Robert Kaderka

Helium ions for radiotherapy? Physical and biological verifications of a novel treatment modality

PURPOSE Modern facilities for actively scanned ion beam radiotherapy allow in principle the use of helium beams, which could present specific advantages, especially for pediatric tumors. In order to assess the potential use of these beams for radiotherapy, i.e., to create realistic treatment plans, the authors set up a dedicated (4)He beam model, providing base data for their treatment planning system TRiP98, and they have reported that in this work together with its physical and biological validations. METHODS A semiempirical beam model for the physical depth dose deposition and the production of nuclear fragments was developed and introduced in TRiP98. For the biological effect calculations the last version of the local effect model was used. The model predictions were experimentally verified at the HIT facility. The primary beam attenuation and the characteristics of secondary charged particles at various depth in water were investigated using (4)He ion beams of 200 MeV/u. The nuclear charge of secondary fragments was identified using a ΔE/E telescope. 3D absorbed dose distributions were measured with pin point ionization chambers and the biological dosimetry experiments were realized irradiating a Chinese hamster ovary cells stack arranged in an extended target. RESULTS The few experimental data available on basic physical processes are reproduced by their beam model. The experimental verification of absorbed dose distributions in extended target volumes yields an overall agreement, with a slight underestimation of the lateral spread. Cell survival along a 4 cm extended target is reproduced with remarkable accuracy. CONCLUSIONS The authors presented a simple simulation model for therapeutical (4)He beams which they introduced in TRiP98, and which is validated experimentally by means of physical and biological dosimetries. Thus, it is now possible to perform detailed treatment planning studies with (4)He beams, either exclusively or in combination with other ion modalities.

Ultrasound tracking for intra-fractional motion compensation in radiation therapy.

Modern techniques as ion beam therapy or 4D imaging require precise target position information. However, target motion particularly in the abdomen due to respiration or patient movement is still a challenge and demands methods that detect and compensate this motion. Ultrasound represents a non-invasive, dose-free and model-independent alternative to fluoroscopy, respiration belt or optical tracking of the patient surface. Thus, ultrasound based motion tracking was integrated into irradiation with actively scanned heavy ions. In a first in vitro experiment, the ultrasound tracking system was used to compensate diverse sinusoidal target motions in two dimensions. A time delay of ∼200 ms between target motion and reported position data was compensated by a prediction algorithm (artificial neural network). The irradiated films proved feasibility of the proposed method. Furthermore, a practicable and reliable calibration workflow was developed to enable the transformation of ultrasound tracking data to the coordinates of the treatment delivery or imaging system - even if the ultrasound probe moves due to respiration. A first proof of principle experiment was performed during time-resolved positron emission tomography (4DPET) to test the calibration workflow and to show the accuracy of an ultrasound based motion tracking in vitro. The results showed that optical ultrasound tracking can reach acceptable accuracies and encourage further research.

Characterization of the secondary neutron field produced during treatment of an anthropomorphic phantom with x-rays, protons and carbon ions.

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 patients 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.

Out-of-field dose studies with an anthropomorphic phantom: Comparison of X-rays and particle therapy treatments

BACKGROUND AND PURPOSE Characterization of the out-of-field dose profile following irradiation of the target with a 3D treatment plan delivered with modern techniques. METHODS An anthropomorphic RANDO phantom was irradiated with a treatment plan designed for a simulated 5 × 2 × 5 cm(3) tumor volume located in the center of the head. The experiment was repeated with all most common radiation treatment types (photons, protons and carbon ions) and delivery techniques (Intensity Modulated Radiation Therapy, passive modulation and spot scanning). The measurements were performed with active diamond detector and passive thermoluminescence (TLD) detectors to investigate the out-of-field dose both inside and outside the phantom. RESULTS The highest out-of-field dose values both on the surface and inside the phantom were measured during the treatment with 25 MV photons. In the proximity of the Planned Target Volume (PTV), the lowest lateral dose profile was observed for passively modulated protons mainly because of the presence of the collimator in combination with the chosen volume shape. In the far out-of-field region (above 100mm from the PTV), passively modulated ions were characterized by a less pronounced dose fall-off in comparison with scanned beams. Overall, the treatment with scanned carbon ions delivered the lowest dose outside the target volume. CONCLUSIONS For the selected PTV, the use of the collimator in proton therapy drastically reduced the dose deposited by ions or photons nearby the tumor. Scanning modulation represents the optimal technique for achieving the highest dose reduction far-out-of-field.

Ion beam tracking using ultrasound motion detection

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 of[Formula: see text] 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.

Atrioventricular Node Ablation in Langendorff-Perfused Porcine Hearts Using Carbon Ion Particle Therapy

Background—Particle therapy, with heavy ions such as carbon-12 (12C), 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 12C 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 &bgr;+ (11C) activity were obtained. A 12C 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 &ggr;H2AX signals in the target region, whereas no &ggr;H2AX signals were detected in the unirradiated control heart. Conclusions—This is the first report of the application of a 12C 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.

Feasibility Study on Cardiac Arrhythmia Ablation Using High-Energy Heavy Ion Beams

High-energy ion beams are successfully used in cancer therapy and precisely deliver high doses of ionizing radiation to small deep-seated target volumes. A similar noninvasive treatment modality for cardiac arrhythmias was tested here. This study used high-energy carbon ions for ablation of cardiac tissue in pigs. Doses of 25, 40, and 55 Gy were applied in forced-breath-hold to the atrioventricular junction, left atrial pulmonary vein junction, and freewall left ventricle of intact animals. Procedural success was tracked by (1.) in-beam positron-emission tomography (PET) imaging; (2.) intracardiac voltage mapping with visible lesion on ultrasound; (3.) lesion outcomes in pathohistolgy. High doses (40–55 Gy) caused slowing and interruption of cardiac impulse propagation. Target fibrosis was the main mediator of the ablation effect. In irradiated tissue, apoptosis was present after 3, but not 6 months. Our study shows feasibility to use high-energy ion beams for creation of cardiac lesions that chronically interrupt cardiac conduction.

A descriptive and broadly applicable model of therapeutic and stray absorbed dose from 6 to 25 MV photon beams

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.

Treatment of arrhythmias by external charged particle beams: a Langendorff feasibility study.

Abstract Hadron therapy has already proven to be successful in cancer therapy, and might be a noninvasive alternative for the ablation of cardiac arrhythmias in humans. We present a pilot experiment investigating acute effects of a 12C irradiation on the AV nodes of porcine hearts in a Langendorff setup. This setup was adapted to the requirements of charged particle therapy. Treatment plans were computed on calibrated CTs of the hearts. Irradiation was applied in units of 5 and 10 Gy over a period of about 3 h until a total dose of up to 160 Gy was reached. Repeated application of the same irradiation field helped to mitigate motion artifacts in the resulting dose distribution. After irradiation, PET scans were performed to verify accurate dose application. Acute AV blocks were identified. No other acute effects were observed. Hearts were kept in sinus rhythm for up to 6 h in the Langendorff setup. We demonstrated that 12C ions can be used to select a small target in the heart and, thereby, influence the electrical conduction system. Second, our pilot study seems to suggest that no adverse effects have to be expected immediately during heavy ion irradiation in performing subsequent experiments with doses of 30–60 Gy and intact pigs.

ECG-based 4D-dose reconstruction of cardiac arrhythmia ablation with carbon ion beams: application in a porcine model

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 GSIs 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.