Research Facility for Radiobiological Studies at the University Proton Therapy Dresden.

PURPOSE: In order to take full advantage of proton radiotherapy, the biological effect of protons in normal and tumor tissue should be investigated and understood in detail. The ongoing discussion on variable relative biological effectiveness along the proton depth dose distribution (eg, Paganetti 2015), and also the administration of concomitant treatments, demands dedicated in vitro trials that prepare the translation into the clinics. Therefore, a setup for radiobiological studies and the corresponding dosimetry should be established that enables in vitro experiments at a horizontal proton beam and a clinical 6 MV photon linear accelerator (Linac) as reference. METHODS: The experimental proton beam at the University Proton Therapy Dresden is characterized by high beam availability and reliability throughout the day in parallel to patient treatment. For cell irradiation, a homogeneous 10 × 10 cm2 proton field with an optional spread-out Bragg-peak can be formed. A water-filled phantom was installed that allows for precise positioning of different sample geometries along the proton path. RESULTS: Depth-dose profiles within the phantom and dose homogeneity over different cell samples were characterized for the proton beam and the photon reference source. A daily quality assurance protocol was implemented that provides absolute dose information required for significant and reproducible in vitro experiments. Cell survival test experiments were performed to demonstrate the feasibility of such experiments. CONCLUSION: In the experimental room of the University Proton Therapy Dresden, clinically relevant conditions for proton in vitro experiments have been realized. The established cell phantom and dosimetry facilitate irradiation in an aqueous environment and are transferable to other proton, photon and ion beam facilities. Precise positioning and easy exchange of cell samples, monitor unit-based dose delivery, and high beam availability allow for systematic in vitro experiments. The close vicinity to the radiotherapy and radiobiology departments provides access to clinical linacs and the interdisciplinary basis for further translational steps.

Modeling in vivo relative biological effectiveness in particle therapy for clinically relevant endpoints.

BACKGROUND: The relative biological effectiveness (RBE) of particle therapy compared to photon radiotherapy is known to be variable but the exact dependencies are still subject to debate. In vitro data suggested that RBE is to a large extend independent of ion type if parametrized by the beam quality Q. This study analyzed the RBE dependence of pre-clinical data on late toxicity with an emphasis on the beam quality. MATERIAL AND METHODS: Published pre-clinical RBE dose-response data of the spinal cord following one and two fractions of photon and carbon ion irradiation were compiled. The beam quality for each treatment condition was obtained from Monte Carlo simulations. The αp and ßp parameters of the linear-quadratic (LQ) model for particle irradiation were determined from the pre-clinical data and was provided as a function of Q. An introduced model proposed αp to increase linearly with Q and ßp to remain constant. RBE values predicted by the model were compared to the published data. RESULTS: The αp parameter was highly correlated with Q (R2 = 0.96) with a linear slope of 0.019 Gy-1. No significant variation of ßp with Q was found. RBE and Q were also highly correlated (R2 = 0.98) for one and two fractions. The (extrapolated) RBE at Q = 0 (theoretical photon limit) for one and two fractions was 1.22 and significantly larger than 1 (p = .004). The model reproduced the dependence of RBE on fractionation well. CONCLUSIONS: Fraction dose and beam quality Q were sufficient to describe the RBE variability for a late toxicity model within a carbon ion treatment field. Assuming the independence of the identified RBE parameters on the ion type might suggest the translation of variable (pre-) clinical RBE data from carbon ion to proton therapy.

In-beam PET at clinical proton beams with pile-up rejection.

Positron emission tomography (PET) is a means of imaging the ß+-activity produced by the radiation field in ion beam therapy and therefore for treatment verification. Prompt γ-rays that are emitted during beam application challenge the detectors and electronics of PET systems, since those are designed for low and medium count rates. Typical PET detectors operated according to a modified Anger principle suffer from multiple events at high rates. Therefore, in-beam PET systems using such detectors rely on a synchronization of beam status and measurement to reject deteriorated data. In this work, a method for pile-up rejection is applied to conventional Anger logic block detectors. It allows for an in-beam data acquisition without further synchronization. Though cyclotrons produce a continuous wave beam, the radiation field shaping technique introduces breaks in the application. Time regimes mimicking synchrotrons as well as cyclotron based ones using double-scattering or pencil beam scanning field shaping at dose rates of 0.5, 1.0 and 2.0Gy/min were investigated. Two types of inhomogeneous phantoms were imaged. The first one simulates cavity structures, the other one mimics a static lung irradiation. It could be shown that, depending on the dose rate and the beam time structure, in-beam measurement including a few seconds decay time only, yield images which revealed all inhomogeneities in the phantoms. This technique can be the basis for the development of an in-beam PET system with traditional detectors and off-the-shelf electronics.

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.

Implementation of a software for REmote COMparison of PARticlE and photon treatment plans: ReCompare.

PURPOSE: To guarantee equal access to optimal radiotherapy, a concept of patient assignment to photon or particle radiotherapy using remote treatment plan exchange and comparison - ReCompare - was proposed. We demonstrate the implementation of this concept and present its clinical applicability. MATERIALS AND METHODS: The ReCompare concept was implemented using a client-server based software solution. A clinical workflow for the remote treatment plan exchange and comparison was defined. The steps required by the user and performed by the software for a complete plan transfer were described and an additional module for dose-response modeling was added. RESULTS: The ReCompare software was successfully tested in cooperation with three external partner clinics and worked meeting all required specifications. It was compatible with several standard treatment planning systems, ensured patient data protection, and integrated in the clinical workflow. CONCLUSION: The ReCompare software can be applied to support non-particle radiotherapy institutions with the patient-specific treatment decision on the optimal irradiation modality by remote treatment plan exchange and comparison.

Systematic analysis on the achievable accuracy of PT-PET through automated evaluation techniques.

INTRODUCTION: Particle Therapy Positron Emission Tomography (PT-PET) is currently the only clinically applied method for in vivo verification of ion-beam radiotherapy during or close in time to the treatment. Since a direct deduction of the delivered dose from the measured activity is not feasible, images are compared to a reference distribution. The achievable accuracy of two image analysis approaches was investigated by means of reproducible phantom benchmark tests. This is an objective method that excludes patient related factors of influence. MATERIAL AND METHODS: Two types of phantoms were designed to produce well defined deviations in the activity distributions. Pure range differences were simulated using the first phantom type while the other emulated cavity structures. The phantoms were irradiated with (12)C-ions. PT-PET measurements were performed by means of a camera system installed at the beamline. Different measurement time scenarios were investigated, assuming a PET scanner directly at the irradiation site or placed within the treatment room. The images were analyzed by means of the Pearson Correlation Coefficient (PCC) and a range calculation algorithm combined with a dedicated cavity filling detection method. RESULTS: Range differences could be measured with an error of less than 2 mm. The range comparison algorithm yielded slightly better results than the PCC method. The filling of a cavity structure could be safely detected if its inner diameter was at least 5 mm. CONCLUSION: Both approaches evaluate the PT-PET data in an objective way and deliver promising results for in-beam and in-room PET for clinical realistic dose rates.

Concept for individualized patient allocation: ReCompare--remote comparison of particle and photon treatment plans.

BACKGROUND: Identifying those patients who have a higher chance to be cured with fewer side effects by particle beam therapy than by state-of-the-art photon therapy is essential to guarantee a fair and sufficient access to specialized radiotherapy. The individualized identification requires initiatives by particle as well as non-particle radiotherapy centers to form networks, to establish procedures for the decision process, and to implement means for the remote exchange of relevant patient information. In this work, we want to contribute a practical concept that addresses these requirements. METHODS: We proposed a concept for individualized patient allocation to photon or particle beam therapy at a non-particle radiotherapy institution that bases on remote treatment plan comparison. We translated this concept into the web-based software tool ReCompare (REmote COMparison of PARticlE and photon treatment plans). RESULTS: We substantiated the feasibility of the proposed concept by demonstrating remote exchange of treatment plans between radiotherapy institutions and the direct comparison of photon and particle treatment plans in photon treatment planning systems. ReCompare worked with several tested standard treatment planning systems, ensured patient data protection, and integrated in the clinical workflow. CONCLUSIONS: Our concept supports non-particle radiotherapy institutions with the patient-specific treatment decision on the optimal irradiation modality by providing expertise from a particle therapy center. The software tool ReCompare may help to improve and standardize this personalized treatment decision. It will be available from our website when proton therapy is operational at our facility.

Automated evaluation of setup errors in carbon ion therapy using PET: feasibility study.

PURPOSE: To investigate the possibility of detecting patient mispositioning in carbon-ion therapy with particle therapy positron emission tomography (PET) in an automated image registration based manner. METHODS: Tumors in the head and neck (H&N), pelvic, lung, and brain region were investigated. Biologically optimized carbon ion treatment plans were created with TRiP98. From these treatment plans, the reference ß(+)-activity distributions were calculated using a Monte Carlo simulation. Setup errors were simulated by shifting or rotating the computed tomography (CT). The expected ß(+) activity was calculated for each plan with shifts. Finally, the reference particle therapy PET images were compared to the "shifted" ß(+)-activity distribution simulations using the Pearson's correlation coefficient (PCC). To account for different PET monitoring options the inbeam PET was compared to three different inroom scenarios. Additionally, the dosimetric effects of the CT misalignments were investigated. RESULTS: The automated PCC detection of patient mispositioning was possible in the investigated indications for cranio-caudal shifts of 4 mm and more, except for prostate tumors. In the rather homogeneous pelvic region, the generated ß(+)-activity distribution of the reference and compared PET image were too much alike. Thus, setup errors in this region could not be detected. Regarding lung lesions the detection strongly depended on the exact tumor location: in the center of the lung tumor misalignments could be detected down to 2 mm shifts while resolving shifts of tumors close to the thoracic wall was more challenging. Rotational shifts in the H&N and lung region of +6° and more could be detected using inroom PET and partly using inbeam PET. Comparing inroom PET to inbeam PET no obvious trend was found. However, among the inroom scenarios a longer measurement time was found to be advantageous. CONCLUSIONS: This study scopes the use of various particle therapy PET verification techniques in four indications. The automated detection of patients' setup errors was investigated in a broad accumulation of data sets. The evaluation of introduced setup errors is performed automatically, which is of utmost importance to introduce highly required particle therapy monitoring devices into the clinical routine.

Analysis of metabolic washout of positron emitters produced during carbon ion head and neck radiotherapy.

PURPOSE: Particle Therapy Positron Emission Tomography (PT-PET) is a suitable method for verification of therapeutic dose delivery by measurements of irradiation-induced ß(+)-activity. Due to metabolic processes in living tissue ß(+)-emitters can be removed from the place of generation. This washout is a limiting factor for image quality. The purpose of this study is to investigate whether a washout model obtained by animal experiments is applicable to patient data. METHODS: A model for the washout has been developed by Mizuno et al. [Phys. Med. Biol. 48(15), 2269-2281 (2003)] and Tomitani et al. [Phys. Med. Biol. 48(7), 875-889 (2003)]. It is based upon measurements in a rabbit in living and dead conditions. This model was modified and applied to PET data acquired during the experimental therapy project at GSI Helmholtzzentrum für Schwerionenforschung Darmstadt, Germany. Three components are expected: A fast one with a half life of 2 s, a medium one in the range of 2-3 min, and a slow component of the order of 2-3 h. Ten patients were selected randomly for investigation of the fast component. To analyze the other two components, 12 one-of-a-kind measurements from a single volunteer patient are available. RESULTS: A fast washout on the time scale of a few seconds was not observed in the patient data. The medium processes showed a mean half life of 155.7 ± 4.6 s. This is in the expected range. Fractions of the activity not influenced by the washout were found. CONCLUSIONS: On the time scale of an in-beam or in-room measurement only the medium-time washout processes play a remarkable role. A slow component may be neglected if the measurements do not exceed 20 min after the end of the irradiation. The fast component is not observed due to the low relative blood filled volume in the brain.

Using statistical measures for automated comparison of in-beam PET data.

PURPOSE: Positron emission tomography (PET) is considered to be the state of the art technique to monitor particle therapy in vivo. To evaluate the beam delivery the measured PET image is compared to a predicted ß(+)-distribution. Nowadays the range assessment is performed by a group of experts via visual inspection. This procedure is rather time consuming and requires well trained personnel. In this study an approach is presented to support human decisions in an automated and objective way. METHODS: The automated comparison presented uses statistical measures, namely, Pearson's correlation coefficient (PCC), to detect ion beam range deviations. The study is based on 12 in-beam PET patient data sets recorded at GSI and 70 artificial beam range modifications per data set. The range modifications were 0, 4, 6, and 10 mm water equivalent path length (WEPL) in positive and negative beam directions. The reference image to calculate the PCC was both an unmodified simulation of the activity distribution (Test 1) and a measured in-beam PET image (Test 2). Based on the PCCs sensitivity and specificity were calculated. Additionally the difference between modified and unmodified data sets was investigated using the Wilcoxon rank sum test. RESULTS: In Test 1 a sensitivity and specificity over 90% was reached for detecting modifications of ±10 and ±6 mm WEPL. Regarding Test 2 a sensitivity and specificity above 80% was obtained for modifications of ±10 and -6 mm WEPL. The limitation of the method was around 4 mm WEPL. CONCLUSIONS: The results demonstrate that the automated comparison using PCC provides similar results in terms of sensitivity and specificity compared to visual inspections of in-beam PET data. Hence the method presented in this study is a promising and effective approach to improve the efficiency in the clinical workflow in terms of particle therapy monitoring by means of PET.