A prototype scintillator real-time beam monitor for ultra-high dose rate radiotherapy.

BACKGROUND: FLASH Radiotherapy (RT) is an emergent cancer RT modality where an entire therapeutic dose is delivered at more than 1000 times higher dose rate than conventional RT. For clinical trials to be conducted safely, a precise and fast beam monitor that can generate out-of-tolerance beam interrupts is required. This paper describes the overall concept and provides results from a prototype ultra-fast, scintillator-based beam monitor for both proton and electron beam FLASH applications. PURPOSE: A FLASH Beam Scintillator Monitor (FBSM) is being developed that employs a novel proprietary scintillator material. The FBSM has capabilities that conventional RT detector technologies are unable to simultaneously provide: (1) large area coverage; (2) a low mass profile; (3) a linear response over a broad dynamic range; (4) radiation hardness; (5) real-time analysis to provide an IEC-compliant fast beam-interrupt signal based on true two-dimensional beam imaging, radiation dosimetry and excellent spatial resolution. METHODS: The FBSM uses a proprietary low mass, less than 0.5 mm water equivalent, non-hygroscopic, radiation tolerant scintillator material (designated HM: hybrid material) that is viewed by high frame rate CMOS cameras. Folded optics using mirrors enable a thin monitor profile of ∼10 cm. A field programmable gate array (FPGA) data acquisition system generates real-time analysis on a time scale appropriate to the FLASH RT beam modality: 100-1000 Hz for pulsed electrons and 10-20 kHz for quasi-continuous scanning proton pencil beams. An ion beam monitor served as the initial development platform for this work and was tested in low energy heavy-ion beams (86Kr+26 and protons). A prototype FBSM was fabricated and then tested in various radiation beams that included FLASH level dose per pulse electron beams, and a hospital RT clinic with electron beams. RESULTS: Results presented in this report include image quality, response linearity, radiation hardness, spatial resolution, and real-time data processing. The HM scintillator was found to be highly radiation damage resistant. It exhibited a small 0.025%/kGy signal decrease from a 216 kGy cumulative dose resulting from continuous exposure for 15 min at a FLASH compatible dose rate of 237 Gy/s. Measurements of the signal amplitude versus beam fluence demonstrate linear response of the FBSM at FLASH compatible dose rates of >40 Gy/s. Comparison with commercial Gafchromic film indicates that the FBSM produces a high resolution 2D beam image and can reproduce a nearly identical beam profile, including primary beam tails. The spatial resolution was measured at 35-40 µm. Tests of the firmware beta version show successful operation at 20 000 Hz frame rate or 50 µs/frame, where the real-time analysis of the beam parameters is achieved in less than 1 µs. CONCLUSIONS: The FBSM is designed to provide real-time beam profile monitoring over a large active area without significantly degrading the beam quality. A prototype device has been staged in particle beams at currents of single particles up to FLASH level dose rates, using both continuous ion beams and pulsed electron beams. Using a novel scintillator, beam profiling has been demonstrated for currents extending from single particles to 10 nA currents. Radiation damage is minimal and even under FLASH conditions would require ≥50 kGy of accumulated exposure in a single spot to result in a 1% decrease in signal output. Beam imaging is comparable to radiochromic films, and provides immediate images without hours of processing. Real-time data processing, taking less than 50 µs (combined data transfer and analysis times), has been implemented in firmware for 20 kHz frame rates for continuous proton beams.

A review of the clinical introduction of 4D particle therapy research concepts.

Background and purpose: Many 4D particle therapy research concepts have been recently translated into clinics, however, remaining substantial differences depend on the indication and institute-related aspects. This work aims to summarise current state-of-the-art 4D particle therapy technology and outline a roadmap for future research and developments. Material and methods: This review focused on the clinical implementation of 4D approaches for imaging, treatment planning, delivery and evaluation based on the 2021 and 2022 4D Treatment Workshops for Particle Therapy as well as a review of the most recent surveys, guidelines and scientific papers dedicated to this topic. Results: Available technological capabilities for motion surveillance and compensation determined the course of each 4D particle treatment. 4D motion management, delivery techniques and strategies including imaging were diverse and depended on many factors. These included aspects of motion amplitude, tumour location, as well as accelerator technology driving the necessity of centre-specific dosimetric validation. Novel methodologies for X-ray based image processing and MRI for real-time tumour tracking and motion management were shown to have a large potential for online and offline adaptation schemes compensating for potential anatomical changes over the treatment course. The latest research developments were dominated by particle imaging, artificial intelligence methods and FLASH adding another level of complexity but also opportunities in the context of 4D treatments. Conclusion: This review showed that the rapid technological advances in radiation oncology together with the available intrafractional motion management and adaptive strategies paved the way towards clinical implementation.

Impact of glioma peritumoral edema, tumor size, and tumor location on alternating electric fields (AEF) therapy in realistic 3D rat glioma models: a computational study.

Objective.Alternating electric fields (AEF) therapy is a treatment modality for patients with glioblastoma. Tumor characteristics such as size, location, and extent of peritumoral edema may affect the AEF strength and distribution. We evaluated the sensitivity of the AEFs in a realistic 3D rat glioma model with respect to these properties.Approach.The electric properties of the peritumoral edema were varied based on calculated and literature-reported values. Models with different tumor composition, size, and location were created. The resulting AEFs were evaluated in 3D rat glioma models.Main results.In all cases, a pair of 5 mm diameter electrodes induced an average field strength >1 V cm-1. The simulation results showed that a negative relationship between edema conductivity and field strength was found. As the tumor core size was increased, the average field strength increased while the fraction of the shell achieving >1.5 V cm-1decreased. Increasing peritumoral edema thickness decreased the shell's mean field strength. Compared to rostrally/caudally, shifting the tumor location laterally/medially and ventrally (with respect to the electrodes) caused higher deviation in field strength.Significance.This study identifies tumor properties that are key drivers influencing AEF strength and distribution. The findings might be potential preclinical implications.

A Prototype Scintillator Real-Time Beam Monitor for Ultra-high Dose Rate Radiotherapy.

Background: FLASH Radiotherapy (RT) is an emergent cancer radiotherapy modality where an entire therapeutic dose is delivered at more than 1000 times higher dose rate than conventional RT. For clinical trials to be conducted safely, a precise and fast beam monitor that can generate out-of-tolerance beam interrupts is required. This paper describes the overall concept and provides results from a prototype ultra-fast, scintillator-based beam monitor for both proton and electron beam FLASH applications. Purpose: A FLASH Beam Scintillator Monitor (FBSM) is being developed that employs a novel proprietary scintillator material. The FBSM has capabilities that conventional RT detector technologies are unable to simultaneously provide: 1) large area coverage; 2) a low mass profile; 3) a linear response over a broad dynamic range; 4) radiation hardness; 5) real-time analysis to provide an IEC-compliant fast beam-interrupt signal based on true two-dimensional beam imaging, radiation do-simetry and excellent spatial resolution. Methods: The FBSM uses a proprietary low mass, less than 0.5 mm water equivalent, non-hygroscopic, radiation tolerant scintillator material (designated HM: hybrid material) that is viewed by high frame rate CMOS cameras. Folded optics using mirrors enable a thin monitor profile of ~10 cm. A field programmable gate array (FPGA) data acquisition system (DAQ) generates real-time analysis on a time scale appropriate to the FLASH RT beam modality: 100-1000 Hz for pulsed electrons and 10-20 kHz for quasi-continuous scanning proton pencil beams. An ion beam monitor served as the initial development platform for this work and was tested in low energy heavy-ion beams (86Kr+26 and protons). A prototype FBSM was fabricated and then tested in various radiation beams that included FLASH level dose per pulse electron beams, and a hospital radiotherapy clinic with electron beams. Results: Results presented in this report include image quality, response linearity, radiation hardness, spatial resolution, and real-time data processing. The HM scintillator was found to be highly radiation damage resistant. It exhibited a small 0.025%/kGy signal decrease from a 216 kGy cumulative dose resulting from continuous exposure for 15 minutes at a FLASH compatible dose rate of 237 Gy/s. Measurements of the signal amplitude vs beam fluence demonstrate linear response of the FBSM at FLASH compatible dose rates of > 40 Gy/s. Comparison with commercial Gafchromic film indicates that the FBSM produces a high resolution 2D beam image and can reproduce a nearly identical beam profile, including primary beam tails. The spatial resolution was measured at 35-40 µm. Tests of the firmware beta version show successful operation at 20,000 Hz frame rate or 50 µs/frame, where the real-time analysis of the beam parameters is achieved in less than 1 µs. Conclusions: The FBSM is designed to provide real-time beam profile monitoring over a large active area without significantly degrading the beam quality. A prototype device has been staged in particle beams at currents of single particles up to FLASH level dose rates, using both continuous ion beams and pulsed electron beams. Using a novel scintillator, beam profiling has been demonstrated for currents extending from single particles to 10 nA currents. Radiation damage is minimal and even under FLASH conditions would require ≥ 50 kGy of accumulated exposure in a single spot to result in a 1% decrease in signal output. Beam imaging is comparable to radiochromic films, and provides immediate images without hours of processing. Real-time data processing, taking less than 50 µs (combined data transfer and analysis times), has been implemented in firmware for 20 kHz frame rates for continuous proton beams.

Unexpected Transient Glioblastoma Regression in a Patient Previously Treated with Bacillus Calmette-Guérin Therapy: A Case Report and Immunomodulatory Effects Hypothesis.

(1) Background: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with limited treatment options and poor prognosis. Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, has been used as an immunotherapeutic agent in bladder cancer and has shown non-specific beneficial effects. This report presents a unique case of GBM regression following BCG therapy for bladder cancer, suggesting the potential systemic immunomodulatory effects of BCG on GBM. (2) Case Presentation: A 67-year-old male with a history of bladder cancer treated with BCG presented with neurological symptoms. Imaging revealed two GBM lesions, and surgery was performed to remove one. Subsequently, the patient experienced complete tumor regression after initial stability. (3) Conclusions: This case highlights the potential of BCG or other immunotherapies in GBM treatment and underscores the need for further research. Understanding the immunomodulatory effects of BCG on GBM could lead to innovative therapies for this devastating disease; although, overcoming the immune evasion mechanisms in the brain is a significant challenge. Further investigation is warranted to explore this promising avenue of research.

Electric field distributions in realistic 3D rat head models during alternating electric field (AEF) therapy: a computational study.

Objective.Application of alternating electrical fields (AEFs) in the kHz range is an established treatment modality for primary and recurrent glioblastoma. Preclinical studies would enable innovations in treatment monitoring and efficacy, which could then be translated to benefit patients. We present a practical translational process converting image-based data into 3D rat head models for AEF simulations and study its sensitivity to parameter choices.Approach.Five rat head models composed of up to 7 different tissue types were created, and relative permittivity and conductivity of individual tissues obtained from the literature were assigned. Finite element analysis was used to model the AEF strength and distribution in the models with different combinations of head tissues, a virtual tumor, and an electrode pair.Main results.The simulations allowed for a sensitivity analysis of the AEF distribution with respect to different tissue combinations and tissue parameter values.Significance.For a single pair of 5 mm diameter electrodes, an average AEF strength inside the tumor exceeded 1.5 V cm-1, expected to be sufficient for a relevant therapeutic outcome. This study illustrates a robust and flexible approach for simulating AEF in different tissue types, suitable for preclinical studies in rodents and translatable to clinical use.

A stopping criterion for iterative proton CT image reconstruction based on correlated noise properties.

BACKGROUND: Whereas filtered back projection algorithms for voxel-based CT image reconstruction have noise properties defined by the filter, iterative algorithms must stop at some point in their convergence and do not necessarily produce consistent noise properties for images with different degrees of heterogeneity. PURPOSE: A least-squares iterative algorithm for proton CT (pCT) image reconstruction converges toward a unique solution for relative stopping power (RSP) that optimally fits the protons. We present a stopping criterion that delivers solutions with the property that correlations of RSP noise between voxels are relatively low. This provides a method to produce pCT images with consistent noise properties useful for proton therapy treatment planning, which relies on summing RSP along lines of voxels. Consistent noise properties will also be useful for future studies of image quality using metrics such as contrast to noise ratio, and to compare RSP noise and dose of pCT with other modalities such as dual-energy CT. METHODS: With simulated and real images with varying heterogeneity from a prototype clinical proton imaging system, we calculate average RSP correlations between voxel pairs in uniform regions-of-interest versus distance between voxels. We define a parameter r, the remaining distance to the unique solution relative to estimated RSP noise, and our stopping criterion is based on r falling below a chosen value. RESULTS: We find large correlations between voxels for larger values of r, and anticorrelations for smaller values. For r in the range of 0.5-1, voxels are relatively uncorrelated, and compared to smaller values of r have lower noise with only slight loss of spatial resolution. CONCLUSIONS: Iterative algorithms not using a specific metric or rationale for stopping iterations may produce images with an unknown and arbitrary level of convergence or smoothing. We resolve this issue by stopping iterations of a least-squares iterative algorithm when r reaches the range of 0.5-1. This defines a pCT image reconstruction method with consistent statistical properties optimal for clinical use, including for treatment planning with pCT images.

Ionization detail parameters and cluster dose: a mathematical model for selection of nanodosimetric quantities for use in treatment planning in charged particle radiotherapy.

Objective. To propose a mathematical model for applying ionization detail (ID), the detailed spatial distribution of ionization along a particle track, to proton and ion beam radiotherapy treatment planning (RTP).Approach. Our model provides for selection of preferred ID parameters (Ip) for RTP, that associate closest to biological effects. Cluster dose is proposed to bridge the large gap between nanoscopicIpand macroscopic RTP. Selection ofIpis demonstrated using published cell survival measurements for protons through argon, comparing results for nineteenIp:Nk,k= 2, 3, …, 10, the number of ionizations in clusters ofkor more per particle, andFk,k= 1, 2, …, 10, the number of clusters ofkor more per particle. We then describe application of the model to ID-based RTP and propose a path to clinical translation.Main results. The preferredIpwereN4andF5for aerobic cells,N5andF7for hypoxic cells. Significant differences were found in cell survival for beams having the same LET or the preferredNk. Conversely, there was no significant difference forF5for aerobic cells andF7for hypoxic cells, regardless of ion beam atomic number or energy. Further, cells irradiated with the same cluster dose for theseIphad the same cell survival. Based on these preliminary results and other compelling results in nanodosimetry, it is reasonable to assert thatIpexist that are more closely associated with biological effects than current LET-based approaches and microdosimetric RBE-based models used in particle RTP. However, more biological variables such as cell line and cycle phase, as well as ion beam pulse structure and rate still need investigation.Significance. Our model provides a practical means to select preferredIpfrom radiobiological data, and to convertIpto the macroscopic cluster dose for particle RTP.

Single proton LET characterization with the Timepix detector and artificial intelligence for advanced proton therapy treatment planning.

Objective.Protons have advantageous dose distributions and are increasingly used in cancer therapy. At the depth of the Bragg peak range, protons produce a mixed radiation field consisting of low- and high-linear energy transfer (LET) components, the latter of which is characterized by an increased ionization density on the microscopic scale associated with increased biological effectiveness. Prediction of the yield and LET of primary and secondary charged particles at a certain depth in the patient is performed by Monte Carlo simulations but is difficult to verify experimentally.Approach.Here, the results of measurements performed with Timepix detector in the mixed radiation field produced by a therapeutic proton beam in water are presented and compared to Monte Carlo simulations. The unique capability of the detector to perform high-resolution single particle tracking and identification enhanced by artificial intelligence allowed to resolve the particle type and measure the deposited energy of each particle comprising the mixed radiation field. Based on the collected data, biologically important physics parameters, the LET of single protons and dose-averaged LET, were computed.Main results.An accuracy over 95% was achieved for proton recognition with a developed neural network model. For recognized protons, the measured LET spectra generally agree with the results of Monte Carlo simulations. The mean difference between dose-averaged LET values obtained from measurements and simulations is 17%. We observed a broad spectrum of LET values ranging from a fraction of keVµm-1to about 10 keVµm-1for most of the measurements performed in the mixed radiation fields.Significance.It has been demonstrated that the introduced measurement method provides experimental data for validation of LETDor LET spectra in any treatment planning system. The simplicity and accessibility of the presented methodology make it easy to be translated into a clinical routine in any proton therapy facility.

A likelihood-based particle imaging filter using prior information.

BACKGROUND: Particle imaging can increase precision in proton and ion therapy. Interactions with nuclei in the imaged object increase image noise and reduce image quality, especially for multinucleon ions that can fragment, such as helium. PURPOSE: This work proposes a particle imaging filter, referred to as the Prior Filter, based on using prior information in the form of an estimated relative stopping power (RSP) map and the principles of electromagnetic interaction, to identify particles that have undergone nuclear interaction. The particles identified as having undergone nuclear interactions are then excluded from the image reconstruction, reducing the image noise. METHODS: The Prior Filter uses Fermi-Eyges scattering and Tschalär straggling theories to determine the likelihood that a particle only interacts electromagnetically. A threshold is then set to reject those particles with a low likelihood. The filter was evaluated and compared with a filter that estimates this likelihood based on the measured distribution of energy and scattering angle within pixels, commonly implemented as the 3σ filter. Reconstructed radiographs from simulated data of a 20-cm water cylinder and an anthropomorphic chest phantom were generated with both protons and helium ions to assess the effect of the filters on noise reduction. The simulation also allowed assessment of secondary particle removal through the particle histories. Experimental data were acquired of the Catphan CTP 404 Sensitometry phantom using the U.S. proton CT (pCT) collaboration prototype scanner. The proton and helium images were filtered with both the prior filtering method and a state-of-the-art method including an implementation of the 3σ filter. For both cases, a dE-E telescope filter, designed for this type of detector, was also applied. RESULTS: The proton radiographs showed a small reduction in noise (1 mm of water-equivalent thickness [WET]) but a larger reduction in helium radiographs (up to 5-6 mm of WET) due to better secondary filtering. The proton and helium CT images reflected this, with similar noise at the center of the phantom (0.02 RSP) for the proton images and an RSP noise of 0.03 for the proposed filter and 0.06 for the 3σ filter in the helium images. Images reconstructed from data with a dose reduction, up to a factor of 9, maintained a lower noise level using the Prior Filter over the state-of-the-art filtering method. CONCLUSIONS: The proposed filter results in images with equal or reduced noise compared to those that have undergone a filtering method typical of current particle imaging studies. This work also demonstrates that the proposed filter maintains better performance against the state of the art with up to a nine-fold dose reduction.

Current status of the preclinical evaluation of alternating electric fields as a form of cancer therapy.

Exposing cancer cells to alternating electric fields of 100-300 kHz frequency and 1-4 V/cm strength has been shown to significantly reduce cancer growth in cell culture and in human patients. This form of anti-cancer therapy is more commonly referred to as tumor treating fields (TTFields), a novel treatment modality that has been approved by the U.S. Food and Drug Administration for use in patients with glioblastoma and malignant pleural mesothelioma. Pivotal trials in other solid organ cancer trials are underway. In regards to overall survival, TTFields alone is comparable to chemotherapy alone in recurrent glioblastoma. However, when combined with adjuvant chemotherapy, TTFields prolong median survival by 4.9 months in newly-diagnosed glioblastoma. TTFields hold promise as a therapeutic approach to numerous solid organ cancers. This review summarizes the current status of TTFields research at the preclinical level, highlighting recent aspects of a relatively complex working hypothesis. In addition, we point out the gaps between limited preclinical in vivo studies and the available clinical data. To date, no customized system for TTFields delivery in rodent models of glioblastoma has been presented. We aim to motivate the expansion of TTFields preclinical research and facilitate the availability of suitable hardware, to ultimately improve outcomes in patients with cancer.

Transformative Technology for FLASH Radiation Therapy.

The general concept of radiation therapy used in conventional cancer treatment is to increase the therapeutic index by creating a physical dose differential between tumors and normal tissues through precision dose targeting, image guidance, and radiation beams that deliver a radiation dose with high conformality, e.g., protons and ions. However, the treatment and cure are still limited by normal tissue radiation toxicity, with the corresponding side effects. A fundamentally different paradigm for increasing the therapeutic index of radiation therapy has emerged recently, supported by preclinical research, and based on the FLASH radiation effect. FLASH radiation therapy (FLASH-RT) is an ultra-high-dose-rate delivery of a therapeutic radiation dose within a fraction of a second. Experimental studies have shown that normal tissues seem to be universally spared at these high dose rates, whereas tumors are not. While dose delivery conditions to achieve a FLASH effect are not yet fully characterized, it is currently estimated that doses delivered in less than 200 ms produce normal-tissue-sparing effects, yet effectively kill tumor cells. Despite a great opportunity, there are many technical challenges for the accelerator community to create the required dose rates with novel compact accelerators to ensure the safe delivery of FLASH radiation beams.

Correction: Belchior et al. Repair Kinetics of DSB-Foci Induced by Proton and α-Particle Microbeams of Different Energies. Life 2022, 12, 2040.

In the original publication [...].

Repair Kinetics of DSB-Foci Induced by Proton and α-Particle Microbeams of Different Energies.

In this work, the induction and repair of radiation-induced 53BP1 foci were studied in human umbilical vein endothelial cells irradiated at the PTB microbeam with protons and α-particles of different energies. The data were analyzed in terms of the mean number of 53BP1 foci induced by the different ion beams. The number of 53BP1 foci found at different times post-irradiation suggests that the disappearance of foci follows first order kinetics. The mean number of initially produced foci shows the expected increase with LET. The most interesting finding of this work is that the absolute number of persistent foci increases with LET but not their fraction. Furthermore, protons seem to produce more persistent foci as compared to α-particles of even higher LET. This may be seen as experimental evidence that protons may be more effective in producing severe DNA lesions, as was already shown in other work, and that LET may not be the best suited parameter to characterize radiation quality.

Comparative accuracy and resolution assessment of two prototype proton computed tomography scanners.

BACKGROUND: Improving the accuracy of relative stopping power (RSP) in proton therapy may allow reducing range margins. Proton computed tomography (pCT) has been shown to provide state-of-the-art RSP accuracy estimation, and various scanner prototypes have recently been built. The different approaches used in scanner design are expected to impact spatial resolution and RSP accuracy. PURPOSE: The goal of this study was to perform the first direct comparison, in terms of spatial resolution and RSP accuracy, of two pCT prototype scanners installed at the same facility and by using the same image reconstruction algorithm. METHODS: A phantom containing cylindrical inserts of known RSP was scanned at the phase-II pCT prototype of the U.S. pCT collaboration and at the commercially oriented ProtonVDA scanner. Following distance-driven binning filtered backprojection reconstruction, the radial edge spread function of high-density inserts was used to estimate the spatial resolution. RSP accuracy was evaluated by the mean absolute percent error (MAPE) over the inserts. No direct imaging dose estimation was possible, which prevented a comparison of the two scanners in terms of RSP noise. RESULTS: In terms of RSP accuracy, both scanners achieved the same MAPE of 0.72% when excluding the porous sinus insert from the evaluation. The ProtonVDA scanner reached a better overall MAPE when all inserts and the body of the phantom were accounted for (0.81%), compared to the phase-II scanner (1.14%). The spatial resolution with the phase-II scanner was found to be 0.61 lp/mm, while for the ProtonVDA scanner somewhat lower at 0.46 lp/mm. CONCLUSIONS: The comparison between two prototype pCT scanners operated in the same clinical facility showed that they both fulfill the requirement of an RSP accuracy of about 1%. Their spatial resolution performance reflects the different design choices of either a scanner with full tracking capabilities (phase-II) or of a more compact tracker system, which only provides the positions of protons but not their directions (ProtonVDA).

A dose-volume constraint (DVC) projection-based algorithm for IMPT inverse planning optimization.

PURPOSE: Provide a projection-based algorithm to solve the class of optimization problems encountered in intensity modulated proton therapy (IMPT). The algorithm can handle percentage dose-volume constraints (DVCs) that are usually found in such problems. METHODS: To seek a feasible solution, the automatic relaxation method was used to project the spot weight vector onto the interval defined by lower and upper bound target dose constraints. The obtained solution was optimized separately based on the objective of each organ at risk (OAR) in addition to maximizing the minimum target dose using the bisection search method using a stopping criterion of 10 cGy. The combined weight was used in the CQ algorithm to solve the split feasibility problem but with a special projection technique due to the nonconvexity of DVCs. The algorithm was applied to four clinical IMPT cases (meningioma, prostate, tongue, and oropharynx) and compared to the corresponding treatment plans optimized in Eclipse. RESULTS: The treatment plans obtained, for the four cases, using the BCQ-ARM algorithm have dosimetric endpoints that are similar to their counterparts generated from Eclipse. The algorithm worked equally well with all cases, including the complex head and neck ones. The stopping criterion of 10 cGy results in making the generated plans slightly less optimal ( ε $\epsilon$ -optimal) rather than optimal, but with the advantage of the possibility of generating a database of plans. CONCLUSIONS: The application of the BCQ-ARM algorithm to different cases of IMPT plans with DVCs was demonstrated. The algorithm is successful in generating plans that are dosimetrically equivalent to their corresponding Eclipse plans. Thus, it is suitable to generate optimized treatment plans in a clinically reasonable time frame.

The role of Monte Carlo simulation in understanding the performance of proton computed tomography.

Proton computed tomography (pCT) is a promising tomographic imaging modality allowing direct reconstruction of proton relative stopping power (RSP) required for proton therapy dose calculation. In this review article, we aim at highlighting the role of Monte Carlo (MC) simulation in pCT studies. After describing the requirements for performing proton computed tomography and the various pCT scanners actively used in recent research projects, we present an overview of available MC simulation platforms. The use of MC simulations in the scope of investigations of image reconstruction, and for the evaluation of optimal RSP accuracy, precision and spatial resolution omitting detector effects is then described. In the final sections of the review article, we present specific applications of realistic MC simulations of an existing pCT scanner prototype, which we describe in detail.

Experimental comparison of photon versus particle computed tomography to predict tissue relative stopping powers.

PURPOSE: Measurements comparing relative stopping power (RSP) accuracy of state-of-the-art systems representing single-energy and dual-energy computed tomography (SECT/DECT) with proton CT (pCT) and helium CT (HeCT) in biological tissue samples. METHODS: We used 16 porcine and bovine samples of various tissue types and water, covering an RSP range from 0.90 ± 0.06 to 1.78 ± 0.05. Samples were packed and sealed into 3D-printed cylinders ( d = 2  cm, h = 5  cm) and inserted into an in-house designed cylindrical polymethyl methacrylate (PMMA) phantom ( d = 10  cm, h = 10  cm). We scanned the phantom in a commercial SECT and DECT (120 kV; 100  and 140 kV/Sn (tin-filtered)); and acquired pCT and HeCT ( E ∼ 200  MeV/u, 2 ∘ steps, ∼ 6.2 × 10 6 (p)/ ∼ 2.3 × 10 6 (He) particles/projection) with a particle imaging prototype. RSP maps were calculated from SECT/DECT using stoichiometric methods and from pCT/HeCT using the DROP-TVS algorithm. We estimated the average RSP of each tissue per modality in cylindrical volumes of interest and compared it to ground truth RSP taken from peak-detection measurements. RESULTS: Throughout all samples, we observe the following root-mean-squared RSP prediction errors ± combined uncertainty from reference measurement and imaging: SECT 3.10 ± 2.88%, DECT 0.75 ± 2.80%, pCT 1.19 ± 2.81%, and HeCT 0.78 ± 2.81%. The largest mean errors ± combined uncertainty per modality are SECT 8.22 ± 2.79% in cortical bone, DECT 1.74 ± 2.00% in back fat, pCT 1.80 ± 4.27% in bone marrow, and HeCT 1.37 ± 4.25% in bone marrow. Ring artifacts were observed in both pCT and HeCT reconstructions, imposing a systematic shift to predicted RSPs. CONCLUSION: Comparing state-of-the-art SECT/DECT technology and a pCT/HeCT prototype, DECT provided the most accurate RSP prediction, closely followed by particle imaging. The novel modalities pCT and HeCT have the potential to further improve on RSP accuracies with work focusing on the origin and correction of ring artifacts. Future work will study accuracy of proton treatment plans using RSP maps from investigated imaging modalities.

A comparison of proton stopping power measured with proton CT and x-ray CT in fresh postmortem porcine structures.

PURPOSE: Currently, calculations of proton range in proton therapy patients are based on a conversion of CT Hounsfield units of patient tissues into proton relative stopping power. Uncertainties in this conversion necessitate larger proximal and distal planned target volume margins. Proton CT can potentially reduce these uncertainties by directly measuring proton stopping power. We aim to demonstrate proton CT imaging with complex porcine samples, to analyze in detail three-dimensional regions of interest, and to compare proton stopping powers directly measured by proton CT to those determined from x-ray CT scans. METHODS: We have used a prototype proton imaging system with single proton tracking to acquire proton radiography and proton CT images of a sample of porcine pectoral girdle and ribs, and a pig's head. We also acquired close in time x-ray CT scans of the same samples and compared proton stopping power measurements from the two modalities. In the case of the pig's head, we obtained x-ray CT scans from two different scanners and compared results from high-dose and low-dose settings. RESULTS: Comparing our reconstructed proton CT images with images derived from x-ray CT scans, we find agreement within 1% to 2% for soft tissues and discrepancies of up to 6% for compact bone. We also observed large discrepancies, up to 40%, for cavitated regions with mixed content of air, soft tissue, and bone, such as sinus cavities or tympanic bullae. CONCLUSIONS: Our images and findings from a clinically realistic proton CT scanner demonstrate the potential for proton CT to be used for low-dose treatment planning with reduced margins.

Applications of nanodosimetry in particle therapy planning and beyond.

This topical review summarizes underlying concepts of nanodosimetry. It describes the development and current status of nanodosimetric detector technology. It also gives an overview of Monte Carlo track structure simulations that can provide nanodosimetric parameters for treatment planning of proton and ion therapy. Classical and modern radiobiological assays that can be used to demonstrate the relationship between the frequency and complexity of DNA lesion clusters and nanodosimetric parameters are reviewed. At the end of the review, existing approaches of treatment planning based on relative biological effectiveness (RBE) models or dose-averaged linear energy transfer are contrasted with an RBE-independent approach based on nandosimetric parameters. Beyond treatment planning, nanodosimetry is also expected to have applications and give new insights into radiation protection dosimetry.