In Vivo Verification of Electron Paramagnetic Resonance Biodosimetry Using Patients Undergoing Radiation Therapy Treatment.

PURPOSE: Electron paramagnetic resonance (EPR) biodosimetry, used to triage large numbers of individuals incidentally exposed to unknown doses of ionizing radiation, is based on detecting a stable physical response in the body that is subject to quantifiable variation after exposure. In vivo measurement is essential to fully characterize the radiation response relevant to a living tooth measured in situ. The purpose of this study was to verify EPR spectroscopy in vivo by estimating the radiation dose received in participants' teeth. METHODS AND MATERIALS: A continuous wave L-band spectrometer was used for EPR measurements. Participants included healthy volunteers and patients undergoing head and neck and total body irradiation treatments. Healthy volunteers completed 1 measurement each, and patients underwent measurement before starting treatment and between subsequent fractions. Optically stimulated luminescent dosimeters and diodes were used to determine the dose delivered to the teeth to validate EPR measurements. RESULTS: Seventy measurements were acquired from 4 total body irradiation and 6 head and neck patients over 15 months. Patient data showed a linear increase of EPR signal with delivered dose across the dose range tested. A linear least-squares weighted fit of the data gave a statistically significant correlation between EPR signal and absorbed dose (P < .0001). The standard error of inverse prediction (SEIP), used to assess the usefulness of fits, was 1.92 Gy for the dose range most relevant for immediate triage (≤7 Gy). Correcting for natural background radiation based on patient age reduced the SEIP to 1.51 Gy. CONCLUSIONS: This study demonstrated the feasibility of using spectroscopic measurements from radiation therapy patients to validate in vivo EPR biodosimetry. The data illustrated a statistically significant correlation between the magnitude of EPR signals and absorbed dose. The SEIP of 1.51 Gy, obtained under clinical conditions, indicates the potential value of this technique in response to large radiation events.

A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply.

Introduction: Radiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning. Methods: The dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation. We deployed a parabolic partial differential equation to account for the generalized radiation oxygen depletion, tissue oxygen diffusion, and metabolic processes to investigate oxygen distribution in 1D, 2D, and 3D solution space. Dose and dose rates, particle LET, vasculature spacing, and blood oxygen supplies were considered. Using a similar framework for the hypoxic reduction factor (HRF) developed previously, the FEDMF was derived as the ratio of the cumulative normoxic-equivalent dose (CNED) between CONV and UHDR deliveries. Results: Dynamic equilibrium between oxygen diffusion and tissue metabolism can result in tissue hypoxia. The hypoxic region displayed enhanced radio-resistance and resulted in lower CNED under UHDR deliveries. In 1D solution, comparing 15 Gy proton dose delivered at CONV 0.5 and UHDR 125 Gy/s, 61.5% of the tissue exhibited ≥20% FEDMF at 175 µm vasculature spacing and 18.9 µM boundary condition. This percentage reduced to 34.5% and 0% for 8 and 2 Gy deliveries, respectively. Similar trends were observed in the 3D solution space. The FLASH versus CONV differential effect remained at larger vasculature spacings. A higher FLASH dose rate showed an increased region with ≥20% FEDMF. A higher LET near the proton Bragg peak region did not appear to alter the FLASH effect. Conclusion: We developed 1D, 2D, and 3D oxygen depletion simulation process to obtain the dynamic HRF and derive the proton FEDMF related to the dose delivery parameters and the local tissue vasculature information. The phenomenological model can be used to simulate or predict FLASH effects based on tissue vasculature and oxygen concentration data obtained from other experiments.

Stricter Postoperative Oropharyngeal Cancer Radiation Therapy Normal Tissue Dose Constraints Are Feasible.

PURPOSE: Although dose de-escalation is one proposed strategy to mitigate long-term toxicity in human papillomavirus associated oropharyngeal cancer, applying more stringent normal tissue constraints may be a complementary approach to further reduce toxicity. Our study demonstrates that in a postoperative setting, improving upon nationally accepted constraints is achievable and leads to reductions in normal tissue complication probabilities (NTCP) without compromising disease control. METHODS AND MATERIALS: We identified 92 patients at our institution between 2015 and 2019 with p16+ oropharyngeal cancer who were treated with adjuvant volumetric modulated arc therapy. We included patients treated to postoperative doses and standard volumes (including bilateral neck). Doses delivered to organs at risk were compared with recommended dose constraints from a recent cooperative group head and neck cancer trial of radiation therapy to 60 Gy. We applied validated and published NTCP models for dysphagia, dysgeusia, esophagitis, oral mucositis, and xerostomia relevant to oropharyngeal cancer. RESULTS: Achievable and delivered mean doses to most normal head and neck tissues were well below national recommended constraints. This translates to notable absolute NTCP reductions for salivary flow (10% improvement in contralateral parotid, 35% improvement in submandibular gland), grade ≥ 2 esophagitis (23% improvement), grade ≥ 3 mucositis (17% improvement), dysgeusia (10% improvement), and dysphagia (8% improvement). Locoregional control at a median follow-up of 26.3 months was 96.7%, with only 3 patients experiencing locoregional recurrence (1 local, 2 regional). CONCLUSIONS: Modern radiation therapy planning techniques allow for improved normal tissue sparing compared with currently established dose constraints without compromising disease control. These improvements may lead to reduced toxicity in a patient population expected to have favorable long-term outcomes. Stricter constraints can be easily achieved and should be used in conjunction with other evolving efforts to mitigate toxicity.

Correlation of LET With MRI Changes in Brain and Potential Implications for Normal Tissue Complication Probability for Patients With Meningioma Treated With Pencil Beam Scanning Proton Therapy.

PURPOSE: This study aimed to investigate the correlation between imaging changes in brain normal tissue and the spatial distribution of linear energy transfer (LET) for a cohort of patients with meningioma treated with scanned proton beams. Then, assuming imaging changes are induced by cell lethality, we studied the correlation between normal tissue complication probability and LET. METHODS AND MATERIALS: Magnetic resonance imaging T2/fluid attenuated inversion recovery acquired at different intervals after proton radiation were coregistered with the planning computed tomography (CT) images from 26 patients with meningioma with abnormalities after proton radiation therapy. For this purpose, the T2/fluid attenuated inversion recovery areas not on the original magnetic resonance images were contoured, and the LET values for each voxel in the patient geometry were calculated to investigate the correlation between the position of imaging changes and the LET at those positions. To separate the effect of the dose as the inductor of these changes, we compared the LET in these areas with a sample of voxels matching the dose distributions across the image change areas. Patients with a higher LET in image change areas were grouped to verify whether they shared common characteristics. RESULTS: Eleven of the patients showed higher dose-averaged LET (LETd) in imaging change regions than in the group of voxels with the same dose. This group of patients had significantly shallower targets for their treatment than the other 15 and used fewer beams and angles. CONCLUSIONS: This study points toward the possibility that areas with imaging change are more likely to occur in regions with high dose or in areas with lower dose but increased LETd. The effect of LETd on imaging changes seems to be more relevant when treating superficial lesions with few nonopposed beams. However, most patients did not show a spatial correlation between their image changes and the LETd values, limiting the cases for the possible role of high LET as a toxicity inductor.

The current status of preclinical proton FLASH radiation and future directions.

We review the current status of proton FLASH experimental systems, including preclinical physical and biological results. Technological limitations on preclinical investigation of FLASH biological mechanisms and determination of clinically relevant parameters are discussed. A review of the biological data reveals no reproduced proton FLASH effect in vitro and a significant in vivo FLASH sparing effect of normal tissue toxicity observed with multiple proton FLASH irradiation systems. Importantly, multiple studies suggest little or no difference in tumor growth delay for proton FLASH when compared to conventional dose rate proton radiation. A discussion follows on future areas of development with a focus on the determination of the optimal parameters for maximizing the therapeutic ratio between tumor and normal tissue response and ultimately clinical translation of proton FLASH radiation.

Microdosimetric Investigation and a Novel Model of Radiosensitization in the Presence of Metallic Nanoparticles.

Auger cascades generated in high atomic number nanoparticles (NPs) following ionization were considered a potential mechanism for NP radiosensitization. In this work, we investigated the microdosimetric consequences of the Auger cascades using the theory of dual radiation action (TDRA), and we propose the novel Bomb model as a general framework for describing NP-related radiosensitization. When triggered by an ionization event, the Bomb model considers the NPs that are close to a radiation sensitive cellular target, generates dense secondary electrons and kills the cells according to a probability distribution, acting like a "bomb." TDRA plus a distance model were used as the theoretical basis for calculating the change in α of the linear-quadratic survival model and the relative biological effectiveness (RBE). We calculated these quantities for SQ20B and Hela human cancer cells under 250 kVp X-ray irradiation with the presence of gadolinium-based NPs (AGuIXTM), and 220 kVp X-ray irradiation with the presence of 50 nm gold NPs (AuNPs), respectively, and compared with existing experimental data. Geant4-based Monte Carlo (MC) simulations were used to (1) generate the electron spectrum and the phase space data of photons entering the NPs and (2) calculate the proximity functions and other related parameters for the TDRA and the Bomb model. The Auger cascade electrons had a greater proximity function than photoelectric and Compton electrons in water by up to 30%, but the resulting increases in α were smaller than those derived from experimental data. The calculated RBEs cannot explain the experimental findings. The relative increase in α predicted by TDRA was lower than the experimental result by a factor of at least 45 for SQ20B cells with AGuIX under 250 kVp X-ray irradiation, and at least four for Hela cells with AuNPs under 220 kVp X-ray irradiation. The application of the Bomb model to Hela cells with AuNPs under 220 kVp X-ray irradiation indicated that a single ionization event for NPs caused by higher energy photons has a higher probability of killing a cell. NPs that are closer to the cell nucleus are more effective for radiosensitization. Microdosimetric calculations of the RBE for cell death of the Auger electron cascade cannot explain the experimentally observed radiosensitization by AGuIX or AuNP, while the proposed Bomb model is a potential candidate for describing NP-related radiosensitization at low NP concentrations.

Characterization of a high-resolution 2D transmission ion chamber for independent validation of proton pencil beam scanning of conventional and FLASH dose delivery.

INTRODUCTION: Ultra-high dose rate (FLASH) radiotherapy has become a popular research topic with the potential to reduce normal tissue toxicities without losing the benefit of tumor control. The development of FLASH proton pencil beam scanning (PBS) delivery requires accurate dosimetry despite high beam currents with correspondingly high ionization densities in the monitoring chamber. In this study, we characterized a newly designed high-resolution position sensing transmission ionization chamber with a purpose-built multichannel electrometer for both conventional and FLASH dose rate proton radiotherapy. METHODS: The dosimetry and positioning accuracies of the ion chamber were fully characterized with a clinical scanning beam. On the FLASH proton beamline, the cyclotron output current reached up to 350 nA with a maximum energy of 226.2 MeV, with 210 ± 3 nA nozzle pencil beam current. The ion recombination effect was characterized under various bias voltages up to 1000 V and different beam intensities. The charge collected by the transmission ion chamber was compared with the measurements from a Faraday cup. RESULTS: Cross-calibrated with an Advanced Markus chamber (PTW, Freiburg, Germany) in a uniform PBS proton beam field at clinical beam setting, the ion chamber calibration was 38.0 and 36.7 GyE·mm2 /nC at 100 and 226.2 MeV, respectively. The ion recombination effect increased with larger cyclotron current at lower bias voltage while remaining ≤0.5 ± 0.5% with ≥200 V of bias voltage. Above 200 V, the normalized ion chamber readings demonstrated good linearity with the mass stopping power in air for both clinical and FLASH beam intensities. The spot positioning accuracy was measured to be 0.10 ± 0.08 mm in two orthogonal directions. CONCLUSION: We characterized a transmission ion chamber system under both conventional and FLASH beam current densities and demonstrated its suitability for use as a proton pencil beam dose and spot position delivery monitor under FLASH dose rate conditions.

Variance-based sensitivity analysis for uncertainties in proton therapy: A framework to assess the effect of simultaneous uncertainties in range, positioning, and RBE model predictions on RBE-weighted dose distributions.

PURPOSE: Treatment plans in proton therapy are more sensitive to uncertainties than in conventional photon therapy. In addition to setup uncertainties, proton therapy is affected by uncertainties in proton range and relative biological effectiveness (RBE). While to date a constant RBE of 1.1 is commonly assumed, the actual RBE is known to increase toward the distal end of the spread-out Bragg peak. Several models for variable RBE predictions exist. We present a framework to evaluate the combined impact and interactions of setup, range, and RBE uncertainties in a comprehensive, variance-based sensitivity analysis (SA). MATERIAL AND METHODS: The variance-based SA requires a large number (104 -105 ) of RBE-weighted dose (RWD) calculations. Based on a particle therapy extension of the research treatment planning system CERR we implemented a fast, graphics processing unit (GPU) accelerated pencil beam modeling of patient and range shifts. For RBE predictions, two biological models were included: The mechanistic repair-misrepair-fixation (RMF) model and the phenomenological Wedenberg model. All input parameters (patient position, proton range, RBE model parameters) are sampled simultaneously within their assumed probability distributions. Statistical formalisms rank the input parameters according to their influence on the overall uncertainty of RBE-weighted dose-volume histogram (RW-DVH) quantiles and the RWD in every voxel, resulting in relative, normalized sensitivity indices (S = 0: noninfluential input, S = 1: only influential input). Results are visualized as RW-DVHs with error bars and sensitivity maps. RESULTS AND CONCLUSIONS: The approach is demonstrated for two representative brain tumor cases and a prostate case. The full SA including ∼ 3 × 10 4 RWD calculations took 39, 11, and 55 min, respectively. Range uncertainty was an important contribution to overall uncertainty at the distal end of the target, while the relatively smaller uncertainty inside the target was governed by biological uncertainties. Consequently, the uncertainty of the RW-DVH quantile D98 for the target was governed by range uncertainty while the uncertainty of the mean target dose was dominated by the biological parameters. The SA framework is a powerful and flexible tool to evaluate uncertainty in RWD distributions and DVH quantiles, taking into account physical and RBE uncertainties and their interactions. The additional information might help to prioritize research efforts to reduce physical and RBE uncertainties and could also have implications for future approaches to biologically robust planning and optimization.