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Particle therapy, with heavy ions such as carbon-12 (12 C), delivered to arrhythmogenic locations of the heart could be a promising new means for catheter-free ablation. As a first investigation, we tested the feasibility of in vivo atrioventricular node ablation, in Langendorff-perfused porcine hearts, using a scanned 12C beam. Methods and Results-Intact hearts were explanted from 4 (30-40 kg) pigs and were perfused in a Langendorff organ bath. Computed tomgraphic scans (1 mm voxel and slice spacing) were acquired and 12 C ion beam treatment planning (optimal accelerator energies, beam positions, and particle numbers) for atrioventricular node ablation was conducted. Orthogonal X-rays with matching of 4 implanted clips were used for positioning. Ten Gray treatment plans were repeatedly administered, using pencil beam scanning. After delivery, positron emission tomography-computed tomgraphic scans for detection of β + (11 C) activity were obtained. A 12 C beam with a full width at half maximum of 10 mm was delivered to the atrioventricular node. Delivery of 130 Gy caused disturbance of atrioventricular conduction with transition into complete heart block after 160 Gy. Positron emission computed tomgraphy demonstrated dose delivery into the intended area. Application did not induce arrhythmias. Macroscopic inspection did not reveal damage to myocardium. Immunostaining revealed strong γH2AX signals in the target region, whereas no γH2AX signals were detected in the unirradiated control heart. Conclusions-This is the first report of the application of a 12 C beam for ablation of cardiac tissue to treat arrhythmias. Catheter-free ablation using 12C beams is feasible and merits exploration in intact animal studies as an energy source for arrhythmia elimination.

Rationale ─ Accelerated carbon ions (12C) are rigorously accurate and effective in cancer radiation therapy. Objective ─ To ablate cardiac locations using a scanned 12C beam in an intact chronic sham-controlled large animal model. Methods and Results ─ Seventeen pigs were randomized to irradiation of atrioventricular junction (AVJ; 25, 40, and 55 Gy), left atrial right superior pulmonary vein junction (40 Gy), freewall LV (40 Gy), and sham-group. Electroanatomical (EA) mapping, fiducial-, and pacemaker implantation were performed. Cardiac gated CTs were obtained during breath-hold at expiration. Targets were contoured and case-specifically expanded for motion coverage. 12C was delivered using rescanned raster pencil-beams. Animals were followed for up to 6 months. Fourteen pigs (mean weight 33.8 ± 3.5 kg) were irradiated using a horizontal beam line. For AVJ a mean volume of 1.8 ± 0.1 cc was irradiated. For PVI and LV, mean volumes were 14.9 ± 1.8, and 2.4 ± 0.3 cc, respectively. Risk structures were spared. Animals stayed in sinus rhythm during irradiation. In-beam positron-emission-tomography confirmed precise 12C delivery. Complete atrioventricular block developed over the course of 4 months in 40 and 55 Gy animals. EA mapping confirmed an area without electrogram in the His-location. Histology revealed strong target fibrosis. Apoptosis was found as one of the mechanisms of cell death, being present after 3, but not 6 months. Conclusion ─ Accelerated 12C is a highly focused form of particle therapy that is a new means for precise cardiac arrhythmia elimination without any invasive procedural access to the body.

GSI Scientific Report 2014 - GSI Report 2015-1

GSI Scientific Report 2014 - GSI Report 2015-1

Heavy-ions beams offer several advantages compared to other radiation such as low lateral scattering and high biological effectiveness (RBE) in the Bragg peak region, making them particularly attractive for the treatment of radio-resistant tumours localized close to organs at risk [1]. The extension of ion therapy to new clinical cases requires the exploitation of a dedicated treatment planning system (TPS) based on the existing version of TRiP98 [2,3], established TPS for carbon ions. The theoretical models and experimental databases included in TRiP98 are presently mainly based on measurements in water. This approximation can be applied successfully to reproduce many biological tissues with the exception of bones, where the presence of heavy elements, like calcium, might change significantly the composition of the resulting mixed radiation field. Presently, the TriP98 physical beam model takes into account for the bone only its density variation, but it neglects difference between bones and water in attenuation of the primary and production of secondary particles through nuclear fragmentation. However, a detailed knowledge of the particle field at each point of the treatment area is crucial for an accurate estimate of the actual dose. A previous study [4] investigated the influence of different types of bone on the carbon particles range. In the present work we aim at understanding the influence of medium inhomogeneities on the 12C beam dose distribution. For the experiment, a bone target was placed inside a water phantom. The irradiation of the target volume positioned partially behind the bone target and partially directly in water was simulated with TRiP98 and the dose at the interface measured at several depths along the primary beam direction. Absolute dose measurements were achieved with a system of pin-point ionization chambers, while the relative dose distribution was investigated with two different solid states detectors: thermoluminescence detectors of type TLD-700 and alanine ESR pellets. The position of the target volume, the thickness and the type of bone were changed to investigate the influence of the inhomogeneity in different quasi-clinical scenarios. The experimental results were compared with the values predicted by TRiP98.

GSI Scientific Report 2013 - GSI Report 2014-1

GSI Scientific Report 2013 - GSI Report 2014-1

no abstract available

Aim: Due to the accessible sharp dose gradients, ion beam therapy is prone to uncertainties introduced by organ motion. Hence, in-vivo treatment verification is highly desirable. At the Heidelberg Ion-Beam Therapy Center, this is realised by comparing the irradiation-induced β+-activity within the patient, measured by a commercial full-ring PET/CT scanner installed next to the treatment site, with a corresponding Monte-Carlo (MC) simulation based on the treatment plan. While 3D PET-based treatment verification is used in clinical practice, the feasibility of 4D PET-based treatment monitoring, accounting for tumour motion during the irradiation and the subsequent PET, still needs to be demonstrated. Methods: PMMA phantoms of different geometries have been irradiated under stationary and moving conditions using a dedicated motion platform. Target movement has been monitored by a pressure sensor motion surrogate, enabling a 4D analysis of the ion beam delivery and the post-irradiation PET. Similarly, 4D datasets of the irradiation and the subsequent PET scans of patients with moving tumours have been collected. The acquired PET images were compared to activity distributions calculated within a dedicated 4D MC simulation framework. Results: It could be shown that, in the case of moving phantoms, motion induced blurring in the acquired offline PET data can significantly be reduced by a gated 4D PET reconstruction, yielding results comparable to static reference measurements and thus enable the verification of the actual beam delivery. The analysis of measured irradiation-induced activities within patients is however limited by the very low counting statistics, hindering a reliable verification of the applied treatment. Conclusion: First moving-phantom studies showed the feasibility of 4D offline PET-based treatment verification. For clinical cases the method is currently limited by the low level of the measured activity. Acknowledgement: FP7 EU project ENVISION

Noninvasive ablation of cardiac arrhythmia by scanned particle radiotherapy is highly promising, but especially challenging due to cardiac and respiratory motion. Irradiations for catheter-free ablation in intact pigs were carried out at the GSI Helmholtz Center in Darmstadt using scanned carbon ions. Here, we present real-time electrocardiogram (ECG) data to estimate time-resolved (4D) delivered dose. For 11 animals, surface ECGs and temporal structure of beam delivery were acquired during irradiation. R waves were automatically detected from surface ECGs. Pre-treatment ECG-triggered 4D-CT phases were synchronized to the R-R interval. 4D-dose calculation was performed using GSI's in-house 4D treatment planning system. Resulting dose distributions were assessed with respect to coverage (D95 and V95), heterogeneity (HI = D5-D95) and normal tissue exposure. Final results shown here were performed offline, but first calculations were started shortly after irradiation The D95 for TV and PTV was above 95% for 10 and 8 out of 11 animals, respectively. HI was reduced for PTV versus TV volumes, especially for some of the animals targeted at the atrioventricular junction, indicating residual interplay effects due to cardiac motion. Risk structure exposure was comparable to static and 4D treatment planning simulations. ECG-based 4D-dose reconstruction is technically feasible in a patient treatment-like setting. Further development of the presented approach, such as real-time dose calculation, may contribute to safe, successful treatments using scanned ion beams for cardiac arrhythmia ablation.

Purpose: To develop a simple model of therapeutic and stray absorbed dose for a variety of treatment machines and techniques without relying on proprietary machine-specific parameters. Methods: Dosimetry measurements conducted in this study and from the literature were used to develop an analytical model of absorbed dose from a variety of treatment machines and techniques in the 6 to 25 MV interval. A modified one-dimensional gamma-index analysis was performed to evaluate dosimetric accuracy of the model on an independent dataset consisting of measured dose profiles from seven treatment units spanning four manufacturers. Results: The average difference between the calculated and measured absorbed dose values was 9.9% for those datasets on which the model was trained. Additionally, these results indicate that the model can provide accurate calculations of both therapeutic and stray radiation dose from a wide variety of radiotherapy units and techniques. Conclusions: We have developed a simple analytical model of absorbed dose from external beam radiotherapy treatments in the 6 to 25 MV beam energy range. The model has been tested on measured data from multiple treatment machines and techniques, and is broadly applicable to contemporary external beam radiation therapy.

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.

Accurate dose delivery to extra-cranial lesions requires tumor motion compensation. An effective compensation can be achieved by real-time tracking of the target position, either measured in fluoroscopy or estimated through correlation models as a function of external surrogate motion. In this work, we integrated two internal/external correlation models (a state space model and an artificial neural network-based model) into a custom infra-red optical tracking system (OTS). Dedicated experiments were designed and conducted at GSI (Helmholtzzentrum für Schwerionenforschung). A robotic breathing phantom was used to reproduce regular and irregular internal target motion as well as external thorax motion. The position of a set of markers placed on the phantom thorax was measured with the OTS and used by the correlation models to infer the internal target position in real-time. Finally, the estimated target position was provided as input for the dynamic steering of a carbon ion beam. Geometric results showed that the correlation models transversal (2D) targeting error was always lower than 1.3 mm (root mean square). A significant decrease of the dosimetric error with respect to the uncompensated irradiation was achieved in four out of six experiments, demonstrating that phase shifts are the most critical irregularity for external/internal correlation models. © 2013 Institute of Physics and Engineering in Medicine.

Short- and long-term side effects following the treatment of cancer with radiation are strongly related to the amount of dose deposited to the healthy tissue surrounding the tumor. The characterization of the radiation field outside the planned target volume is the first step for estimating health risks, such as developing a secondary radioinduced malignancy. In ion and high-energy photon treatments, the major contribution to the dose deposited in the far-out-of-field region is given by neutrons, which are produced by nuclear interaction of the primary radiation with the beam line components and the patient's body. Measurements of the secondary neutron field and its contribution to the absorbed dose and equivalent dose for different radiotherapy technologies are presented in this work. An anthropomorphic RANDO phantom was irradiated with a treatment plan designed for a simulated 5 × 2 × 5 cm3 cancer volume located in the center of the head. The experiment was repeated with 25 MV IMRT (intensity modulated radiation therapy) photons and charged particles (protons and carbon ions) delivered with both passive modulation and spot scanning in different facilities. The measurements were performed with active (silicon-scintillation) and passive (bubble, thermoluminescence 6LiF:Mg, Ti (TLD-600) and 7LiF:Mg, Ti (TLD-700)) detectors to investigate the production of neutral particles both inside and outside the phantom. These techniques provided the whole energy spectrum (E 20 MeV) and corresponding absorbed dose and dose equivalent of photo neutrons produced by x-rays, the fluence of thermal neutrons for all irradiation types and the absorbed dose deposited by neutrons with 0.8 < E < 10 MeV during the treatment with scanned carbon ions. The highest yield of thermal neutrons is observed for photons and, among ions, for passively modulated beams. For the treatment with high-energy x-rays, the contribution of secondary neutrons to the dose equivalent is of the same order of magnitude as the primary radiation. In carbon therapy delivered with raster scanning, the absorbed dose deposited by neutrons in the energy region between 0.8 and 10 MeV is almost two orders of magnitude lower than charged fragments. We conclude that, within the energy range explored in this experimental work, the out-of-field dose from secondary neutrons is lowest for ions delivered by scanning, followed by passive modulation, and finally by high-energy IMRT photons. © 2014 Institute of Physics and Engineering in Medicine.

The integrated use of optical technologies for patient monitoring is addressed in the framework of time-resolved treatment delivery for scanned ion beam therapy. A software application has been designed to provide the therapy control system (TCS) with a continuous geometrical feedback by processing the external surrogates tridimensional data, detected in real-time via optical tracking. Conventional procedures for phase-based respiratory phase detection were implemented, as well as the interface to patient specific correlation models, in order to estimate internal tumor motion from surface markers. In this paper, particular attention is dedicated to the quantification of time delays resulting from system integration and its compensation by means of polynomial interpolation in the time domain. Dedicated tests to assess the separate delay contributions due to optical signal processing, digital data transfer to the TCS and passive beam energy modulation actuation have been performed. We report the system technological commissioning activities reporting dose distribution errors in a phantom study, where the treatment of a lung lesion was simulated, with both lateral and range beam position compensation. The zero-delay systems integration with a specific active scanning delivery machine was achieved by tuning the amount of time prediction applied to lateral (14.61 ± 0.98 ms) and depth (34.1 ± 6.29 ms) beam position correction signals, featuring sub-millimeter accuracy in forward estimation. Direct optical target observation and motion phase (MPh) based tumor motion discretization strategies were tested, resulting in 20.3(2.3)% and 21.2(9.3)% median (IQR) percentual relative dose difference with respect to static irradiation, respectively. Results confirm the technical feasibility of the implemented strategy towards 4D treatment delivery, with negligible percentual dose deviations with respect to static irradiation. © Adenine Press (2014).

Purpose: The use of motion mitigation techniques such as tracking and gating in particle therapy requires real-time knowledge of tumor position with millimeter precision. The aim of this phantom-based study was to evaluate the option of diagnostic ultrasound (US) imaging (sonography) as real-time motion detection method for scanned heavy ion beam irradiation of moving targets. Methods: For this pilot experiment, a tumor surrogate was moved inside a water bath along two-dimensional trajectories. A rubber ball was used for this purpose. This ball was moved by a robotic arm in two dimensions lateral to the heavy ion beam. Trajectories having a period of 3 s and peak to peak amplitude of 20 mm were used. Square radiation fields 3 × 3 cm2 were irradiated on radiosensitive films with a 200 MeV/u beam of calcium ions having a FWHM of 6 mm. Pencil beam scanning and beam tracking were employed. The films were attached on the robotic arm and thus moved with the rubber ball. The position of the rubber ball was continuously measured by a US tracking system (Mediri GmbH, Heidelberg) and sent to the GSI therapy control system (TCS). This position was used as tracking vector. Position reconstruction from the US tracking system and data communication introduced a delay leading to a position error of several millimeters. An artificial neural network (ANN) was implemented in the TCS to predict motion from US measurements and thus to compensate for the delay. Results: Using ANN delay compensation and large motion amplitudes, the authors could produce irradiation patterns with a few percent inhomogeneity and about 1 mm geometrical conformity. Conclusions: This pilot experiment suggests that diagnostic US should be further investigated as dose-free, high frame-rate, and model-independent motion detection method for scanning heavy ion beam irradiation of moving targets. © 2014 American Association of Physicists in Medicine.