D Unholtz

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.

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.

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

Post-therapeutical β + -activity measurements in comparison to simulations towards in-vivo verification of ion beam therapy

In ion beam therapy the incidental activation of the irradiated tissue during patient treatment provides a unique opportunity for in-vivo verification. At the Heidelberg Ion Beam Therapy Center (HIT) the post-therapeutical measurement of the irradiation-induced β+-activity, marking the spatial volume of the dose deposition, is planned to be integrated into the clinical workflow to infer valuable information on the correctness of the delivered treatment dose. Currently, a commercial off-line PET/CT scanner and Monte-Carlo methods are under investigation to measure and simulate quantitatively the β+-activity minutes after patient treatment with protons and carbon ions. The comparison of the measured activity with the expected distribution obtained from the simulation, however, requires the following series of dedicated tasks, which are being largely automated through the development of a customized software framework. First, the patient data set is stored anonymously in a separate patient archive (PACS). Affine transformations between the different coordinate systems can be established by a one-time CT-CT registration. Second, the simulation on a properly processed CT is started and monitored on a remote computer cluster. Third, the β+-activity is calculated from the simulated isotope distributions, including time course information and a dedicated model of the biological washout. Finally, measured and simulated activities are visually overlayed to their respective CT volumes for synchronized quantitative analysis. We will present the framework and its application to the analysis of a first patient study with several PET scans acquired few minutes after individual therapy fractions. The comparison with the calculations shows that the beam range can be reliably estimated in bony structures in front of the critical organs, but the modeling of the dynamic washout process has to be improved in soft tissue to allow more specific conclusions about the applied treatment dose. Moreover, a second more recent patient study will be addressed, demonstrating the newly developed tools of the framework for a quantitative PET-based in-vivo range assessment.

Comparing the biological washout of β+-activity induced in mice brain after 12C-ion and proton irradiation

In clinical ion beam therapy, protons as well as heavier ions such as carbon are used for treatment. For protons, β(+)-emitters are only induced by fragmentation reactions in the target (target fragmentation), whereas for heavy ions, they are additionally induced by fragmentations of the projectile (further referred to as autoactivation). An approach utilizing these processes for treatment verification, by comparing measured Positron Emission Tomography (PET) data to predictions from Monte Carlo simulations, has already been clinically implemented. For an accurate simulation, it is important to consider the biological washout of β(+)-emitters due to vital functions. To date, mathematical expressions for washout have mainly been determined by using radioactive beams of (10)C- and (11)C-ions, both β(+)-emitters, to enhance the counting statistics in the irradiated area. Still, the question of how the choice of projectile (autoactivating or non-autoactivating) influences the washout coefficients, has not been addressed. In this context, an experiment was carried out at the Heidelberg Ion Beam Therapy Center with the purpose of directly comparing irradiation-induced biological washout coefficients in mice for protons and (12)C-ions. To this aim, mice were irradiated in the brain region with protons and (12)C-ions and measured after irradiation with a PET/CT scanner (Siemens Biograph mCT). After an appropriate waiting time, the mice were sacrificed, then irradiated and measured again under similar conditions. The resulting data were processed and fitted numerically to deduce the main washout parameters. Despite the very low PET counting statistics, a consistent difference could be identified between (12)C-ion and proton irradiated mice, with the (12)C data being described best by a two component fit with a combined medium and slow washout fraction of 0.50 ± 0.05 and the proton mice data being described best by a one component fit with only one (slow) washout fraction of 0.73 ± 0.06.

Preclinical investigations towards the first spacer gel application in prostate cancer treatment during particle therapy at HIT

BackgroundThe application of spacer gel represents a promising approach to reliably spare the rectal frontal wall during particle therapy (IJROBP 76:1251-1258, 2010). In order to qualify the spacer gel for the clinical use in particle therapy, a variety of measurements were performed in order to ensure the biological compatibility of the gel, its physical stability during and after the irradiation, and a proper definition of the gel in terms of the Hounsfield Unit (HU) values for the treatment planning system. The potential for the use of the spacer gel for particle therapy monitoring with off-line Positron Emission Tomography (PET) was also investigated.ResultsThe spacer gel implanted to the prostate patient in direct neighbourhood to the clinical target volume does not interfere with the particle therapy treatment planning procedure applied at Heidelberg Ion Beam Therapy Centre (HIT). The performed measurements show that Bragg-peak position of the particles can be properly predicted on the basis of computed tomography imaging with the treatment planning system used at HIT (measured water equivalent path length of 1.011 ±0.011 (2σ), measured Hounsfield Unit of 28.9 ±6.1 (2σ)). The spacer gel samples remain physically unchanged after irradiation with a dose exceeding the therapeutic dose level. The independently measured Bragg-Peak position does not change within the time interval of 10 weeks.ConclusionsAs a result of the presented experiments, the first clinical application of spacer gel implant during prostate cancer treatment with carbon ions and protons was possible at HIT in 2012. The reported pre-clinical investigations demonstrate that use of spacer gel is safe in particle therapy in presence of therapy target motion and patient positioning induced particle range variations. The spacer gel injected between prostate and rectum enlarge the distance between both organs, which is expected to clinically significantly decrease the undesirable exposure of the most critical organ at risk, i.e. rectal frontal wall. Further research on the composition of spacer gel material might lead to additional clinical benefits by validation of particle therapy of prostate via post-therapeutic PET-imaging or by patient positioning based on the gel as a radio-opaque marker.

Initial clinical evaluation of PET-based ion beam therapy monitoring under consideration of organ motion.

PURPOSE Intrafractional organ motion imposes considerable challenges to scanned ion beam therapy and demands for a thorough verification of the applied treatment. At the Heidelberg Ion-Beam Therapy Center (HIT), the scanned ion beam delivery is verified by means of postirradiation positron-emission-tomography (PET) imaging. This work presents a first clinical evaluation of PET-based treatment monitoring in ion beam therapy under consideration of target motion. METHODS Three patients with mobile liver lesions underwent scanned carbon ion irradiation at HIT and postirradiation PET/CT (x-ray-computed-tomography) imaging with a commercial scanner. Respiratory motion was recorded during irradiation and subsequent image acquisition. This enabled a time-resolved (4D) calculation of the expected irradiation-induced activity pattern and, for one patient where an additional 4D CT was acquired at the PET/CT scanner after treatment, a motion-compensated PET image reconstruction. For the other patients, PET data were reconstructed statically. To verify the treatment, calculated prediction and reconstructed measurement were compared with a focus on the ion beam range. RESULTS Results in the current three patients suggest that for motion amplitudes in the order of 2 mm there is no benefit from incorporating respiratory motion information into PET-based treatment monitoring. For a target motion in the order of 10 mm, motion-related effects become more severe and a time-resolved modeling of the expected activity distribution can lead to an improved data interpretation if a sufficient number of true coincidences is detected. Benefits from motion-compensated PET image reconstruction could not be shown conclusively at the current stage. CONCLUSIONS The feasibility of clinical PET-based treatment verification under consideration of organ motion has been shown for the first time. Improvements in noise-robust 4D PET image reconstruction are deemed necessary to enhance the clinical potential.

4D offline PET-based treatment verification in scanned ion beam therapy: a phantom study.

At the Heidelberg Ion-Beam Therapy Center, patient irradiation with scanned proton and carbon ion beams is verified by offline positron emission tomography (PET) imaging: the β+-activity measured within the patient is compared to a prediction calculated on the basis of the treatment planning data in order to identify potential delivery errors. Currently, this monitoring technique is limited to the treatment of static target structures. However, intra-fractional organ motion imposes considerable additional challenges to scanned ion beam radiotherapy. In this work, the feasibility and potential of time-resolved (4D) offline PET-based treatment verification with a commercial full-ring PET/CT (x-ray computed tomography) device are investigated for the first time, based on an experimental campaign with moving phantoms. Motion was monitored during the gated beam delivery as well as the subsequent PET acquisition and was taken into account in the corresponding 4D Monte-Carlo simulations and data evaluation. Under the given experimental conditions, millimeter agreement between the prediction and measurement was found. Dosimetric consequences due to the phantom motion could be reliably identified. The agreement between PET measurement and prediction in the presence of motion was found to be similar as in static reference measurements, thus demonstrating the potential of 4D PET-based treatment verification for future clinical applications.

Current status of 4D offline PET-based treatment verification at the Heidelberg Ion-Beam Therapy Center

At the Heidelberg Ion-Beam Therapy Center, patient treatment is monitored offline by comparing the irradiation-induced β+-activity, measured by a commercial full-ring PET/CT scanner installed next to the treatment site, with a corresponding Monte-Carlo (MC) simulation on the basis of the planned treatment. While the usefulness of 3D offline PET-based treatment verification has already been shown, the feasibility of 4D offline PET-based treatment monitoring, accounting for the tumour motion during the irradiation and the subsequent PET acquisition, still needs to be demonstrated. In this work, PMMA phantoms of different geometries were irradiated once under stationary and once under moving conditions. In the latter case, a pressure sensor motion surrogate was used to monitor the rigid target movement during the gated ion-beam application and the following PET acquisition. In the same way, respiratory motion was monitored during the irradiation and subsequent PET/CT scans of several patients with respiratory motion affected target volumes in the liver. In all cases, the knowledge or estimation (from 4D CT) of the target trajectory enabled a 4D analysis of the actual ion-beam delivery and the post-irradiation PET. The reconstructed 4D PET data were compared to the stationary reference (phantom study only) and to the results of a dedicated 4D MC simulation framework. In the simplified scenario of high dose irradiation of moving phantoms results comparable to the static reference measurements could be obtained by using the available gated 4D PET image reconstruction. However, time-resolved analysis of the clinical data was found to suffer from the very low counting statistics, hindering a reliable verification of the applied treatment under consideration of the tumour motion. Still, in the case of small respiratory motion amplitudes (below 1cm), therapy application could be verified by comparing the 3D reconstructed PET data to a 3D MC prediction.