Julia Bauer

Hypofractionated carbon ion therapy delivered with scanned ion beams for patients with hepatocellular carcinoma – feasibility and clinical response

PurposePhoton-based radiation therapy does currently not play a major role as local ablative treatment for hepatocellular carcinoma (HCC). Carbon ions offer distinct physical and biological advantages. Due to their inverted dose profile and the high local dose deposition within the Bragg peak, precise dose application and sparing of normal tissue is possible. Furthermore, carbon ions have an increased relative biological effectiveness (RBE) compared to photons.Methods and materialsA total of six patients with one or more HCC-lesions were treated with carbon ions delivered by the raster-scanning technique according to our clinical trial protocol. Diagnosis of HCC was confirmed by histology or two different imaging modalities (CT and MRI) according to the AASLD-guidelines. Applied fractionation scheme was 4 × 10 Gy(RBE). Correct dose application was controlled by in-vivo PET measurement of β + −activity in the irradiated tissue shortly after treatment.ResultsPatients were observed for a median time period of 11.0 months (range, 3.4 – 12.7 months). Imaging studies showed a partial response in 4/7 lesions and a stable disease in 3/7 lesions in follow-up CT- and MRI scans. Local control was 100%. One patient with multifocal intrahepatic disease underwent liver transplantation 3 months after carbon ion therapy. During radiotherapy and the follow-up period no severe adverse events have occurred.ConclusionsWe report the first clinical results of patients with HCC undergoing carbon ion therapy using the rasterscanning technique at our institution. All patients are locally controlled and experienced no higher toxicities in a short follow-up period. Further patients will be included in our prospective Phase-I clinical trial PROMETHEUS-01 (NCT01167374).

Implementation and initial clinical experience of offline PET/CT-based verification of scanned carbon ion treatment

BACKGROUND AND PURPOSE We report on the implementation of offline PET/CT-based treatment verification at the Heidelberg Ion Beam Therapy Centre (HIT) and present first clinical cases for post-activation measurements after scanned carbon ion irradiation. Key ingredient of this in-vivo treatment verification is the comparison of irradiation-induced patient activation measured by a PET scanner with a prediction simulated by means of Monte Carlo techniques. MATERIAL AND METHODS At HIT, a commercial full-ring PET/CT scanner has been installed in close vicinity to the treatment rooms. After selected irradiation fractions, the patient either walks to the scanner for acquisition of the activation data or is transported using a shuttle system. The expected activity distribution is obtained from the production of β(+)-active isotopes simulated by the FLUKA code on the basis of the patient-specific treatment plan, post-processed considering the time course of the respective treatment fraction, the estimated biological washout of the induced activity and a simplified model of the imaging process. RESULTS We present four patients with different indications of head, head/neck, liver and pelvic tumours. A clear correlation between the measured PET signal and the simulated activity pattern is observed for all patients, thus supporting a proper treatment delivery. In the case of a pelvic tumour patient it was possible to detect minor treatment delivery inaccuracies. CONCLUSIONS The initial clinical experience proves the feasibility of the implemented strategy for offline confirmation of scanned carbon ion irradiation and therefore constitutes a first step towards a comprehensive PET/CT-based treatment verification in the clinical routine at HIT.

Monte Carlo calculations of positron emitter yields in proton radiotherapy

Positron emission tomography (PET) is a promising tool for monitoring the three-dimensional dose distribution in charged particle radiotherapy. PET imaging during or shortly after proton treatment is based on the detection of annihilation photons following the ß(+)-decay of radionuclides resulting from nuclear reactions in the irradiated tissue. Therapy monitoring is achieved by comparing the measured spatial distribution of irradiation-induced ß(+)-activity with the predicted distribution based on the treatment plan. The accuracy of the calculated distribution depends on the correctness of the computational models, implemented in the employed Monte Carlo (MC) codes that describe the interactions of the charged particle beam with matter and the production of radionuclides and secondary particles. However, no well-established theoretical models exist for predicting the nuclear interactions and so phenomenological models are typically used based on parameters derived from experimental data. Unfortunately, the experimental data presently available are insufficient to validate such phenomenological hadronic interaction models. Hence, a comparison among the models used by the different MC packages is desirable. In this work, starting from a common geometry, we compare the performances of MCNPX, GATE and PHITS MC codes in predicting the amount and spatial distribution of proton-induced activity, at therapeutic energies, to the already experimentally validated PET modelling based on the FLUKA MC code. In particular, we show how the amount of ß(+)-emitters produced in tissue-like media depends on the physics model and cross-sectional data used to describe the proton nuclear interactions, thus calling for future experimental campaigns aiming at supporting improvements of MC modelling for clinical application of PET monitoring.

Integration and evaluation of automated Monte Carlo simulations in the clinical practice of scanned proton and carbon ion beam therapy

Monte Carlo (MC) simulations of beam interaction and transport in matter are increasingly considered as essential tools to support several aspects of radiation therapy. Despite the vast application of MC to photon therapy and scattered proton therapy, clinical experience in scanned ion beam therapy is still scarce. This is especially the case for ions heavier than protons, which pose additional issues like nuclear fragmentation and varying biological effectiveness. In this work, we present the evaluation of a dedicated framework which has been developed at the Heidelberg Ion Beam Therapy Center to provide automated FLUKA MC simulations of clinical patient treatments with scanned proton and carbon ion beams. Investigations on the number of transported primaries and the dimension of the geometry and scoring grids have been performed for a representative class of patient cases in order to provide recommendations on the simulation settings, showing that recommendations derived from the experience in proton therapy cannot be directly translated to the case of carbon ion beams. The MC results with the optimized settings have been compared to the calculations of the analytical treatment planning system (TPS), showing that regardless of the consistency of the two systems (in terms of beam model in water and range calculation in different materials) relevant differences can be found in dosimetric quantities and range, especially in the case of heterogeneous and deep seated treatment sites depending on the ion beam species and energies, homogeneity of the traversed tissue and size of the treated volume. The analysis of typical TPS speed-up approximations highlighted effects which deserve accurate treatment, in contrast to adequate beam model simplifications for scanned ion beam therapy. In terms of biological dose calculations, the investigation of the mixed field components in realistic anatomical situations confirmed the findings of previous groups so far reported only in homogenous water targets. This work can thus be useful to other centers commencing clinical experience in scanned ion beam therapy.

The FLUKA Code: An Accurate Simulation Tool for Particle Therapy

Monte Carlo (MC) codes are increasingly spreading in the hadrontherapy community due to their detailed description of radiation transport and interaction with matter. The suitability of a MC code for application to hadrontherapy demands accurate and reliable physical models capable of handling all components of the expected radiation field. This becomes extremely important for correctly performing not only physical but also biologically based dose calculations, especially in cases where ions heavier than protons are involved. In addition, accurate prediction of emerging secondary radiation is of utmost importance in innovative areas of research aiming at in vivo treatment verification. This contribution will address the recent developments of the FLUKA MC code and its practical applications in this field. Refinements of the FLUKA nuclear models in the therapeutic energy interval lead to an improved description of the mixed radiation field as shown in the presented benchmarks against experimental data with both 4He and 12C ion beams. Accurate description of ionization energy losses and of particle scattering and interactions lead to the excellent agreement of calculated depth–dose profiles with those measured at leading European hadron therapy centers, both with proton and ion beams. In order to support the application of FLUKA in hospital-based environments, Flair, the FLUKA graphical interface, has been enhanced with the capability of translating CT DICOM images into voxel-based computational phantoms in a fast and well-structured way. The interface is capable of importing also radiotherapy treatment data described in DICOM RT standard. In addition, the interface is equipped with an intuitive PET scanner geometry generator and automatic recording of coincidence events. Clinically, similar cases will be presented both in terms of absorbed dose and biological dose calculations describing the various available features.

TPS(PET)-A TPS-based approach for in vivo dose verification with PET in proton therapy.

Since the interest in ion-irradiation for tumour therapy has significantly increased over the last few decades, intensive investigations are performed to improve the accuracy of this form of patient treatment. One major goal is the development of methods for in vivo dose verification. In proton therapy, a PET (positron emission tomography)-based approach measuring the irradiation-induced tissue activation inside the patient has been already clinically implemented. The acquired PET images can be compared to an expectation, derived under the assumption of a correct treatment application, to validate the particle range and the lateral field position in vivo. In the context of this work, TPSPET is introduced as a new approach to predict proton-irradiation induced three-dimensional positron emitter distributions by means of the same algorithms of the clinical treatment planning system (TPS). In order to perform additional activity calculations, reaction-channel-dependent input positron emitter depth distributions are necessary, which are determined from the application of a modified filtering approach to the TPS reference depth dose profiles in water. This paper presents the implementation of TPSPET on the basis of the research treatment planning software treatment planning for particles. The results are validated in phantom and patient studies against Monte Carlo simulations, and compared to β(+)-emitter distributions obtained from a slightly modified version of the originally proposed one-dimensional filtering approach applied to three-dimensional dose distributions. In contrast to previously introduced methods, TPSPET provides a faster implementation, the results show no sensitivity to lateral field extension and the predicted β(+)-emitter densities are fully consistent to the planned treatment dose as they are calculated by the same pencil beam algorithms. These findings suggest a large potential of the application of TPSPET for in vivo dose verification in the daily clinical routine.

Monitoring of patients treated with particle therapy using positron-emission-tomography (PET): the MIRANDA study.

BackgroundThe purpose of this clinical study is to investigate the clinical feasibility and effectiveness of offline Positron-Emission-Tomography (PET) quality assurance for promoting the accuracy of proton and carbon ion beam therapy.Methods/DesignA total of 240 patients will be recruited, evenly sampled among different analysis groups including tumors of the brain, skull base, head and neck region, upper gastrointestinal tract including the liver, lower gastrointestinal tract, prostate and pelvic region. From the comparison of the measured activity with the planned dose and its corresponding simulated activity distribution, conclusions on the delivered treatment will be inferred and, in case of significant deviations, correction strategies will be elaborated.DiscussionThe investigated patients are expected to benefit from this study, since in case of detected deviations between planned and actual treatment delivery a proper intervention (e.g., correction) could be performed in a subsequent irradiation fraction. In this way, an overall better treatment could be achieved than without any in-vivo verification. Moreover, site-specific patient-population information on the precision of the ion range at HIT might enable improvement of the CT-range calibration curve as well as safe reduction of the treatment margins to promote enhanced treatment plan conformality and dose escalation for full clinical exploitation of the promises of ion beam therapy.Trial RegistrationNCT01528670

Clinical implementation and range evaluation of in vivo PET dosimetry for particle irradiation in patients with primary glioma.

PURPOSE The physical and biological properties of ion-beams offer various advantages in comparison to conventional radiotherapy, though uncertainties concerning quality assurance are still left. Due to the inverted depth dose profile, range accuracy is of paramount importance. We investigated the range deviations between planning simulation and post-fractional PET/CT measurement from particle therapy in primary glioblastoma. METHODS AND MATERIALS 20 patients with glioblastoma undergoing particle therapy at our institution were selected. 10 received a proton-boost, 10 a carbon-ion-boost in addition to standard treatment. After two fractions, we performed a PET/CT-scan of the brain. We compared the resulting range deviation based on the Most-likely-shift method between the two measurements, and the measurements with corresponding expectations, calculated with the Monte-Carlo code FLUKA. RESULTS A patients two measurements deviated by 0.7mm (±0.7mm). Overall comparison between measurements and simulation resulted in a mean range deviation of 3.3mm (±2.2mm) with significant lower deviations in the (12)C-arm. CONCLUSION The used planning concepts display the actual dose distributions adequately. The carbon ion groups results are below the used PTV safety margins (3mm). Further adjustments to the simulation are required for proton irradiations. Some anatomical situations require particular attention to ensure highest accuracy and safety.

Investigating the limits of PET/CT imaging at very low true count rates and high random fractions in ion‐beam therapy monitoring

PURPOSE External beam radiotherapy with protons and heavier ions enables a tighter conformation of the applied dose to arbitrarily shaped tumor volumes with respect to photons, but is more sensitive to uncertainties in the radiotherapeutic treatment chain. Consequently, an independent verification of the applied treatment is highly desirable. For this purpose, the irradiation-induced β(+)-emitter distribution within the patient is detected shortly after irradiation by a commercial full-ring positron emission tomography/x-ray computed tomography (PET/CT) scanner installed next to the treatment rooms at the Heidelberg Ion-Beam Therapy Center (HIT). A major challenge to this approach is posed by the small number of detected coincidences. This contribution aims at characterizing the performance of the used PET/CT device and identifying the best-performing reconstruction algorithm under the particular statistical conditions of PET-based treatment monitoring. Moreover, this study addresses the impact of radiation background from the intrinsically radioactive lutetium-oxyorthosilicate (LSO)-based detectors at low counts. METHODS The authors have acquired 30 subsequent PET scans of a cylindrical phantom emulating a patientlike activity pattern and spanning the entire patient counting regime in terms of true coincidences and random fractions (RFs). Accuracy and precision of activity quantification, image noise, and geometrical fidelity of the scanner have been investigated for various reconstruction algorithms and settings in order to identify a practical, well-suited reconstruction scheme for PET-based treatment verification. Truncated listmode data have been utilized for separating the effects of small true count numbers and high RFs on the reconstructed images. A corresponding simulation study enabled extending the results to an even wider range of counting statistics and to additionally investigate the impact of scatter coincidences. Eventually, the recommended reconstruction scheme has been applied to exemplary postirradiation patient data-sets. RESULTS Among the investigated reconstruction options, the overall best results in terms of image noise, activity quantification, and accurate geometrical recovery were achieved using the ordered subset expectation maximization reconstruction algorithm with time-of-flight (TOF) and point-spread function (PSF) information. For this algorithm, reasonably accurate (better than 5%) and precise (uncertainty of the mean activity below 10%) imaging can be provided down to 80,000 true coincidences at 96% RF. Image noise and geometrical fidelity are generally improved for fewer iterations. The main limitation for PET-based treatment monitoring has been identified in the small number of true coincidences, rather than the high intrinsic random background. Application of the optimized reconstruction scheme to patient data-sets results in a 25% - 50% reduced image noise at a comparable activity quantification accuracy and an improved geometrical performance with respect to the formerly used reconstruction scheme at HIT, adopted from nuclear medicine applications. CONCLUSIONS Under the poor statistical conditions in PET-based treatment monitoring, improved results can be achieved by considering PSF and TOF information during image reconstruction and by applying less iterations than in conventional nuclear medicine imaging. Geometrical fidelity and image noise are mainly limited by the low number of true coincidences, not the high LSO-related random background. The retrieved results might also impact other emerging PET applications at low counting statistics.

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.