trends as a function of leaf tip radius. RESULTS: In the analysis of the Varian high-definition MLC, two regions were identified: a quasi-static inner region centered about central axis (CAX), and an outer one, in which large deviations were observed. A phenomenon was identified where the half-attenuation ray position, relative to that of the tip or tangential ray, increases dramatically at definitive points from CAX. Similar behavior is seen for BEB. An analysis shows that as the leaf radius parameter value is made smaller, the size of the quasi-static region is greater (and vice versa). CONCLUSION: The MLC transmission curve properties determined by this study have implications both for MLC position calibrations and modeling within TPSs. Two-dimensional ray tracing can be utilized to identify where simple behaviors hold, and where they deviate. These results can help clinical physicists engage with vendors to improve MLC models, subsequent fluence calculations, and hence dose calculation accuracy.

Investigation of tumor and vessel motion correlation in the liver.

Intrafraction imaging-based motion management systems for external beam radiotherapy can rely on internal surrogate structures when the target is not easily visualized. This work evaluated the validity of using liver vessels as internal surrogates for the estimation of liver tumor motion. Vessel and tumor motion were assessed using ten two-dimensional sagittal MR cine datasets collected on the ViewRay MRIdian. For each case, a liver tumor and at least one vessel were tracked for 175 s. A tracking approach utilizing block matching and multiple simultaneous templates was applied. Accuracy of the tracked motion was calculated from the error between the tracked centroid position and manually defined ground truth annotations. The patient's abdomen surface and diaphragm were manually annotated in all frames. The Pearson correlation coefficient (CC) was used to compare the motion of the features and tumor in the anterior-posterior (AP) and superior-inferior (SI) directions. The distance between the centroids of the features and the tumors was calculated to assess if feature proximity affects relative correlation, and the tumor range of motion was determined. Intra- and interfraction motion amplitude variabilities were evaluated to further assess the relationship between tumor and feature motion. The mean CC between the motion of the vessel and the tumor were 0.85 ± 0.11 (AP) and 0.92 ± 0.04 (SI), 0.83 ± 0.11 (AP) and -0.89 ± 0.06 (SI) for the surface and tumor, and 0.80 ± 0.17 (AP) and 0.94 ± 0.03 (SI) for the diaphragm and tumor. For intrafraction analysis, the average amplitude variability was 2.47 ± 0.77 mm (AP) and 3.14 ± 1.49 mm (SI) for the vessels, 2.70 ± 1.08 mm (AP) and 3.43 ± 1.73 mm (SI) for the surface, and 2.76 ± 1.41 mm (AP) and 2.91 ± 1.38 mm (SI) for the diaphragm. No relationship between distance and motion correlation was observed. The motion of liver tumors and liver vessels was well correlated, making vessels a suitable surrogate for tumor motion in the liver.

Deformable abdominal phantom for the validation of real-time image guidance and deformable dose accumulation.

PURPOSE: End-to-end testing with quality assurance (QA) phantoms for deformable dose accumulation and real-time image-guided radiotherapy (IGRT) has recently been recommended by American Association of Physicists in Medicine (AAPM) Task Groups 132 and 76. The goal of this work was to develop a deformable abdominal phantom containing a deformable three-dimensional dosimeter that could provide robust testing of these systems. METHODS: The deformable abdominal phantom was fabricated from polyvinyl chloride plastisol and phantom motion was simulated with a programmable motion stage and plunger. A deformable normoxic polyacrylamide gel (nPAG) dosimeter was incorporated into the phantom apparatus to represent a liver tumor. Dosimeter data were acquired using magnetic resonance imaging (MRI). Static measurements were compared to planned dose distributions. Static and dynamic deformations were used to simulate inter- and intrafractional motion in the phantom and measurements were compared to baseline measurements. RESULTS: The statically irradiated dosimeters matched the planned dose distribution with an average γ pass rates of 97.0 ± 0.5% and 97.5 ± 0.2% for 3%/5 mm and 5%/5 mm criteria, respectively. Static deformations caused measured dose distribution shifts toward the phantom plunger. During the dynamic deformation experiment, the dosimeter that utilized beam gating showed an improvement in the γ pass rate compared to the dosimeter that did not. CONCLUSIONS: A deformable abdominal phantom apparatus which incorporates a deformable nPAG dosimeter was developed to test real-time IGRT systems and deformable dose accumulation algorithms. This apparatus was used to benchmark simple static irradiations in which it was found that measurements match well to the planned distributions. Deformable dose accumulation could be tested by directly measuring the shifts and blurring of the target dose due to interfractional organ deformation and motion. Dosimetric improvements were achieved from the motion management during intrafractional motion.

A Magnetic Resonance Compatible E4D Ultrasound Probe for Motion Management of Radiation Therapy.

We developed a magnetic resonance compatible real-time, three-dimensional imaging ultrasound probe for motion management of radiation therapy for liver cancer. The probe contains an 18,000-element, 46.8 mm × 21.5 mm matrix array constructed from three tiled transducer modules with integrated beamforming ASICs. The center frequency and -6 dB fractional bandwidth of the probe was 3.6 MHz and 85 percent respectively. Ferromagnetic materials in the acoustic stack, flex interconnect and electronics boards were greatly minimized for magnetic resonance compatibility. The probe and cable were shielded to minimize the impact of radiofrequency noise on both the ultrasound and magnetic resonance images. The probe's low-profile, side-viewing design allows it to be strapped to a patient so that images may be acquired hands-free. We present simultaneously acquired ultrasound and 3 Tesla magnetic resonance images with minimal artifacts in both images.

An analysis of the ArcCHECK-MR diode array's performance for ViewRay quality assurance.

The ArcCHECK-MR diode array utilizes a correction system with a virtual inclinometer to correct the angular response dependencies of the diodes. However, this correction system cannot be applied to measurements on the ViewRay MR-IGRT system due to the virtual inclinometer's incompatibility with the ViewRay's multiple simultaneous beams. Additionally, the ArcCHECK's current correction factors were determined without magnetic field effects taken into account. In the course of performing ViewRay IMRT quality assurance with the ArcCHECK, measurements were observed to be consistently higher than the ViewRay TPS predictions. The goals of this study were to quantify the observed discrepancies and test whether applying the current factors improves the ArcCHECK's accuracy for measurements on the ViewRay. Gamma and frequency analysis were performed on 19 ViewRay patient plans. Ion chamber measurements were performed at a subset of diode locations using a PMMA phantom with the same dimensions as the ArcCHECK. A new method for applying directionally dependent factors utilizing beam information from the ViewRay TPS was developed in order to analyze the current ArcCHECK correction factors. To test the current factors, nine ViewRay plans were altered to be delivered with only a single simultaneous beam and were measured with the ArcCHECK. The current correction factors were applied using both the new and current methods. The new method was also used to apply corrections to the original 19 ViewRay plans. It was found the ArcCHECK systematically reports doses higher than those actually delivered by the ViewRay. Application of the current correction factors by either method did not consistently improve measurement accuracy. As dose deposition and diode response have both been shown to change under the influence of a magnetic field, it can be concluded the current ArcCHECK correction factors are invalid and/or inadequate to correct measurements on the ViewRay system.

Dosimetric comparison of DEFGEL and PAGAT formulae paired with an MRI acquisition.

Normoxic Polyacrylamide Gels, or nPAGs, are 3D gel dosimeters that measure dose through the process of radiation-induced polymerization. Two nPAG formulae are DEFGEL and PAGAT, which are very similar, but differ mainly due to different weight fractions of monomers. The dosimetric resolutions of the two formulae when paired with a Spin-Echo (SE) MRI sequence and a monoexponential fit were compared over a range of 0-15 Gy. It was found that in the dose range 0-6 Gy the PAGAT formula generally showed a much finer dose resolution, while the DEFGEL formula showed a finer resolution from 8-15 Gy.

Monte Carlo-Based Nanoscale Dosimetry Holds Promise for Radiopharmaceutical Therapy Involving Auger Electron Emitters.

Radiopharmaceutical therapy (RPT) is evolving as a promising strategy for treating cancer. As interest grows in short-range particles, like Auger electrons, understanding the dose-response relationship at the deoxyribonucleic acid (DNA) level has become essential. In this study, we used the Geant4-DNA toolkit to evaluate DNA damage caused by the Auger-electron-emitting isotope I-125. We compared the energy deposition and single strand break (SSB) yield at each base pair location in a short B-form DNA (B-DNA) geometry with existing simulation and experimental data, considering both physical direct and chemical indirect hits. Additionally, we evaluated dosimetric differences between our high-resolution B-DNA target and a previously published simple B-DNA geometry. Overall, our benchmarking results for SSB yield from I-125 decay exhibited good agreement with both simulation and experimental data. Using this simulation, we then evaluated the SSB and double strand break (DSB) yields caused by a theranostic Br-77-labeled poly ADP ribose polymerase (PARP) inhibitor radiopharmaceutical. The results indicated a predominant contribution of chemical indirect hits over physical direct hits in generating SSB and DSB. This study lays the foundation for future investigations into the nano-dosimetric properties of RPT.

Voxel-Level Dosimetry for Combined Iodine 131 Radiopharmaceutical Therapy and External Beam Radiation Therapy Treatment Paradigms for Head and Neck Cancer.

PURPOSE: Targeted radiopharmaceutical therapy (RPT) in combination with external beam radiation therapy (EBRT) shows promise as a method to increase tumor control and mitigate potential high-grade toxicities associated with re-treatment for patients with recurrent head and neck cancer. This work establishes a patient-specific dosimetry framework that combines Monte Carlo-based dosimetry from the 2 radiation modalities at the voxel level using deformable image registration (DIR) and radiobiological constructs for patients enrolled in a phase 1 clinical trial combining EBRT and RPT. METHODS AND MATERIALS: Serial single-photon emission computed tomography (SPECT)/computed tomography (CT) patient scans were performed at approximately 24, 48, 72, and 168 hours postinjection of 577.2 MBq/m2 (15.6 mCi/m2) CLR 131, an iodine 131-containing RPT agent. Using RayStation, clinical EBRT treatment plans were created with a treatment planning CT (TPCT). SPECT/CT images were deformably registered to the TPCT using the Elastix DIR module in 3D Slicer software and assessed by measuring mean activity concentrations and absorbed doses. Monte Carlo EBRT dosimetry was computed using EGSnrc. RPT dosimetry was conducted using RAPID, a GEANT4-based RPT dosimetry platform. Radiobiological metrics (biologically effective dose and equivalent dose in 2-Gy fractions) were used to combine the 2 radiation modalities. RESULTS: The DIR method provided good agreement for the activity concentrations and calculated absorbed dose in the tumor volumes for the SPECT/CT and TPCT images, with a maximum mean absorbed dose difference of -11.2%. Based on the RPT absorbed dose calculations, 2 to 4 EBRT fractions were removed from patient EBRT treatments. For the combined treatment, the absorbed dose to target volumes ranged from 57.14 to 75.02 Gy. When partial volume corrections were included, the mean equivalent dose in 2-Gy fractions to the planning target volume from EBRT + RPT differed -3.11% to 1.40% compared with EBRT alone. CONCLUSIONS: This work demonstrates the clinical feasibility of performing combined EBRT + RPT dosimetry on TPCT scans. Dosimetry guides treatment decisions for EBRT, and this work provides a bridge for the same paradigm to be implemented within the rapidly emerging clinical RPT space.

Effects of clinically relevant radionuclides on the activation of a type I interferon response by radiopharmaceuticals in syngeneic murine tumor models.

Radiopharmaceutical therapies (RPT) activate a type I interferon (IFN1) response in tumor cells. We hypothesized that the timing and amplitude of this response varies by isotope. We compared equal doses delivered by 90 Y, 177 Lu, and 225 Ac in vitro as unbound radionuclides and in vivo when chelated to NM600, a tumor-selective alkylphosphocholine. Response in murine MOC2 head and neck carcinoma and B78 melanoma was evaluated by qPCR and flow cytometry. Therapeutic response to 225 Ac-NM600+anti-CTLA4+anti-PD-L1 immune checkpoint inhibition (ICI) was evaluated in wild-type and stimulator of interferon genes knockout (STING KO) B78. The timing and magnitude of IFN1 response correlated with radionuclide half-life and linear energy transfer. CD8 + /Treg ratios increased in tumors 7 days after 90 Y- and 177 Lu-NM600 and day 21 after 225 Ac-NM600. 225 Ac-NM600+ICI improved survival in mice with WT but not with STING KO tumors, relative to monotherapies. Immunomodulatory effects of RPT vary with radioisotope and promote STING-dependent enhanced response to ICIs in murine models. Teaser: This study describes the time course and nature of tumor immunomodulation by radiopharmaceuticals with differing physical properties.

Theranostics and Patient-Specific Dosimetry.

Radiopharmaceutical therapy (RPT) is an invigorated form of cancer therapy that systemically delivers targeted radioactive drugs to cancer cells. Theranostics is a type of RPT that utilizes imaging, either of the RPT drug directly or a companion diagnostic, to inform whether a patient will benefit from the treatment. Given the ability to image the drug onboard theranostic treatments also lends itself readily to patient-specific dosimetry, which is a physics-based process that determines the overall absorbed dose burden to healthy organs and tissues and tumors in patients. While companion diagnostics identify who will benefit from RPT treatments, dosimetry determines how much activity these beneficiaries can receive to maximize therapeutic efficacy. Clinical data is starting to accrue suggesting tremendous benefits when dosimetry is performed for RPT patients. RPT dosimetry, which was once performed by florid and often inaccurate workflows, can now be performed more efficiently and accurately with FDA-cleared dosimetry software. Therefore, there is no better time for the field of oncology to adopt this form of personalize medicine to improve outcomes for cancer patients.

Corrigendum: Comparison of 3DCRT and IMRT out-of-field doses in pediatric patients using Monte Carlo simulations with treatment planning system calculations and measurements.

[This corrects the article DOI: 10.3389/fonc.2022.879167.].

Creation of waterproof, TLD probes for dose measurements to validate image-based radiopharmaceutical therapy dosimetry workflow.

Voxel-level dosimetry based on nuclear medicine images offers patient-specific personalization of radiopharmaceutical therapy (RPT) treatments. Clinical evidence is emerging demonstrating improvements in treatment precision in patients when voxel-level dosimetry is used compared to MIRD. Voxel-level dosimetry requires absolute quantification of activity concentrations in the patient, but images from SPECT/CT scanners are not quantitative and require calibration using nuclear medicine phantoms. While phantom studies can validate a scanner's ability to recover activity concentrations, these studies provide only a surrogate for the true metric of interest: absorbed doses. Measurements using thermoluminescent dosimeters (TLDs) are a versatile and accurate method of measuring absorbed dose. In this work, a TLD probe was manufactured that can fit into currently available nuclear medicine phantoms for the measurement of absorbed dose of RPT agents. Next, 748 MBq of I-131 was administered to a 16 ml hollow source sphere placed in a 6.4 L Jaszczak phantom in addition to six TLD probes, each holding 4 TLD-100 1 × 1 × 1 mm TLD-100 (LiF:Mg,Ti) microcubes. The phantom then underwent a SPECT/CT scan in accordance with a standard SPECT/CT imaging protocol for I-131. The SPECT/CT images were then input into a Monte Carlo based RPT dosimetry platform named RAPID and a three dimensional dose distribution in the phantom was estimated. Additionally, a GEANT4 benchmarking scenario (denoted 'idealized') was created using a stylized representation of the phantom. There was good agreement for all six probes, the differences between measurement and RAPID ranged between -5.5% and 0.9%. The difference between the measured and the idealized GEANT4 scenario was calculated and ranged from -4.3% and -20.5%. This work demonstrates good agreement between TLD measurements and RAPID. In addition, it introduces a novel TLD probe that can be easily introduced into clinical nuclear medicine workflows to provide QA of image-based dosimetry for RPT treatments.

Use of deep learning to segment bolus during videofluoroscopic swallow studies.

Anatomical segmentations generated using artificial intelligence (AI) have the potential to significantly improve video fluoroscopic swallow study (VFS) analysis. AI segments allow for various metrics to be determined without additional time constraints streamlining and creating new opportunities for analysis. While the opportunity is vast, it is important to understand the challenges and limitations of the underlying AI task. This work evaluates a bolus segmentation network. The first swallow of thin or liquid bolus from 80 unique patients were manually contoured from bolus first seen in the oral cavity to end of swallow motion. The data was split into a 75/25 training and validation set and a 4-fold cross validation was done. A U-Net architecture along with variations were tested with the dice coefficient as the loss function and overall performance metric. The average validation set resulted in a dice coefficient of 0.67. Additional analysis to characterize the variability of images and performance on sub intervals was conducted indicating high variability among the processes required for training the network. It was found that bolus in the oral cavity consistently degrades performance due to misclassification of teeth and unimportant residue. The dice coefficients dependence on structure size can have substantial effects on the reported value. This work shows the efficacy of bolus segmentation and identifies key areas that are detriments to the performance of the network.

Targeting of Head and Neck Cancer by Radioiodinated CLR1404 in Murine Xenograft Tumor Models with Partial Volume Corrected Theranostic Dosimetry.

Background: Delivery of radiotherapeutic dose to recurrent head and neck cancer (HNC) is primarily limited by locoregional toxicity in conventional radiotherapy. As such, HNC patients stand to benefit from the conformal targeting of primary and remnant disease achievable with radiopharmaceutical therapies. In this study, the authors investigated the tumor targeting capacity of 131I-CLR1404 (iopofosine I-131) in various HNC xenograft mouse models and the impact of partial volume correction (PVC) on theranostic dosimetry based on 124I-CLR1404 (CLR 124) positron emission tomography (PET)/computed tomography (CT) imaging. Methods: Mice bearing flank tumor xenograft models of HNC (six murine cell line and six human patient derived) were intravenously administered 6.5-9.1 MBq of CLR 124 and imaged five times over the course of 6 d using microPET/CT. In vivo tumor uptake of CLR 124 was assessed and PVC for 124I was applied using a novel preclinical phantom. Using subject-specific theranostic dosimetry estimations for iopofosine I-131 based on CLR 124 imaging, a discrete radiation dose escalation study (2, 4, 6, and 8 Gy) was performed to evaluate tumor growth response to iopofosine I-131 relative to a single fraction of external beam radiation therapy (6 Gy). Results: PET imaging demonstrated consistent tumor selective uptake and retention of CLR 124 across all HNC xenograft models. Peak uptake of 4.4% ± 0.8% and 4.2% ± 0.4% was observed in squamous cell carcinoma-22B and UW-13, respectively. PVC application increased uptake measures by 47%-188% and reduced absolute differences between in vivo and ex vivo uptake measurements from 3.3% to 1.0 percent injected activity per gram. Tumor dosimetry averaged over all HNC models was 0.85 ± 0.27 Gy/MBq (1.58 ± 0.46 Gy/MBq with PVC). Therapeutic iopofosine I-131 studies demonstrated a variable, but linear relationship between iopofosine I-131 radiation dose and tumor growth delay (p < 0.05). Conclusions: Iopofosine I-131 demonstrated tumoricidal capacity in preclinical HNC tumor models and the theranostic pairing with CLR 124 presents a promising new treatment approach for personalizing administration of iopofosine I-131.

A hybrid deformable registration method to generate motion-compensated 3D virtual MRI for fusion with interventional real-time 3D ultrasound.

PURPOSE: Ultrasound is often the preferred modality for image-guided therapy or treatment in organs such as liver due to real-time imaging capabilities. However, the reduced conspicuity of tumors in ultrasound images adversely impacts the precision and accuracy of treatment delivery. This problem is compounded by deformable motion due to breathing and other physiological activity. This creates the need for a fusion method to align interventional US with pre-interventional modalities that provide superior soft-tissue contrast (e.g., MRI) to accurately target a structure-of-interest and compensate for liver motion. METHOD: In this work, we developed a hybrid deformable fusion method to align 3D pre-interventional MRI and 3D interventional US volumes to target the structures-of-interest in liver accurately in real-time. The deformable multimodal fusion method involved an offline alignment of a pre-intervention MRI with a pre-intervention US volume using a traditional registration method, followed by real-time prediction of deformation using a trained deep-learning model between interventional US volumes across different respiratory states. This framework enables motion-compensated MRI-US image fusion in real-time for image-guided treatment. RESULTS: The proposed hybrid deformable registration method was evaluated on three healthy volunteers across the pre-intervention MRI and 20 US volume pairs in the free-breathing respiratory cycle. The mean Euclidean landmark distance of three homologous targets in all three volunteers was less than 3 mm for percutaneous liver procedures. CONCLUSIONS: Preliminary results show that clinically acceptable registration accuracies for near real-time, deformable MRI-US fusion can be achieved by our proposed hybrid approach. The proposed combination of traditional and deep-learning deformable registration techniques is thus a promising approach for motion-compensated MRI-US fusion to improve targeting in image-guided liver interventions.

Image-Based Dosimetry in Dogs and Cross-Reactivity with Human Tissues of IGF2R-Targeting Human Antibody.

BACKGROUND: Osteosarcoma (OS) represents the most common primary bone tumor in humans and in companion dogs, being practically phenotypically identical. There is a need for effective treatments to extend the survival of patients with OS. Here, we examine the dosimetry in beagle dogs and cross-reactivity with human tissues of a novel human antibody, IF3, that targets the insulin growth factor receptor type 2 (IGF2R), which is overexpressed on OS cells, making it a candidate for radioimmunotherapy of OS. METHODS: [89Zr]Zr-DFO-IF3 was injected into three healthy beagle dogs. PET/CT was conducted at 4, 24, 48, and 72 h. RAPID analysis was used to determine the dosimetry of [177Lu]Lu-CHXA"-IF3 for a clinical trial in companion dogs with OS. IF3 antibody was biotinylated, and a multitude of human tissues were assessed with immunohistochemistry. RESULTS: PET/CT revealed that only the liver, bone marrow, and adrenal glands had high uptake. Clearance was initially through renal and hepatobiliary excretion in the first 72 h followed by primarily physical decay. RAPID analysis showed bone marrow to be the dose-limiting organ with a therapeutic range for 177Lu calculated to be 0.487-0.583 GBq. Immunohistochemistry demonstrated the absence of IGF2R expression on the surface of healthy human cells, thus suggesting that radioimmunotherapy with [177Lu]Lu-CHXA"-IF3 will be well tolerated. CONCLUSIONS: Image-based dosimetry has defined a safe therapeutic range for canine clinical trials, while immunohistochemistry has suggested that the antibody will not cross-react with healthy human tissues.

Radiation to all macroscopic sites of tumor permits greater systemic antitumor response to in situ vaccination.

BACKGROUND: The antitumor effects of external beam radiation therapy (EBRT) are mediated, in part, by an immune response. We have reported that a single fraction of 12 Gy EBRT combined with intratumoral anti-GD2 hu14.18-IL2 immunocytokine (IC) generates an effective in situ vaccine (ISV) against GD2-positive murine tumors. This ISV is effective in eradicating single tumors with sustained immune memory; however, it does not generate an adequate abscopal response against macroscopic distant tumors. Given the immune-stimulatory capacity of radiation therapy (RT), we hypothesized that delivering RT to all sites of disease would augment systemic antitumor responses to ISV. METHODS: We used a syngeneic B78 murine melanoma model consisting of a 'primary' flank tumor and a contralateral smaller 'secondary' flank tumor, treated with 12 Gy EBRT and intratumoral IC immunotherapy to the primary and additional EBRT to the secondary tumor. As a means of delivering RT to all sites of disease, both known and occult, we also used a novel alkylphosphocholine analog, NM600, conjugated to 90Y as a targeted radionuclide therapy (TRT). Tumor growth, overall survival, and cause of death were measured. Flow cytometry was used to evaluate immune population changes in both tumors. RESULTS: Abscopal effects of local ISV were amplified by delivering as little as 2-6 Gy of EBRT to the secondary tumor. When the primary tumor ISV regimen was delivered in mice receiving 12 Gy EBRT to the secondary tumor, we observed improved overall survival and more disease-free mice with immune memory compared with either ISV or 12 Gy EBRT alone. Similarly, TRT combined with ISV resulted in improved overall survival and a trend towards reduced tumor growth rates when compared with either treatment alone. Using flow cytometry, we identified an influx of CD8+ T cells with a less exhausted phenotype in both the ISV-targeted primary and the distant secondary tumor following the combination of secondary tumor EBRT or TRT with primary tumor ISV. CONCLUSIONS: We report a novel use for low-dose RT, not as a direct antitumor modality but as an immunomodulator capable of driving and expanding antitumor immunity against metastatic tumor sites following ISV.

Comparative Study of the Effect of Radiation Delivered by Lutetium-177 or Actinium-225 on Anti-GD2 Chimeric Antigen Receptor T Cell Viability and Functions.

BACKGROUND AND PURPOSE: Chimeric antigen receptor (CAR) T cells have been relatively ineffective against solid tumors. Low-dose radiation which can be delivered to multiple sites of metastases by targeted radionuclide therapy (TRT) can elicit immunostimulatory effects. However, TRT has never been combined with CAR T cells against solid tumors in a clinical setting. This study investigated the effects of radiation delivered by Lutetium-177 (177Lu) and Actinium-225 (225Ac) on the viability and effector function of CAR T cells in vitro to evaluate the feasibility of such therapeutic combinations. After the irradiation of anti-GD2 CAR T cells with various doses of radiation delivered by 177Lu or 225Ac, their viability and cytotoxic activity against GD2-expressing human CHLA-20 neuroblastoma and melanoma M21 cells were determined by flow cytometry. The expression of the exhaustion marker PD-1, activation marker CD69 and the activating receptor NKG2D was measured on the irradiated anti-GD2 CAR T cells. Both 177Lu and 225Ac displayed a dose-dependent toxicity on anti-GD2 CAR T cells. However, radiation enhanced the cytotoxic activity of these CAR T cells against CHLA-20 and M21 irrespective of the dose tested and the type of radionuclide. No significant changes in the expression of PD-1, CD69 and NKG2D was noted on the CAR T cells following irradiation. Given a lower CAR T cell viability at equal doses and an enhancement of cytotoxic activity irrespective of the radionuclide type, 177Lu-based TRT may be preferred over 225Ac-based TRT when evaluating a potential synergism between these therapies in vivo against solid tumors.

ASTRO's Framework for Radiopharmaceutical Therapy Curriculum Development for Trainees.

In 2017, the American Society for Radiation Oncology (ASTRO) board of directors prioritized radiopharmaceutical therapy (RPT) as a leading area for new therapeutic development, and the ASTRO RPT workgroup was created. Herein, the workgroup has developed a framework for RPT curriculum development upon which education leaders can build to integrate this modality into radiation oncology resident education. Through this effort, the workgroup aims to provide a guide to ensure robust training in an emerging therapeutic area within the context of existing radiation oncology training in radiation biology, medical physics, and clinical radiation oncology. The framework first determines the core RPT knowledge required to select patients, prescribe, safely administer, and manage related adverse events. Then, it defines the most important topics for preparing residents for clinical RPT planning and delivery. This framework is designed as a tool to supplement the current training that exists for radiation oncology residents. The final document was approved by the ASTRO board of directors in the fall of 2021.

Comparison of 3DCRT and IMRT out-of-field doses in pediatric patients using Monte Carlo simulations with treatment planning system calculations and measurements.

3DCRT and IMRT out-of-field doses in pediatric patients were compared using Monte Carlo simulations with treatment planning system calculations and measurements. Purpose: Out-of-field doses are given to healthy tissues, which may allow the development of second tumors. The use of IMRT in pediatric patients has been discussed, as it leads to a "bath" of low doses to large volumes of out-of-field organs and tissues. This study aims to compare out-of-field doses in pediatric patients comparing IMRT and 3DCRT techniques using measurements, Monte Carlo (MC) simulations, and treatment planning system (TPS) calculations. Materials and methods: A total dose of 54 Gy was prescribed to a PTV in the brain of a pediatric anthropomorphic phantom, for both techniques. To assess the out-of-field organ doses for both techniques, two treatment plans were performed with the 3DCRT and IMRT techniques in TPS. Measurements were carried out in a LINAC using a pediatric anthropomorphic phantom and thermoluminescent dosimeters to recreate the treatment plans, previously performed in the TPS. A computational model of a LINAC, the associated multileaf collimators, and a voxelized pediatric phantom implemented in the Monte Carlo N-Particle 6.1 computer program were also used to perform MC simulations of the out-of-field organ doses, for both techniques. Results: The results obtained by measurements and MC simulations indicate a significant increase in dose using the IMRT technique when compared to the 3DCRT technique. More specifically, measurements show higher doses with IMRT, namely, in right eye (13,041 vs. 593 mGy), left eye (6,525 vs. 475 mGy), thyroid (79 vs. 70 mGy), right lung (37 vs. 28 mGy), left lung (27 vs. 20 mGy), and heart (31 vs. 25 mGy). The obtained results indicate that out-of-field doses can be seriously underestimated by TPS. Discussion: This study presents, for the first time, out-of-field dose measurements in a realistic scenario and calculations for IMRT, centered on a voxelized pediatric phantom and an MC model of a medical LINAC, including MLC with log file-based simulations. The results pinpoint significant discrepancies in out-of-field doses for the two techniques and are a cause of concern because TPS calculations cannot accurately predict such doses. The obtained doses may presumably increase the risk of development of second tumors.