Deep learning-based voxel sampling for particle therapy treatment planning.

OBJECTIVE: Scanned particle therapy often requires complex treatment plans, robust optimization, as well as treatment adaptation. Plan optimization is especially complicated for heavy ions due to the variable relative biological effectiveness. We present a novel deep-learning model to select a subset of voxels in the planning process thus reducing the planning problem size for improved computational efficiency. Approach: Using only a subset of the voxels in target and organs at risk (OARs) we produced high-quality treatment plans, but heuristic selection strategies require manual input. We designed a deep-learning model based on P-Net to obtain an optimal voxel sampling without relying on patient-specific user input. A cohort of 70 head and neck patients that received carbon ion therapy was used for model training (50), validation (10) and testing (10). For training, a total of 12,500 carbon ion plans were optimized, using a highly efficient artificial intelligence (AI) infrastructure implemented into a research treatment planning platform. A custom loss function increased sampling density in underdosed regions, while aiming to reduce the total number of voxels. Main results: On the test dataset, the number of voxels in the optimization could be reduced by 84.8% (median) at <1% median loss in plan quality. When the model was trained to reduce sampling in the target only while keeping all voxels in OARs, a median reduction up to 71.6% was achieved, with 0.5% loss in the plan quality. The optimization time was reduced by a factor of 7.5 for the total AI selection model and a factor of 3.7 for the model with only target selection. Significance: The novel deep-learning voxel sampling technique achieves a significant reduction in computational time with a negligible loss in the plan quality. The reduction in optimization time can be especially useful for future real-time adaptation strategies. .

Focus stacking single-event particle radiography for high spatial resolution images and 3D feature localization.

Objective.We demonstrate a novel focus stacking technique to improve spatial resolution of single-event particle radiography (pRad), and exploit its potential for 3D feature detection.Approach.Focus stacking, used typically in optical photography and microscopy, is a technique to combine multiple images with different focal depths into a single super-resolution image. Each pixel in the final image is chosen from the image with the largest gradient at that pixel's position. pRad data can be reconstructed at different depths in the patient based on an estimate of each particle's trajectory (called distance-driven binning; DDB). For a given feature, there is a depth of reconstruction for which the spatial resolution of DDB is maximal. Focus stacking can hence be applied to a series of DDB images reconstructed from a single pRad acquisition for different depths, yielding both a high-resolution projection and information on the features' radiological depth at the same time. We demonstrate this technique with Geant4 simulated pRads of a water phantom (20 cm thick) with five bone cube inserts at different depths (1 × 1 × 1 cm3) and a lung cancer patient.Main results.For proton radiography of the cube phantom, focus stacking achieved a median resolution improvement of 136% compared to a state-of-the-art maximum likelihood pRad reconstruction algorithm and a median of 28% compared to DDB where the reconstruction depth was the center of each cube. For the lung patient, resolution was visually improved, without loss in accuracy. The focus stacking method also enabled to estimate the depth of the cubes within few millimeters accuracy, except for one shallow cube, where the depth was underestimated by 2.5 cm.Significance.Focus stacking utilizes the inherent 3D information encoded in pRad by the particle's scattering, overcoming current spatial resolution limits. It further opens possibilities for 3D feature localization. Therefore, focus stacking holds great potential for future pRad applications.

Evaluation of proton and carbon ion beam models in TReatment Planning for Particles 4D (TRiP4D) referring to a commercial treatment planning system.

PURPOSE: To investigate the accuracy of the treatment planning system (TPS) TRiP4D in reproducing doses computed by the clinically used TPS SyngoRT. METHODS: Proton and carbon ion beam models in TRiP4D were converted from SyngoRT. Cubic plans with different depths in a water-tank phantom (WP) and previously treated and experimentally verified patient plans from SyngoRT were recalculated in TRiP4D. The target mean dose deviation (ΔDmean,T) and global gamma index (2%-2 mm for the absorbed dose and 3%-3mm for the RBE-weighted dose with 10% threshold) were evaluated. RESULTS: The carbon and proton absorbed dose gamma passing rates (γ-PRs) were ≥99.93% and ΔDmean,T smaller than -0.22%. On average, the RBE-weighted dose Dmean,T was -1.26% lower for TRiP4D than SyngoRT for cubic plans. In TRiP4D, the faster analytical 'low dose approximation' (Krämer, 2006) was used, while SyngoRT used a stochastic implementation (Krämer, 2000). The average ΔDmean, T could be reduced to -0.59% when applying the same biological effect calculation algorithm. However, the dose recalculation time increased by a factor of 79-477. ΔDmean,T variation up to -2.27% and -2.79% was observed for carbon absorbed and RBE-weighted doses in patient plans. The γ-PRs were ≥93.92% and ≥91.83% for patient plans, except for one proton beam with a range shifter (γ-PR of 64.19%). CONCLUSION: The absorbed dose between TRiP4D and SyngoRT were identical for both proton and carbon ion plans in the WP. Compared to SyngoRT, TRiP4D underestimated the target RBE-weighted dose; however more efficient in RBE-weighted dose calculation. Large variation for proton beam with range shifter was observed. TRiP4D will be used to evaluate doses delivered to moving targets. Uncertainties inherent to the 4D-dose reconstruction calculation are expected to be significantly larger than the dose errors reported here. For this reason, the residual differences between TRiP4D and SyngoRT observed in this study are considered acceptable. The study was approved by the Institutional Research Board of Shanghai Proton and Heavy Ion Center (approval number SPHIC-MP-2020-04, RS).

Emerging technologies for cancer therapy using accelerated particles.

Cancer therapy with accelerated charged particles is one of the most valuable biomedical applications of nuclear physics. The technology has vastly evolved in the past 50 years, the number of clinical centers is exponentially growing, and recent clinical results support the physics and radiobiology rationale that particles should be less toxic and more effective than conventional X-rays for many cancer patients. Charged particles are also the most mature technology for clinical translation of ultra-high dose rate (FLASH) radiotherapy. However, the fraction of patients treated with accelerated particles is still very small and the therapy is only applied to a few solid cancer indications. The growth of particle therapy strongly depends on technological innovations aiming to make the therapy cheaper, more conformal and faster. The most promising solutions to reach these goals are superconductive magnets to build compact accelerators; gantryless beam delivery; online image-guidance and adaptive therapy with the support of machine learning algorithms; and high-intensity accelerators coupled to online imaging. Large international collaborations are needed to hasten the clinical translation of the research results.

Experimental Validation of a Real-Time Adaptive 4D-Optimized Particle Radiotherapy Approach to Treat Irregularly Moving Tumors.

PURPOSE: Treatment of locally advanced lung cancer is limited by toxicity and insufficient local control. Particle therapy could enable more conformal treatment than intensity modulated photon therapy but is challenged by irregular tumor motion, associated range changes, and tumor deformations. We propose a new strategy for robust, online adaptive particle therapy, synergizing 4-dimensional optimization with real-time adaptive beam tracking. The strategy was tested and the required motion monitoring precision was determined. METHODS AND MATERIALS: In multiphase 4-dimensional dose delivery (MP4D), a dedicated quasistatic treatment plan is delivered to each motion phase of periodic 4-dimensional computed tomography (4DCT). In the new extension, "MP4D with residual tracking" (MP4DRT), lateral beam tracking compensates for the displacement of the tumor center-of-mass relative to the current phase in the planning 4DCT. We implemented this method in the dose delivery system of a clinical carbon facility and tested it experimentally for a lung cancer plan based on a periodic subset of a virtual lung 4DCT (planned motion amplitude 20 mm). Treatments were delivered in a quality assurance-like setting to a moving ionization chamber array. We considered variable motion amplitudes and baseline drifts. The required motion monitoring precision was evaluated by adding noise to the motion signal. Log-file-based dose reconstructions were performed in silico on the entire 4DCT phantom data set capable of simulating nonperiodic motion. MP4DRT was compared with MP4D, rescanned beam tracking, and internal target volume plans. Treatment quality was assessed in terms of target coverage (D95), dose homogeneity (D5-D95), conformity number, and dose to heart and lung. RESULTS: For all considered motion scenarios and metrics, MP4DRT produced the most favorable metrics among the tested motion mitigation strategies and delivered high-quality treatments. The conformity was similar to static treatments. The motion monitoring precision required for D95 >95% was 1.9 mm. CONCLUSIONS: With clinically feasible motion monitoring, MP4DRT can deliver highly conformal dose distributions to irregularly moving targets.

Potential benefits of using radioactive ion beams for range margin reduction in carbon ion therapy.

Sharp dose gradients and high biological effectiveness make ions such as 12C an ideal tool to treat deep-seated tumors, however, at the same time, sensitive to errors in the range prediction. Tumor safety margins mitigate these uncertainties, but during the irradiation they lead to unavoidable damage to the surrounding healthy tissue. To fully exploit the Bragg peak benefits, a large effort is put into establishing precise range verification methods. Despite positron emission tomography being widely in use for this purpose in 12C therapy, the low count rates, biological washout, and broad activity distribution still limit its precision. Instead, radioactive beams used directly for treatment would yield an improved signal and a closer match with the dose fall-off, potentially enabling precise in vivo beam range monitoring. We have performed a treatment planning study to estimate the possible impact of the reduced range uncertainties, enabled by radioactive 11C ions treatments, on sparing critical organs in tumor proximity. Compared to 12C treatments, (i) annihilation maps for 11C ions can reflect sub- millimeter shifts in dose distributions in the patient, (ii) outcomes of treatment planning with 11C significantly improve and (iii) less severe toxicities for serial and parallel critical organs can be expected.

Considerations for Upright Particle Therapy Patient Positioning and Associated Image Guidance.

Particle therapy is a rapidly growing field in cancer therapy. Worldwide, over 100 centers are in operation, and more are currently in construction phase. The interest in particle therapy is founded in the superior target dose conformity and healthy tissue sparing achievable through the particles' inverse depth dose profile. This physical advantage is, however, opposed by increased complexity and cost of particle therapy facilities. Particle therapy, especially with heavier ions, requires large and costly equipment to accelerate the particles to the desired treatment energy and steer the beam to the patient. A significant portion of the cost for a treatment facility is attributed to the gantry, used to enable different beam angles around the patient for optimal healthy tissue sparing. Instead of a gantry, a rotating chair positioning system paired with a fixed horizontal beam line presents a suitable cost-efficient alternative. Chair systems have been used already at the advent of particle therapy, but were soon dismissed due to increased setup uncertainty associated with the upright position stemming from the lack of dedicated image guidance systems. Recently, treatment chairs gained renewed interest due to the improvement in beam delivery, commercial availability of vertical patient CT imaging and improved image guidance systems to mitigate the problem of anatomical motion in seated treatments. In this review, economical and clinical reasons for an upright patient positioning system are discussed. Existing designs targeted for particle therapy are reviewed, and conclusions are drawn on the design and construction of chair systems and associated image guidance. Finally, the different aspects from literature are channeled into recommendations for potential upright treatment layouts, both for retrofitting and new facilities.

Clinical necessity of multi-image based (4DMIB) optimization for targets affected by respiratory motion and treated with scanned particle therapy - A comprehensive review.

4D multi-image-based (4DMIB) optimization is a form of robust optimization where different uncertainty scenarios, due to anatomy variations, are considered via multiple image sets (e.g., 4DCT). In this review, we focused on providing an overview of different 4DMIB optimization implementations, introduced various frameworks to evaluate the robustness of scanned particle therapy affected by breathing motion and summarized the existing evidence on the necessity of using 4DMIB optimization clinically. Expected potential benefits of 4DMIB optimization include more robust and/or interplay-effect-resistant doses for the target volume and organs-at-risk for indications affected by anatomical variations (e.g., breathing, peristalsis, etc.). Although considerable literature is available on the research and technical aspects of 4DMIB, clinical studies are rare and often contain methodological limitations, such as, limited patient number, motion amplitude, motion and delivery time structure considerations, number of repeat CTs, etc. Therefore, the data are not conclusive. In addition, multiple studies have found that robust 3D optimized plans result in dose distributions within the set clinical tolerances and, therefore, are suitable for a treatment of moving targets with scanned particle therapy. We, therefore, consider the clinical necessity of 4DMIB optimization, when treating moving targets with scanned particle therapy, as still to be demonstrated.

Preliminary tests of dosimetric quality and projected therapeutic outcomes of multi-phase 4D radiotherapy with proton and carbon ion beams.

Objective. The purpose of this study was to perform preliminary pre-clinical tests to compare the dosimetric quality of two approaches to treating moving tumors with ion beams: synchronously delivering the beam with the motion of a moving planning target volume (PTV) using the recently developed multi-phase 4D dose delivery (MP4D) approach, and asynchronously delivering the ion beam to a motion-encompassing internal tumor volume (ITV) combined with rescanning.Approach. We created 4D optimized treatment plans with proton and carbon ion beams for two patients who had previously received treatment for non-small cell lung cancer. For each patient, we created several treatment plans, using approaches with and without motion mitigation: MP4D, ITV with rescanning, static deliveries to a stationary PTV, and deliveries to a moving tumor without motion compensation. Two sets of plans were optimized with margins or robust uncertainty scenarios. Each treatment plan was delivered using a recently-developed motion-synchronized dose delivery system (M-DDS); dose distributions in water were compared to measurements using gamma index analysis to confirm the accuracy of the calculations. Reconstructed dose distributions on the patient CT were analyzed to assess the dosimetric quality of the deliveries (conformity, uniformity, tumor coverage, and extent of hotspots).Main results. Gamma index analysis pass rates confirmed the accuracy of dose calculations. Dose coverage was >95% for all static and MP4D treatments. The best conformity and the lowest lung doses were achieved with MP4D deliveries. Robust optimization led to higher lung doses compared to conventional optimization for ITV deliveries, but not for MP4D deliveries.Significance. We compared dosimetric quality for two approaches to treating moving tumors with ion beams. Our findings suggest that the MP4D approach, using an M-DDS, provides conformal motion mitigation, with full target coverage and lower OAR doses.

Compensating for beam modulation due to microscopic lung heterogeneities in carbon ion therapy treatment planning.

PURPOSE: To predict and mitigate for the degradation in physical and biologically effective dose distributions of particle beams caused by microscopic heterogeneities in lung tissue. MATERIALS AND METHODS: The TRiP98 treatment planning system was adapted to account for the beam-modulating effect of heterogeneous lung tissue in physical and biological inverse treatment planning. The implementation employs an analytical model that derives the degradation from the established "modulation power" parameter P mod and the total water-equivalent thickness of lung parenchyma traversed by the beam. Beam modulation was reproduced through an on-the-fly convolution of the reference Bragg curve with Gaussian kernels depending on the modulation power of lung tissue (upstream). For biological doses, the degradation was determined by modulating dose-averaged α , ß , and LET distributions. Carbon SOBP measurements behind lung substitute material were performed to validate the code. The implementation was then applied to a phantom and patient case. RESULTS: Experimental results show the passage through a 20-cm Gammex LN300 slab led to a decrease in target coverage and broadening of the SOBP distal fall-off. However, dose coverage was regained through optimization. A good agreement between calculated and measured SOBPs was also found. In addition, a patient case study revealed a 3.2% decrease in D 95 from degradation ( P mod = 450 µ m), which was reduced to a 0.4% difference after optimization. Furthermore, widening of the RBE distribution beyond the target distal edge was observed. This implies an increased degradation in the biological dose, which could be harmful to healthy tissues distal to the target. CONCLUSIONS: This is the first implementation capable of compensating for lung dose perturbations, which is more effective than margin extensions. A larger patient study is needed to examine the observed modulation in the RBE distribution and judge the clinical relevance also in IMPT, where margins might prove insufficient to recover target coverage.

Extension of RBE-weighted 4D particle dose calculation for non-periodic motion.

PURPOSE: Highly conformal scanned Carbon Ion Radiotherapy (CIRT) might permit dose escalation and improved local control in advanced stage thoracic tumors, but is challenged by target motion. Dose calculation algorithms typically assume a periodically repeating, regular motion. To assess the effect of realistic, irregular motion, new algorithms of validated accuracy are needed. METHODS: We extended an in-house treatment planning system to calculate RBE-weighted dose distributions in CIRT on non-periodic CT image sequences. Dosimetric accuracy was validated experimentally on a moving, time-resolved ionization chamber array. Log-file based dose reconstructions were compared by gamma analysis and correlation to measurements at every intermediate detector frame during delivery. The impact of irregular motion on treatment quality was simulated on a virtual 4DCT thorax phantom. Periodic motion was compared to motion with varying amplitude and period ± baseline drift. Rescanning as a mitigation strategy was assessed on all scenarios. RESULTS: In experimental validation, average gamma pass rates were 99.89+-0.30% for 3%/3 mm and 88.2+-2.2% for 2%/2 mm criteria. Average correlation for integral dose distributions was 0.990±0.002. Median correlation for single 200 ms frames was 0.947±0.006. In the simulations, irregular motion deteriorated V95 target coverage to 81.2%, 76.6% and 79.0% for regular, irregular motion and irregular motion with base-line drift, respectively. Rescanning restored V95 to >98% for both scenarios without baseline drift, but not with additional baseline drift at 83.7%. CONCLUSIONS: The validated algorithm permits to study the effects of irregular motion and to develop and adapt appropriate motion mitigation techniques.

Dosimetric Validation of a System to Treat Moving Tumors Using Scanned Ion Beams That Are Synchronized With Anatomical Motion.

PURPOSE: The purpose of this study was to validate the dosimetric performance of scanned ion beam deliveries with motion-synchronization to heterogenous targets. METHODS: A 4D library of treatment plans, comprised of up to 10 3D sub-plans, was created with robust and conventional 4D optimization methods. Each sub-plan corresponded to one phase of periodic target motion. The plan libraries were delivered to a test phantom, comprising plastic slabs, dosimeters, and heterogenous phantoms. This phantom emulated range changes that occur when treating moving tumors. Similar treatment plans, but without motion synchronization, were also delivered to a test phantom with a stationary target and to a moving target; these were used to assess how the target motion degrades the quality of dose distributions and the extent to which motion synchronization can improve dosimetric quality. The accuracy of calculated dose distributions was verified by comparison with corresponding measurements. Comparisons utilized the gamma index analysis method. Plan quality was assessed based on conformity, dose coverage, overdose, and homogeneity values, each extracted from calculated dose distributions. RESULTS: High pass rates for the gamma index analysis confirmed that the methods used to calculate and reconstruct dose distributions were sufficiently accurate for the purposes of this study. Calculated and reconstructed dose distributions revealed that the motion-synchronized and static deliveries exhibited similar quality in terms of dose coverage, overdose, and homogeneity for all deliveries considered. Motion-synchronization substantially improved conformity in deliveries with moving targets. Importantly, measurements at multiple locations within the target also confirmed that the motion-synchronized delivery system satisfactorily compensated for changes in beam range caused by the phantom motion. Specifically, the overall planning and delivery approach achieved the desired dose distribution by avoiding range undershoots and overshoots caused by tumor motion. CONCLUSIONS: We validated a dose delivery system that synchronizes the movement of the ion beam to that of a moving target in a test phantom. Measured and calculated dose distributions revealed that this system satisfactorily compensated for target motion in the presence of beam range changes due to target motion. The implication of this finding is that the prototype system is suitable for additional preclinical research studies, such as irregular anatomic motion.

Radioactive Beams for Image-Guided Particle Therapy: The BARB Experiment at GSI.

Several techniques are under development for image-guidance in particle therapy. Positron (ß+) emission tomography (PET) is in use since many years, because accelerated ions generate positron-emitting isotopes by nuclear fragmentation in the human body. In heavy ion therapy, a major part of the PET signals is produced by ß+-emitters generated via projectile fragmentation. A much higher intensity for the PET signal can be obtained using ß+-radioactive beams directly for treatment. This idea has always been hampered by the low intensity of the secondary beams, produced by fragmentation of the primary, stable beams. With the intensity upgrade of the SIS-18 synchrotron and the isotopic separation with the fragment separator FRS in the FAIR-phase-0 in Darmstadt, it is now possible to reach radioactive ion beams with sufficient intensity to treat a tumor in small animals. This was the motivation of the BARB (Biomedical Applications of Radioactive ion Beams) experiment that is ongoing at GSI in Darmstadt. This paper will present the plans and instruments developed by the BARB collaboration for testing the use of radioactive beams in cancer therapy.

A Modular System for Treating Moving Anatomical Targets With Scanned Ion Beams at Multiple Facilities: Pre-Clinical Testing for Quality and Safety of Beam Delivery.

BACKGROUND: Quality management and safety are integral to modern radiotherapy. New radiotherapy technologies require new consensus guidelines on quality and safety. Established analysis strategies, such as the failure modes and effects analysis (FMEA) and incident learning systems have been developed as tools to assess the safety of several types of radiation therapies. An extensive literature documents the widespread application of risk analysis methods to photon radiation therapy. Relatively little attention has been paid to performing risk analyses of nascent radiation therapy systems to treat moving tumors with scanned heavy ion beams. The purpose of this study was to apply a comprehensive safety analysis strategy to a motion-synchronized dose delivery system (M-DDS) for ion therapy. METHODS: We applied a risk analysis method to new treatment planning and treatment delivery processes with scanned heavy ion beams. The processes utilize a prototype, modular dose delivery system, currently undergoing preclinical testing, that provides new capabilities for treating moving anatomy. Each step in the treatment process was listed in a process map, potential errors for each step were identified and scored using the risk probability number in an FMEA, and the possible causes of each error were described in a fault tree analysis. Solutions were identified to mitigate the risk of these errors, including permanent corrective actions, periodic quality assurance (QA) tests, and patient specific QA (PSQA) tests. Each solution was tested experimentally. RESULTS: The analysis revealed 58 potential errors that could compromise beam delivery quality or safety. Each of the 14 binary (pass-or-fail) tests passed. Each of the nine QA and four PSQA tests were within anticipated clinical specifications. The modular M-DDS was modified accordingly, and was found to function at two centers. CONCLUSION: We have applied a comprehensive risk analysis strategy to the M-DDS and shown that it is a clinically viable motion mitigation strategy. The described strategy can be utilized at any ion therapy center that operates with the modular M-DDS. The approach can also be adapted for use at other facilities and can be combined with existing safety analysis systems.

Biomedical Research Programs at Present and Future High-Energy Particle Accelerators.

Biomedical applications at high-energy particle accelerators have always been an important section of the applied nuclear physics research. Several new facilities are now under constructions or undergoing major upgrades. While the main goal of these facilities is often basic research in nuclear physics, they acknowledge the importance of including biomedical research programs and of interacting with other medical accelerator facilities providing patient treatments. To harmonize the programs, avoid duplications, and foster collaboration and synergism, the International Biophysics Collaboration is providing a platform to several accelerator centers with interest in biomedical research. In this paper, we summarize the programs of various facilities in the running, upgrade, or construction phase.

A modular dose delivery system for treating moving targets with scanned ion beams: Performance and safety characteristics, and preliminary tests.

PURPOSE: The purpose of this study was to develop a modular dose-delivery system (DDS) for scanned-ion radiotherapy that mitigates against organ motion artifacts by synchronizing the motion of the beam with that of the moving anatomy. METHODS: We integrated a new motion synchronization system and an existing DDS into two centers. The modular approach to integration utilized an adaptive layer of software and hardware interfaces. The method of synchronization comprised three major tasks, namely, the creation of 3D treatment plans (each representing one phase of respiratory motion and together comprising a 4D plan), monitoring anatomic motion during treatment, and synchronization of the beam to anatomic motion. The synchronization was accomplished in real time by repeatedly selecting and delivering a 3D plan, i.e., the one that most closely corresponded to the current anatomic state, until all plans were delivered. The performance characteristics of the motion mitigation system were tested by delivering 4D treatment plans to a moving phantom and comparing planned and measured dose distributions. Dosimetric performance was considered acceptable when the gamma-index pass rate was >90%, homogeneity-index value was >95%, and conformity-index value was >60%. Selected safety characteristics were tested by introducing errors during treatment and testing DDS response. RESULTS: Acceptable dosimetric performance and safety characteristics were observed for all treatment plans. CONCLUSIONS: We demonstrated, for the first time, that a modular prototype system, synchronizing scanned ion beams with moving targets can deliver conformal, motion-compensated dose distributions. The prototype system was implemented and characterized at GSI and CNAO.

Biological Cardiac Tissue Effects of High-Energy Heavy Ions - Investigation for Myocardial Ablation.

Noninvasive X-ray stereotactic treatment is considered a promising alternative to catheter ablation in patients affected by severe heart arrhythmia. High-energy heavy ions can deliver high radiation doses in small targets with reduced damage to the normal tissue compared to conventional X-rays. For this reason, charged particle therapy, widely used in oncology, can be a powerful tool for radiosurgery in cardiac diseases. We have recently performed a feasibility study in a swine model using high doses of high-energy C-ions to target specific cardiac structures. Interruption of cardiac conduction was observed in some animals. Here we report the biological effects measured in the pig heart tissue of the same animals six months after the treatment. Immunohistological analysis of the target tissue showed (1.) long-lasting vascular damage, i.e. persistent hemorrhage, loss of microvessels, and occurrence of siderophages, (2.) fibrosis and (3.) loss of polarity of targeted cardiomyocytes and wavy fibers with vacuolization. We conclude that the observed physiological changes in heart function are produced by radiation-induced fibrosis and cardiomyocyte functional inactivation. No effects were observed in the normal tissue traversed by the particle beam, suggesting that charged particles have the potential to produce ablation of specific heart targets with minimal side effects.

Noninvasive cardiac arrhythmia ablation with particle beams.

Cardiac arrhythmias are a major health burden, associated with reduced quality of life and substantial morbidity and mortality. Current therapy includes moderately effective medication and catheter-based ablation of arrhythmogenic substrates in the heart. Catheter interventions frequently have to be repeated due to recurrent arrhythmia, can have rare but severe side-effects and are less suited especially for potentially lethal left ventricular tachycardia. Noninvasive alternatives are therefore warranted. Photon and ion beam radiotherapy has been studied in animal models and first patient cases have been reported using photons. Ion beams might offer the possibility to greatly reduce dose to surrounding healthy tissue, including critical cardiac substructures. Based on a recently conducted animal study, we report advantages and disadvantages of 4D-ion beam therapy, and strategies necessary for a clinical transition. Motion management of both respiration and heartbeat are discussed, as well as range uncertainty resulting from both regular motion and interfractional anatomic changes. Image guidance both in 3D and 4D has to be employed for a safe irradiation, but also population-based data on motion variability and time behavior of interfractional changes are necessary. Range verification could play a crucial role at least during development of clinical protocols. For clinical realization, it appears necessary to suppress or conformally mitigate the large respiratory motion to avoid normal tissue complications. Cardiac motion has to be incorporated into treatment planning, either through adequate range-considering internal margins or through more conformal strategies such as ECG-based gating or even 4D-optimization. The latter strategies would necessitate online 4D image guidance.

Treatment planning with intensity modulated particle therapy for multiple targets in stage IV non-small cell lung cancer.

Intensity modulated particle therapy (IMPT) can produce highly conformal plans, but is limited in advanced lung cancer patients with multiple lesions due to motion and planning complexity. A 4D IMPT optimization including all motion states was expanded to include multiple targets, where each target (isocenter) is designated to specific field(s). Furthermore, to achieve stereotactic treatment planning objectives, target and OAR weights plus objective doses were automatically iteratively adapted. Finally, 4D doses were calculated for different motion scenarios. The results from our algorithm were compared to clinical stereotactic body radiation treatment (SBRT) plans. The study included eight patients with 24 lesions in total. Intended dose regimen for SBRT was 24 Gy in one fraction, but lower fractionated doses had to be delivered in three cases due to OAR constraints or failed plan quality assurance. The resulting IMPT treatment plans had no significant difference in target coverage compared to SBRT treatment plans. Average maximum point dose and dose to specific volume in OARs were on average 65% and 22% smaller with IMPT. IMPT could also deliver 24 Gy in one fraction in a patient where SBRT was limited due to the OAR vicinity. The developed algorithm shows the potential of IMPT in treatment of multiple moving targets in a complex geometry.

Immobilization for carbon ion beam ablation of cardiac structures in a porcine model.

INTRODUCTION: Whereas hadron therapy of static targets is clinically established, treatment of moving organs remains a challenge. One strategy is to minimize motion of surrounding tissue mechanically and to mitigate residual motion with an appropriate irradiation technique. In this technical note, we present and characterize such an immobilization technique for a novel noncancerous application: the irradiation of small targets in hearts with scanned carbon ion beams in a porcine model for elimination of arrhythmias. MATERIAL AND METHODS: A device for immobilization was custom-built. Both for the treatment planning 4D-CT scan and for irradiation, breath-hold at end-exhale was enforced using a remotely-controlled respirator. Target motion was thus reduced to heartbeat only. Positioning was verified by orthogonal X-rays followed by couch shift if necessary. Reproducibility of bony anatomy, diaphragm, and heart position after repositioning and between repeated breath-hold maneuvers was evaluated on X-rays and cardiac-gated 4D-CTs. Treatment was post hoc simulated on sequential 4D-CTs for a subset of animals, after immediate repositioning and after a delay of one week, similar to the delay between imaging and irradiation. RESULTS: Breath-hold without repositioning was highly reproducible with an RMS deviation of at most one millimeter. 4D-CTs showed larger deformations in soft tissue, but treatment simulation on sequential images resulted in full target coverage (V95 >95%). CONCLUSION: The method of immobilization permitted reproducible positioning of mobile, thoracic targets for range-sensitive particle therapy. The presented immobilization strategy could be a reasonable approach for future animal investigations with the ultimate goal of translation to therapy in men.