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Air-filled ionization chambers (ICs) are extensively used in the dosimetry of charged particle radiotherapy [1]. The calibration procedure of ionization chambers for the determination of absorbed dose to water, which is the standard quantity used for dose determination in external radiotherapy [2] is known as ND,w formalism. In this formalism, the readout of the chamber is converted into absorbed dose to water via two factors: the calibration factor of the chamber, and a quality factor that accounts for the specificity of the beam. The water-to-air stopping power ratio, or sw,air, is one of the main components of these quality factors, and, in the case of carbon ion beams, its biggest source of uncertainty [2]. In a previous work by our group [3], an expression was proposed to calculate sw,air for carbon ion beams at different residual ranges, based on a set of Monte Carlo calculations and experimental measurements, namely: (1) where Rres is expressed in cm and calculated using a practical range at the 50% dose level Rres(z) = R50 – z, where z is the depth in water. This expression is based on a 1D analysis of dose and sw,air distributions, which is enough to model the variations in sw,air for homogeneous dose distributions, like the ones mostly used for calibration and quality assurance (QA) purposes. However, this 1D description might be insufficient in some cases. An example of this would be treatment plan verification with a matrix of ionization chambers [4], a protocol often used in scanning-beam facilities where a patient plan is shot into a water phantom and the deposited dose is measured at several points (see Fig. ​Fig.1).1). In such a case, the residual range Rres is not defined at every point, so the application of equation (1) is not possible.

Clinical outcomes of charged particle therapy are very promising. Currently, several dedicated centers that use scanning beam technology are either close to clinical use or under construction. Since scanned beam treatments of targets that move with respiration most likely result in marked local over- and underdosage due to interplay of target motion and dynamic beam application, dedicated motion mitigation techniques have to be employed. To date, the motion mitigation techniques, rescanning, beam gating, and beam tracking, have been proposed and tested in experimental studies. Rescanning relies on repeated irradiations of the target with the number of particles reduced accordingly per scan to statistically average local misdosage. Specific developments to prohibit temporal correlation between beam scanning and target motion will be required to guarantee adequate averaging. For beam gating, residual target motion within gating windows has to be mitigated in order to avoid local misdosage. Possibly the most promising strategy is to increase the overlap of adjacent particle pencil beams laterally as well as longitudinally to effectively reduce the sensitivity against small residual target motion. The most conformal and potentially most precise motion mitigation technique is beam tracking. Individual particle pencil beams have to be adapted laterally as well as longitudinally according to the target motion. Within the next several years, it can be anticipated that rescanning as well as beam gating will be ready for clinical use. For rescanning, treatment planning margins that incorporate the full extent of target motion as well as motion induced density variations in the beam paths will result in reduced target conformity of the applied dose distributions. Due to the limited precision of motion monitoring devices, it seems likely that beam gating will be used initially to mitigate interplay effects only but not to considerably decrease treatment planning margins. Then, in the next step, beam gating, based on more accurate motion monitoring systems, provides the possibility to restore target conformity as well as steep dose gradients due to reduced treatment planning margins. Accurate motion monitoring systems will be required for beam tracking. Even though beam tracking has already been successfully tested experimentally, full clinical implementation requires direct feedback of the actual target position in quasireal time to the treatment control system and can be anticipated to be several more years ahead.

Purpose: Clinically safe and effective treatment of intrafractionally moving targets with scanned ion beams requires dedicated delivery techniques such as beam tracking. Apart from treatment delivery, also appropriate methods for validation of the actual tumor irradiation are highly desirable. In this contribution the feasibility of four-dimensionally (space and time) resolved, motion-compensated in-beam positron emission tomography (4DibPET) was addressed in experimental studies with scanned carbon ion beams. Methods: A polymethyl methracrylate block sinusoidally moving left-right in beam's eye view was used as target. Radiological depth changes were introduced by placing a stationary ramp-shaped absorber proximal of the moving target. Treatment delivery was compensated for motion by beam tracking. Time-resolved, motion-correlated in-beam PET data acquisition was performed during beam delivery with tracking the moving target and prolonged after beam delivery first with the activated target still in motion and, finally, with the target at rest. Motion-compensated 4DibPET imaging was implemented and the results were compared to a stationary reference irradiation of the same treatment field. Data were used to determine feasibility of 4DibPET but also to evaluate offline in comparison to in-beam PET acquisition. Results: 4D in-beam as well as offline PET imaging was found to be feasible and offers the possibilitymore » to verify the correct functioning of beam tracking. Motion compensation of the imaged {beta}{sup +}-activity distribution allows recovery of the volumetric extension of the delivered field for direct comparison with the reference stationary condition. Observed differences in terms of lateral field extension and penumbra in the direction of motion were typically less than 1 mm for both imaging strategies in comparison to the corresponding reference distributions. However, in-beam imaging retained a better spatial correlation of the measured activity with the delivered dose. Conclusions: 4DibPET is a feasible and promising method to validate treatment delivery of scanned ion beams to moving targets. Further investigations will focus on more complex geometries and treatment planning studies with clinical data.« less

To demonstrate mitigation of the interplay effects of scanned particle beams and residual target motion within a gating window by increased overlap of pencil beams.Lateral overlap was increased by increasing the pencil beam widths or by decreasing the distance between the pencil beams (scan grid). Longitudinal overlap was increased by reducing the distance between iso-range slices. For scanned carbon ion beams, simulation studies were performed and validated experimentally to determine the required parameters for different residual motion characteristics. The dose distributions were characterized by the maximal local deviations representing local over- and underdosage.For residual lateral motion, the local deviations were5% for 2, 4, and 7 mm residual motion within the gating window for a 2-mm scan grid and pencil beams of 10, 14, and 18 mm full width at half maximum, respectively. Decreasing the iso-range slice distance from 3 mm to 1 mm effectively mitigatedor=10 mm water-equivalent range changes. Experimental data reproduced the simulation results.In charged particle therapy with a scanned beam, interplay effects between gated beam delivery and residual target motion can be decreased effectively by increasing the overlap between pencil beams laterally, as well as longitudinally.

Scanned particle beams and target motion interfere. This interplay leads to deterioration of the dose distribution. Experiments and a treatment planning study were performed to investigate interplay. Experiments were performed with moving radiographic films for different motion parameters. Resulting dose distributions were analyzed for homogeneity and dose coverage. The treatment planning study was based on the time-resolved computed tomography (4DCT) data of five lung tumor patients. Treatment plans with margins to account for respiratory motion were optimized, and resulting dose distributions for 108 different motion parameters for each patient were calculated. Data analysis for a single fraction was based on dose-volume histograms and the volume covered with 95% of the planned dose. Interplay deteriorated dose conformity and homogeneity (1-standard deviation/mean) in the experiments as well as in the treatment-planning study. The homogeneity on radiographic films was below approximately 80% for motion amplitudes of approximately 15 mm. For the treatment-planning study based on patient data, the target volume receiving at least 95% of the prescribed dose was on average (standard deviation) 71.0% (14.2%). Interplay of scanned particle beams and moving targets has severe impact on the resulting dose distributions. Fractionated treatment delivery potentially mitigates at least parts of these interplay effects. However, especially for small fraction numbers, e.g. hypo-fractionation, treatment of moving targets with scanned particle beams requires motion mitigation techniques such as rescanning, gating, or tracking.

Deformable registration is needed for a variety of tasks in establishing the voxel correspondence between respiratory phases. Most registration algorithms assume or imply that the deformation field is smooth and continuous everywhere. However, the lungs are contained within closed invaginated sacs called pleurae and are allowed to slide almost independently along the chest wall. This sliding motion is characterized by a discontinuous vector field, which cannot be generated using standard deformable registration methods. The authors have developed a registration method that can create discontinuous vector fields at the boundaries of anatomical subregions. Registration is performed independently on each subregion, with a boundary-matching penalty used to prevent gaps. This method was implemented and tested using both the B-spline and Demons registration algorithms in the Insight Segmentation and Registration Toolkit. The authors have validated this method on four patient 4DCT data sets for registration of the end-inhalation and end-exhalation volumes. Multiple experts identified homologous points in the lungs and along the ribs in the two respiratory phases. Statistical analyses of the mismatch of the homologous points before and after registration demonstrated improved overall accuracy for both algorithms.

Treatment of moving targets with scanned particle beams results in local over- and under-dosage due to interplay of beam and target motion. To mitigate the impact of respiratory motion, a motion tracking system has been developed and integrated in the therapy control system at Gesellschaft fuer Schwerionenforschung. The system adapts pencil beam positions as well as the beam energy according to target motion to irradiate the planned position. Motion compensation performance of the tracking system was assessed by measurements with radiographic films and a 3D array of 24 ionization chambers. Measurements were performed for stationary detectors and moving detectors using the tracking system. Film measurements showed comparable homogeneity inside the target area. Relative differences of 3D dose distributions within the target volume were 1{+-}2% with a maximum of 4%. Dose gradients and dose to surrounding areas were in good agreement. The motion tracking system successfully preserved dose distributions delivered to moving targets and maintained target conformity.

Four-dimensional radiotherapy requires deformable registration to track delivered dose across varying anatomical states. Deformable registration based on B-splines was implemented to register 4D computed tomography data to a reference respiratory phase. To assess registration performance, anatomical landmarks were selected across ten respiratory phases in five patients. These point landmarks were transformed according to global registration parameters between different respiratory phases. Registration uncertainties were computed by subtraction of transformed and reference landmark positions. The selection of appropriate registration masks to separate independently moving anatomical subunits is crucial to registration performance. The average registration error for five landmarks for each of five patients was 2.1 mm. This level of accuracy is acceptable for most radiotherapy applications.

The susceptibility of IMRT dose distributions to intrafraction organ motion: An investigation into smoothing filters derived from four dimensional computed tomography data This study investigated the sensitivity of static planning of intensity-modulated beams (IMBs) to intrafraction deformable organ motion and assessed whether smoothing of the IMBs at the treatment-planning stage can reduce this sensitivity. The study was performed with a 4D computed tomography (CT) data set for an IMRT treatment of a patient with liver cancer. Fluence profiles obtained from inverse-planning calculations on a standard reference CT scan were redelivered on a CT scan from the 4D data set at a different part of the breathing cycle. The use of a nonrigid registration model on the 4D data set additionally enabled detailed analysis of the overall intrafraction motion effects on the IMRT delivery during free breathing. Smoothing filters were then applied to the beam profiles within the optimization process to investigate whether this could reduce the sensitivity of IMBs to intrafraction organ motion. In addition, optimal fluence profiles from calculations on each individual phase of the breathing cycle were averaged to mimic the convolution of a static dose distribution with a motion probability kernel and assess its usefulness. Results from nonrigid registrations of the CT scan data showed a maximum liver motion of 7 mm in superior-inferior direction for this patient. Dose-volume histogram (DVH) comparison indicated a systematic shift when planning treatment on a motion-frozen, standard CT scan but delivering over a full breathing cycle. The ratio of the dose to 50% of the normal liver to 50% of the planning target volume (PTV) changed up to 28% between different phases. Smoothing beam profiles with a median-window filter did not overcome the substantial shift in dose due to a difference in breathing phase between planning and delivery of treatment. Averaging of optimal beam profiles at different phases of the breathing cycle mainly resulted in an increase in dose to the organs at risk (OAR) and did not seem beneficial to compensate for organ motion compared with using a large margin. Additionally, the results emphasized the need for 4D CT scans when aiming to reduce the internal margin (IM). Using only a single planning scan introduces a systematic shift in the dose distribution during delivery. Smoothing beam profiles either based on a single scan or over the different breathing phases was not beneficial for reducing this shift. (C) 2006 American Association of Physicists in Medicine.

Respiration-induced target motion is a major problem in intensity-modulated radiation therapy. Beam segments are delivered serially to form the total dose distribution. In the presence of motion, the spatial relation between dose deposition from different segments will be lost. Usually, this results in over- and underdosage. Besides such interplay effects between target motion and dynamic beam delivery as known from photon therapy, changes in internal density have an impact on delivered dose for intensity-modulated charged particle therapy. In this study, we have analysed interplay effects between raster scanned carbon ion beams and target motion. Furthermore, the potential of an online motion strategy was assessed in several simulations. An extended version of the clinical treatment planning software was used to calculate dose distributions to moving targets with and without motion compensation. For motion compensation, each individual ion pencil beam tracked the planned target position in the lateral as well as longitudinal direction. Target translations and rotations, including changes in internal density, were simulated. Target motion simulating breathing resulted in severe degradation of delivered dose distributions. For example, for motion amplitudes of +/-15 mm, only 47% of the target volume received 80% of the planned dose. Unpredictability of resulting dose distributions was demonstrated by varying motion parameters. On the other hand, motion compensation allowed for dose distributions for moving targets comparable to those for static targets. Even limited compensation precision (standard deviation approximately 2 mm), introduced to simulate possible limitations of real-time target tracking, resulted in less than 3% loss in dose homogeneity.

Respiratory gating based on external surrogates is performed in many clinics. We have developed a new technique for treatment verification using an electronic portal imaging device (EPID) in cine mode for gated 3D conformal therapy. Implanted radiopaque fiducial markers inside or near the target are required for this technique. The markers are contoured on the planning CT set, enabling us to create digitally reconstructed radiographs (DRRs) for each treatment beam. During the treatment, a sequence of EPID images can be acquired without disrupting the treatment. Implanted markers are visualized in the images and their positions in the beam's eye view are calculated off-line and compared to the reference position by matching the field apertures in corresponding EPID and DRR images. The precision of the patient set-up, the placement of the beam-gating window, as well as the residual tumour motion can be assessed for each treatment fraction. This technique has been demonstrated with a case study patient, who had three markers implanted in his liver. For this patient, the intra-fractional variation of all marker positions in the gating window had a 95% range of 4.8 mm in the SI direction (the primary axis of motion). This was about the same (5 mm) as the residual motion considered in the planning process. The inter-fractional variation of the daily mean positions of the markers, which indicates the uncertainty in the set-up procedure, was within +8.3 mm/-4.5 mm (95% range) in the SI direction for this case.

Respiratory motion can introduce significant errors in radiotherapy. Conventional CT scans as commonly used for treatment planning can include severe motion artifacts that result from interplay effects between the advancing scan plane and object motion. To explicitly include organ/target motion in treatment planning and delivery, time-resolved CT data acquisition (4D Computed Tomography) is needed. 4DCT can be accomplished by oversampled CT data acquisition at each slice. During several CT tube rotations projection data are collected in axial cine mode for the duration of the patient's respiratory cycle (plus the time needed for a full CT gantry rotation). Multiple images are then reconstructed per slice that are evenly distributed over the acquisition time. Each of these images represents a different anatomical state during a respiratory cycle. After data acquisition at one couch position is completed, x rays are turned off and the couch advances to begin data acquisition again until full coverage of the scan length has been obtained. Concurrent to CT data acquisition the patient's abdominal surface motion is recorded in precise temporal correlation. To obtain CT volumes at different respiratory states, reconstructed images are sorted into different spatio-temporally coherent volumes based on respiratory phase as obtained from the patient's surface motion. During binning, phase tolerances are chosen to obtain complete volumetric information since images at different couch positions are reconstructed at different respiratory phases. We describe 4DCT image formation and associated experiments that characterize the properties of 4DCT. Residual motion artifacts remain due to partial projection effects. Temporal coherence within resorted 4DCT volumes is dominated by the number of reconstructed images per slice. The more images are reconstructed, the smaller phase tolerances can be for retrospective sorting. From phantom studies a precision of about 2.5 mm for quasiregular motion and typical respiratory periods could be concluded. A protocol for 4DCT scanning was evaluated and clinically implemented at the MGH. Patient data are presented to elucidate how additional patient specific parameters can impact 4DCT imaging.

Summary Background and Purpose Clinical target volumes of the thorax and abdomen are typically expanded to account for inter- and intrafractional organ motion. Usually, such expansions are based on clinical experience and planar observations of target motion during simulation. More precise, 4- dimensional motion margins for a specific patient may improve dose coverage of mobile targets and yet limit unnecessarily large field expansions. We are studying approaches to targeting moving tumors throughout the entire treatment process, from treatment planning to beam delivery. Material and Methods Radio-opaque markers were implanted under CT guidance in the liver at the gross tumor periphery. Organ motion during light respiration was volumetrically imaged by 4D Computed Tomography. Marker motion was also acquired by fluoroscopy and compared with 4DCT data. During treatment, daily diagnostic x-ray images were captured at end-exhale and -inhale for patient set-up and target localization. Results Based on the time-resolved CT data, target volumes can be designed to account for respiratory motion during treatment. Motion of the tumor as derived from 4DCT was consistent with fluoroscopic motion analysis. Radiographs acquired in the treatment room enabled millimeter-level patient set-up and assessment of target position relative to bony anatomy. Daily positional variations between bony anatomy and implanted markers were observed. Conclusions Image guided therapy, based on 4DCT imaging, fluoroscopic imaging studies, and daily gated diagonstic energy set-up radiographs is being developed to improve beam delivery precision. Monitoring internal target motion throughout the entire treatment process will ensure adequate dose coverage of the target while sparing the maximum healthy tissue.

Summary Since 1997 a radiotherapy unit using fast carbon ions is operational at GSI. An intensity-controlled magnetic raster scanner together with a synchrotron allowing fast energy variation enable a unique method of purely active dose shaping in three dimensions. This contribution describes the necessary steps to establish a treatment planning system for this novel modality. We discuss the requirements for the physical beam model and the radiobiological model. Based on these we chose to implement a home-grown pencil beam model to describe the ion-tissue interaction and the Local Effect Model to calculate the RBE voxel-by-voxel. Given the large number of degrees of freedom biological dose optimization must be achieved by means of inverse treatment planning. All ion-related aspects are collected in our TRiP98 software. Biological dosimetry measuring cell survival in two dimensions turns out to be a good way to verify the model predictions as well as the actual irradiation procedure. We show a patient example and outline the future steps towards a dedicated clinic facility for all light ions.

We propose a new scanning protocol for generating 4D-CT image data sets influenced by respiratory motion. A cine scanning protocol is used during data acquisition, and two registration methods are used to sort images into temporal phases. A volume is imaged in multiple acquisitions of 1 or 2 cm length along the cranial-caudal direction. In each acquisition, the scans are continuously acquired for a time interval greater than or equal to the average respiratory cycle plus the duration of the data for an image reconstruction. The x ray is turned off during CT table translation and the acquisition is repeated until the prescribed volume is completely scanned. The scanning for 20 cm coverage takes about 1 min with an eight-slice CT or 2 mins with a four-slice CT. After data acquisition, the CT data are registered into respiratory phases based on either an internal anatomical match or an external respiratory signal. The internal approach registers the data according to correlation of anatomy in the CT images between two adjacent locations in consecutive respiratory cycles. We have demonstrated the technique with ROIs placed in the region of diaphragm. The external approach registers the image data according to an externally recorded respiratory signal generated by the Real-Time Position Management (RPM) Respiratory Gating System (Varian Medical Systems, Palo Alto, CA). Compared with previously reported prospective or retrospective imaging of the respiratory motion with a single-slice or multi-slice CT, the 4D-CT method proposed here provides (1) a shorter scan time of three to six times faster than the single-slice CT with prospective gating; (2) a shorter scan time of two to four times improvement over a previously reported multi-slice CT implementation, and (3) images over all phases of a breathing cycle. We have applied the scanning and registration methods on phantom, animal and patients, and initial results suggest the applicability of both the scanning and the registration methods.

Fast radiological range adaptation of the ion beam is essential when target motion is mitigated by beam tracking using scanned ion beams for dose delivery. Electromagnetically controlled deflection of a well-focused ion beam on a small static wedge degrader positioned between two dipole magnets, inside the beam delivery system, has been considered as a fast range adaptation method. The principle of the range adaptation method was tested in experiments and Monte Carlo simulations for the therapy beam line at the GSI Helmholtz Centre for Heavy Ions Research. Based on the simulations, ion optical settings of beam deflection and realignment of the adapted beam were experimentally applied to the beam line, and additional tuning was manually performed. Different degrader shapes were employed for the energy adaptation. Measured and simulated beam profiles, i.e. lateral distribution and range in water at isocentre, were analysed and compared with the therapy beam values for beam scanning. Deflected beam positions of up to +/-28 mm on degrader were performed which resulted in a range adaptation of up to +/-15 mm water equivalence (WE). The maximum deviation between the measured adapted range from the nominal range adaptation was below 0.4 mm WE. In experiments, the width of the adapted beam at the isocentre was adjustable between 5 and 11 mm full width at half maximum. The results demonstrate the feasibility/proof of the proposed range adaptation method for beam tracking from the beam quality point of view.

The technical performance of an integrated three-dimensional carbon ion pencil beam tracking system that was developed at GSI was investigated in phantom studies. Aim of the beam tracking system is to accurately treat tumours that are subject to respiratory motion with scanned ion beams. The current system provides real-time control of ion pencil beams to track a moving target laterally using the scanning magnets and longitudinally with a dedicated range shifter. The system response time was deduced to be approximately 1 ms for lateral beam tracking. The range shifter response time has been measured for various range shift amounts. A value of 16 +/- 2 ms was achieved for a water equivalent shift of 5 mm. An additional communication delay of 11 +/- 2 ms was taken into account in the beam tracking process via motion prediction. Accuracy of the lateral beam tracking was measured with a multi-wire position detector toor =0.16 mm standard deviation. Longitudinal beam tracking accuracy was parameterized based on measured responses of the range shifter and required time durations to maintain a specific particle range. For example, 5 mm water equivalence (WE) longitudinal beam tracking results in accuracy of 1.08 and 0.48 mm WE in root mean square for time windows of 10 and 50 ms, respectively.

Respiratory correlated CT is commercially available, and we have implemented its routine clinical use in planning lungtumor patients. Its value is determined by the fidelity of the spatiotemporal data set after processing the acquired reconstructed slices. Retrospective sorting of reconstructed slices is based on respiratory phase. However, the existing commercial software inadequately models respiratory phase for about 30% of the patients, mainly due to irregularities in the respiratory cycle. We have developed software that improves phase determination and consequently leads to an improvement of retrospective data sorting to make 4DCT data acquisition feasible for routine clinical use. Peak inhalation and exhalation respiratory states are selected manually; intermediate phases are interpolated. Residual motion artifacts in the resulting 4DCT volumes are reduced and allow use of the 4D imaging studies for treatment planning.

We propose a patient-specific planning target volume (PTV) to deal with interfractional variations, and test its feasibility in a retrospective treatment-planning study. Instead of using one planning image only, multiple scans are taken on different days. The target and organs at risk (OARs) are delineated on each images. The proposed PTV is generated from a union of those target contours on the planning images, excluding voxels of the OARs, and is denoted the PTV ‘GP–OAR’ (global prostate–organs at risk). The study is performed using ‘plan of the day’ adaptive workflow, which selects a daily plan from a library of plans based on a similarity comparison between the daily scan and planning images. The daily plans optimized for GP–OAR volumes are compared with those optimized for PTVs generated from a single prostate contour (PTV SP). Four CT serials of prostate cancer patient datasets are included in the test, and in total 28 fractions are simulated. The results show that the daily chosen GP–OAR plans provide excellent target coverage, with V95 values of the prostate mostly > 95%. In addition, dose delivered to the OARs as calculated from applying daily chosen GP–OAR plans is slightly increased but comparable to that calculated from applying daily SP plans. In general, the PTV GP–OARs are able to cover possible target variations while keeping dose delivered to the OARs at a similar level to that of the PTV SPs.

We propose a plan adaptation method for fast treatment plan generation in scanned ion beam therapy. Analysis of optimized treatment plans with carbon ions indicates that the particle number modulation of consecutive rasterspots in depth shows little variation throughout target volumes with convex shape. Thus, we extract a depth-modulation curve (DMC) from existing reference plans and adapt it for creation of new plans in similar treatment situations. The proposed method is tested with seven CT serials of prostate patients and three digital phantom datasets generated with the MATLAB code. Plans are generated with a treatment planning software developed by GSI using single-field uniform dose optimization for all the CT datasets to serve as reference plans and ?gold standard?. The adapted plans are generated based on the DMC derived from the reference plans of the same patient (intra-patient), different patient (inter-patient) and phantoms (phantom-patient). They are compared with the reference plans and a re-positioning strategy. Generally, in 1?min on a standard PC, either a physical plan or a biological plan can be generated with the adaptive method provided that the new target contour is available. In all the cases, the V95 values of the adapted plans can achieve 97% for either physical or biological plans. V107 is always 0 indicating no overdosage, and target dose homogeneity is above 0.98 in all cases. The dose received by the organs at risk is comparable to the optimized plans. The plan adaptation method has the potential for on-line adaptation to deal with inter-fractional motion, as well as fast off-line treatment planning, with either the prescribed physical dose or the RBE-weighted dose.

Intensity modulated, active beam delivery, like magnetic raster scanning, strongly relies on target immobilisation. If target motion cannot be avoided, interferences between the scanning procedure and the tumour displacement destroy the volume conformity. A prototype setup for 3D online motion compensation (3D-OMC) with a scanned particle beam is described, transferring the full potential of volume conformal irradiation to moving targets.

Previous calculations of the water-to-air stopping power ratio (sw,air) for carbon ion beams did not involve tracking of delta ray electrons, even though previous calculations with protons predict an effect up to 1%. We investigate the effect of the delta ray production threshold insw,air calculations and propose an empirical expression which takes into account the effect of the delta ray threshold as well as the uncertainty in the mean ionization potentials (I-values) of air and water. The formula is derived from the results of Monte Carlo calculations using the most up-to-date experimental data for I-values and a delta ray production threshold of 10 keV. It allows us to reduce the standard uncertainty insw,air below 0.8%, instead of the current 2% given in international protocols, which results in a reduction of the overall uncertainty for absolute dosimetry based on air-filled ionization chambers. (Some figures may appear in colour only in the online journal)

Reference dosimetry with ionization chambers requires a number of chamber-specific and beam-specific calibration factors. For carbon ion beams, IAEA report TRS-398 yields a total uncertainty of 3% in the determination of the absorbed dose to water, for which the biggest contribution arises from the water-to-air stopping power ratio (s(w, air)), with an uncertainty of 2%. The variation of (s(w, air)) along the treatment field has been studied in several Monte Carlo works presented over the last few years. Their results were, in all cases, strongly dependent on the choice of mean ionization potentials (I-values) for air and water. A smaller dependence of (s(w, air)) with penetration depth was observed. Since a consensus on I(w, air) and I(air) has not yet been reached, the validity of such studies for clinical use cannot be assessed independently. Our approach is based on a direct experimental measurement of water-equivalent thicknesses of different air gaps at different beam energies. A theoretical expression describing the variation of the stopping power ratio with kinetic energy, s(w,air)(E), was derived from the Bethe-Bloch formula and fit to the measured data, yielding a coherent pair of I(w) and I(air) values with I(air)/I(w) = 1.157 ± 0.023. Additionally, the data from five different beam energies were combined in an average value of s(w,air) = 1.132 ± 0.003 (statistical) ± 0.003 (variation over energy range), valid for monoenergetic carbon ion beams at the plateau area of the depth dose distribution. A detailed uncertainty analysis was performed on the data, in order to assess the limitations of the method, yielding an overall standard uncertainty below 1% in s(w,air)(E). Therefore, when properly combined with the appropriate models for the fragment spectra, our experimental work can contribute to narrow the uncertainty margins currently in use in absorbed dose to water determination for dosimetry of carbon ion beam radiotherapy.

Beam tracking as a mitigation technique for treatment of intra-fractionally moving organs requires prediction to overcome latencies in the adaptation process. We implemented and experimentally tested a prediction method for scanned carbon beam tracking. Beam tracking parameters, i.e. the shift of the Bragg peak position in 3D, are determined prior to treatment in 4D treatment planning and applied during treatment delivery in dependence on the motion state of the target as well as on the scanning spot in the target. Hence, prediction is required for the organ motion trajectory as well as the scanning progress to achieve maximal performance. Prediction algorithms to determine beam displacements that overcome these latencies were implemented. Prediction times of 25 ms for target spot prediction were required for ∼6 mm water-equivalent longitudinal beam shifts. The experimental tests proved feasibility of the implemented prediction algorithm.

We present an algorithm suitable for the calculation of the RBE-weighted dose for moving targets with a scanned particle beam. For verification of the algorithm, we conducted a series of cell survival measurements that were compared to the calculations. Calculation of the relative biological effectiveness (RBE) with respect to tumor motion was included in the treatment planning procedure, in order to fully assess its impact on treatment delivery with a scanned ion beam. We implemented an algorithm into our treatment planning software TRiP4D which allows determination of the RBE including its dependence on target tissue, absorbed dose, energy and particle spectra in the presence of organ motion. The calculations are based on time resolved computed tomography (4D-CT) and the corresponding deformation maps. The principal of the algorithm is illustrated in in silico simulations that provide a detailed view of the different compositions of the energy and particle spectra at different target positions and their consequence on the resulting RBE. The calculations were experimentally verified with several cell survival measurements using a dynamic phantom and a scanned carbon ion beam. The basic functionality of the new dose calculation algorithm has been successfully tested in in silico simulations. The algorithm has been verified by comparing its predictions to cell survival measurements. Four experiments showed in total a mean difference (standard deviation) of ?1.7% (6.3%) relative to the target dose of 9 Gy (RBE). The treatment planning software TRiP is now capable to calculate the patient relevant RBE-weighted dose in the presence of target motion and was verified against cell survival measurements.

In ion beam therapy (IBT), organ motion requires special procedures. Of general concern is the impact on the dose distribution as a result of motion-related changes in the beam’s range. In addition, interplay effects can arise for scanned beam application which cannot be addressed by the so-called margins to increase the treated volume. Dedicated motion mitigation techniques and/or 4D treatment planning are required. This chapter introduces the main concepts for management of respiratory motion in IBT.

In this paper we propose a novel similarity metric and a method for deformable registration of two images for a specific clinical application. The basic assumption in almost all deformable registration approaches is that there exist explicit correspondences between pixels across the two images. This principle is used to design image (dis)similarity metrics, such as sum of squared differences (SSD) or mutual information (MI). This assumption is strongly violated, for instance, within specific regions of images from abdominal or pelvic section of a patient taken at two different time points. Nevertheless, in some clinical applications, it is required to compute a smooth deformation field for all the regions within the image including the boundaries of such regions. In this paper, we propose a deformable registration method, which utilizes a priori intensity distributions of the regions delineated on one of the images to devise a new similarity measure that varies across regions of the image to establish a smooth and robust deformation field. We present validation results of the proposed method in mapping bladder, prostate, and rectum contours of computer tomography (CT) volumes of 10 patients taken for prostate cancer radiotherapy treatment planning and verification.

Clinical outcomes of charged particle therapy are very promising. Currently, several dedicated centers that use scanning beam technology are either close to clinical use or under construction. Since scanned beam treatments of targets that move with respiration most likely result in marked local over- and underdosage due to interplay of target motion and dynamic beam application, dedicated motion mitigation techniques have to be employed. To date, the motion mitigation techniques, rescanning, beam gating, and beam tracking, have been proposed and tested in experimental studies. Rescanning relies on repeated irradiations of the target with the number of particles reduced accordingly per scan to statistically average local misdosage. Specific developments to prohibit temporal correlation between beam scanning and target motion will be required to guarantee adequate averaging. For beam gating, residual target motion within gating windows has to be mitigated in order to avoid local misdosage. Possibly the most promising strategy is to increase the overlap of adjacent particle pencil beams laterally as well as longitudinally to effectively reduce the sensitivity against small residual target motion. The most conformal and potentially most precise motion mitigation technique is beam tracking. Individual particle pencil beams have to be adapted laterally as well as longitudinally according to the target motion. Within the next several years, it can be anticipated that rescanning as well as beam gating will be ready for clinical use. For rescanning, treatment planning margins that incorporate the full extent of target motion as well as motion induced density variations in the beam paths will result in reduced target conformity of the applied dose distributions. Due to the limited precision of motion monitoring devices, it seems likely that beam gating will be used initially to mitigate interplay effects only but not to considerably decrease treatment planning margins. Then, in the next step, beam gating, based on more accurate motion monitoring systems, provides the possibility to restore target conformity as well as steep dose gradients due to reduced treatment planning margins. Accurate motion monitoring systems will be required for beam tracking. Even though beam tracking has already been successfully tested experimentally, full clinical implementation requires direct feedback of the actual target position in quasireal time to the treatment control system and can be anticipated to be several more years ahead.

Treatment of intra-fractionally moving targets with scanned ion beams requires motion mitigation techniques due to interplay effects. We implemented Gating (paused irradiation) and Beam Tracking (position adaptive irradiation) at GSI and performed experimental studies to validate both techniques. Gating requires mitigation of interplay effects within the gating window. An increased overlap, e.g. larger beam spots at constant spacing of rasterpoints was successfully tested. At 5 mm gating windows and 1 mm spacing, 10 mm FWHM beam spot sizes are required. Beam Tracking accuracy was studied in comparison to stationary irradiations with an ionization chamber array. Within the target volume deviations of 0.3 ± 1.5 % were measured. Clinical implementation at the Heidelberg Ion Beam therapy (HIT) will start with Gating. The mid-term goal is Beam Tracking because treatment planning studies for lung tumors showed that Tracking results in a reduced dose to the ipsilateral lung in comparison to Gating.

The software treatment planning for particles (TRiP) was extended by the functionality to calculate the clinically relevant RBE-weighted dose for scanned ion beams in the presence of motion. Calculations are based on 4D-CT and deformable registration. The underlying biological model is the local effect model. To validate the dose calculation algorithm experimentally a dedicated motion phantom for biological dosimetry was developed. In-vitro cell survival measurements were performed with a target dose of 9 Gy (RBE). The mean dose difference between the calculation and the measurement and its standard deviation was obtained to be 155±400 mGy (RBE). This validates the calculation within the measurement error of 519 mGy (RBE).

In carbon ion radiotherapy treatment planning it is necessary to convert CT values in Hounsfield units (HU) measured with a computed tomography (CT) system into a water-equivalent path length. Therefore it is essential that the CT values are exactly known along the carbon ion beam paths.

Tumor irradiations using scanned particle beams provide superior target conformity and dose homogeneity for stationary tumors. In case of intrafractional motion interference between beam scanning and tumor motion causes deteriorations of the deposited dose distributions necessitating dedicated motion mitigation techniques. Different techniques are currently investigated at GSI. The most favorable among them in terms of target conformity and sparing of organs at risk and normal tissues is beam tracking, i.e. adapting the Bragg peak positions on-line according to the tumor motion in all three dimensions. Adaptation of Bragg peak positions only does not mitigate possible dose changes along the beam’s path. Consideration of the respective dose changes has been shown to be beneficial for a future clinical implementation of beam tracking but has to be performed on-line, i.e. during treatment, because of tumor trajectory variations between different respiratory cycles. Functionality to account for these dose changes caused by tumor motion has been implemented in the experimental branch of the therapy control system at GSI. Basic functionality of the on-line dose compensation was tested experimentally with a series of measurements in 2D with radiographic films and in 3D with an array of ionization chambers. In both cases a reference irradiation could be reproduced using the dose compensation functionality. In case of the ionization chamber measurement severe over- and under-dosages of up to 25% compared to reference irradiation for 3D beam tracking without on-line dose compensation could be reduced to below 3% by additionally employing the dose compensation functionality. It has been shown that the fluence of every rasterpoint can be individually adapted during irradiation.

In this paper we propose a novel similarity metric and a method for deformable registration of two images for a specific clinical application. The basic assumption in almost all deformable registration approaches is that there exist explicit correspondences between pixels across the two images. This principle is used to design image (dis)similarity metrics, such as sum of squared differences (SSD) or mutual information (MI). This assumption is strongly violated, for instance, within specific regions of images from abdominal or pelvic section of a patient taken at two different time points. Nevertheless, in some clinical applications, it is required to compute a smooth deformation field for all the regions within the image including the boundaries of such regions. In this paper, we propose a deformable registration method, which utilizes a priori intensity distributions of the regions delineated on one of the images to devise a new similarity measure that varies across regions of the image to establish a smooth and robust deformation field. We present validation results of the proposed method in mapping bladder, prostate, and rectum contours of computer tomography (CT) volumes of 10 patients taken for prostate cancer radiotherapy treatment planning and verification.

Fast range adaptation is essential for three dimensional (3D) beam tracking for precise irradiations of moving targets with scanned ion beams.

More than 10 years of clinical operation of in-beam PET at GSI Darmstadt have proven its positive impact on quality assurance of carbon ion therapy, mostly for head-and-neck sites. Due to the promise of ion beam therapy for indications such as lung and liver tumors which are influenced by respiratory motion we started to investigate the potential of time-resolved, 4D in-beam PET. 4D in-beam PET is expected to facilitate in-vivo assessment of tumor miss or unwanted involvement of nearby critical structures in the presence of organ motion. In a first experiment performed at GSI, in-beam PET was used in combination with beam tracking. A homogeneous PMMA phantom was placed in the center of the field of view of the PET camera and moved parallel to the two detector heads (left-right in beam’s eye view, amplitude: 3 cm peak-to-peak, period: ∼ 3 s). Dose was delivered by beam tracking as a two-dimensionally spread-out Bragg-peak of 5 cm × 5 cm extension, centered at a depth of 10 cm in the central plane of the phantom. The dynamic PET acquisition was performed during the 6 min of beam delivery and for 25 min after irradiation. The data stream was synchronized with the time course of the dynamic beam application and with the phantom motion. Additional 18 min of decay were acquired with the activated phantom kept steady, for comparison with a separate measurement of the same treatment field without motion. Reconstruction of the data taken with a steady phantom yielded comparable activation patterns after beam tracking and stationary irradiation. For the acquisition under phantom motion with beam tracking, motion phase-sorted 4D PET reconstruction with 4D attenuation correction has been implemented. Summation of the phase-sorted distributions co-registered to the motion phase of the stationary reference irradiation shows the feasibility of 4D in-beam PET for recovery of the volumetric extension of fields delivered to moving targets. As for conventional 3D in-beam PET, counting statistics is a critical issue for the achievable accuracy in treatment verification.

Deformable registration is needed for a variety of tasks in establishing the voxel correspondence between respiratory phases. Most registration algorithms assume or imply that the deformation field is smooth and continuous everywhere. However, the lungs are contained within closed invaginated sacs called pleurae and are allowed to slide almost independently along the chest wall. This sliding motion is characterized by a discontinuous vector field, which cannot be generated using standard deformable registration methods. The authors have developed a registration method that can create discontinuous vector fields at the boundaries of anatomical subregions. Registration is performed independently on each subregion, with a boundary-matching penalty used to prevent gaps. This method was implemented and tested using both the B-spline and Demons registration algorithms in the Insight Segmentation and Registration Toolkit. The authors have validated this method on four patient 4DCT data sets for registration of the end-inhalation and end-exhalation volumes. Multiple experts identified homologous points in the lungs and along the ribs in the two respiratory phases. Statistical analyses of the mismatch of the homologous points before and after registration demonstrated improved overall accuracy for both algorithms.

Background Intrafractional motion results in local over- and under-dosage in particle therapy with a scanned beam. Scanned beam delivery offers the possibility to compensate target motion by tracking with the treatment beam. Methods Lateral motion components were compensated directly with the beam scanning system by adapting nominal beam positions according to the target motion. Longitudinal motion compensation to mitigate motion induced range changes was performed with a dedicated wedge system that adjusts effective particle energies at isocenter. Results Lateral compensation performance was better than 1% for a homogeneous dose distribution when comparing irradiations of a stationary radiographic film and a moving film using motion compensation. The accuracy of longitudinal range compensation was well below 1 mm. Conclusion Motion compensation with scanned particle beams is technically feasible with high precision.

Treatment of moving targets with scanned particle beams results in local over- and under-dosage due to interplay of beam and target motion. To mitigate the impact of respiratory motion, a motion tracking system has been developed and integrated in the therapy control system at Gesellschaft für Schwerionenforschung. The system adapts pencil beam positions as well as the beam energy according to target motion to irradiate the planned position. Motion compensation performance of the tracking system was assessed by measurements with radiographic films and a 3D array of 24 ionization chambers. Measurements were performed for stationary detectors and moving detectors using the tracking system. Film measurements showed comparable homogeneity inside the target area. Relative differences of 3D dose distributions within the target volume were 1 +/- 2% with a maximum of 4%. Dose gradients and dose to surrounding areas were in good agreement. The motion tracking system successfully preserved dose distributions delivered to moving targets and maintained target conformity.

To assess the accuracy of maximum-intensity volumes (MIV) for fast contouring of lung tumors including respiratory motion.Four-dimensional computed tomography (4DCT) data of 10 patients were acquired. Maximum-intensity volumes were constructed by assigning the maximum Hounsfield unit in all CT volumes per geometric voxel to a new, synthetic volume. Gross tumor volumes (GTVs) were contoured on all CT volumes, and their union was constructed. The GTV with all its respiratory motion was contoured on the MIV as well. Union GTVs and GTVs including motion were compared visually. Furthermore, planning target volumes (PTVs) were constructed for the union of GTVs and the GTV on MIV. These PTVs were compared by centroid position, volume, geometric extent, and surface distance.Visual comparison of GTVs demonstrated failure of the MIV technique for 5 of 10 patients. For adequate GTV(MIV)s, differences between PTVs were1.0 mm in centroid position, 5% in volume, +/-5 mm in geometric extent, and +/-0.5 +/- 2.0 mm in surface distance. These values represent the uncertainties for successful MIV contouring.Maximum-intensity volumes are a good first estimate for target volume definition including respiratory motion. However, it seems mandatory to validate each individual MIV by overlaying it on a movie loop displaying the 4DCT data and editing it for possible inadequate coverage of GTVs on additional 4DCT motion states.

Four-dimensional CT acquisition is commercially available, and provides important information on the shape and trajectory of the tumor and normal tissues. The primary advantage of four-dimensional imaging over light breathing helical scans is the reduction of motion artifacts during scanning that can significantly alter tumor appearance. Segmentation, image registration, visualization are new challenges associated with four-dimensional data sets because of the overwhelming increase in the number of images. Four-dimensional dose calculations, while currently laborious, provide insights into dose perturbations due to organ motion. Imaging before treatment (image guidance) improves accuracy of radiation delivery, and recording transmission images can provide a means of verifying gated delivery.

At Gesellschaft für Schwerionenforschung (GSI) more than 330 patients have been treated with scanned carbon ion beams in a pilot project. To date, only stationary tumors have been treated. In the presence of motion, scanned ion beam therapy is not yet possible because of interplay effects between scanned beam and target motion which can cause severe mis-dosage. We have started a project to treat tumors that are subject to respiratory motion. A prototype beam application system for target tracking with the scanned pencil beam has been developed and commissioned.To facilitate treatment planning for tumors that are subject to organ motion, we have extended our standard treatment planning system TRiP to full 4D functionality. The 4D version of TRiP allows to calculate dose distributions in the presence of motion. Furthermore, for motion mitigation techniques tracking, gating, rescanning, and internal margins optimization of treatment parameters has been implemented. 4D calculations are based on 4D computed tomography data, deformable registration maps, organ motion traces, and beam scanning parameters.We describe the methods of our 4D treatment planning approach and demonstrate functionality of the system for phantom as well as patient data.

We propose a novel numerical approach for solving the free-form deformable registration problem. The central idea is to utilize the well understood techniques from variational deformable registration problems. We demonstrate that it is possible to formulate the free-form deformable registration problem as the optimization of an energy functional as in the dense deformation case. This energy functional possesses image distance and regularization terms, which are both functions of the free-form deformation control points. We then setup a semi-backward (implicit) partial differential equation that optimizes the established energy functional. In addition to being mathematically justified, this approach provides both accuracy and speed. Our evaluation on synthetic, real, two dimensional, and three dimensional data demonstrates accuracy and computational effectiveness.

Four-dimensional CT acquisition is commercially available, and provides important information on the shape and trajectory of the tumor and normal tissues. The primary advantage of four-dimensional imaging over light breathing helical scans is the reduction of motion artifacts during scanning that can significantly alter tumor appearance. Segmentation, image registration, visualization are new challenges associated with four-dimensional data sets because of the overwhelming increase in the number of images. Four-dimensional dose calculations, while currently laborious, provide insights into dose perturbations due to organ motion. Imaging before treatment (image guidance) improves accuracy of radiation delivery, and recording transmission images can provide a means of verifying gated delivery.

Precise localization of moving targets is essential to increase local control of the cancer via dose escalation while reducing the severity of normal tissue complication. Localization of targets in real time with radio-opaque marker is less favorable considering the excess radiation dose to the patient and potential complications of implantation. Various external surrogates could provide indications of the targets' positions during the breathing process. However, there is a great deal of uncertainty in the correlation between external surrogates and internal target positions/trajectory during respiratory cycles. In order to address this problem, we have developed an algorithm that automatically establishes correspondences between the fluoroscopic sequence frames taken from the patient on the day of treatment and the various phases of a 4DCT planning data set. Image based mapping/synchronization procedure is performed using an underlying Markov model established for the breathing process. The mapping procedure is formulated as an optimization process and is solved efficiently using a dynamic programming technique. Results on the phantom, synthetic, and real patient data demonstrate the effectiveness of the proposed method in coping with respiratory correlation variations. The approach could primarily be used for automatic gating interval adaptation in the gated radiotherapy.

Four-dimensional radiotherapy requires deformable registration to track delivered dose across varying anatomical states. Deformable registration based on B-splines was implemented to register 4D computed tomography data to a reference respiratory phase. To assess registration performance, anatomical landmarks were selected across ten respiratory phases in five patients. These point landmarks were transformed according to global registration parameters between different respiratory phases. Registration uncertainties were computed by subtraction of transformed and reference landmark positions. The selection of appropriate registration masks to separate independently moving anatomical subunits is crucial to registration performance. The average registration error for five landmarks for each of five patients was 2.1 mm. This level of accuracy is acceptable for most radiotherapy applications.

This study investigated the sensitivity of static planning of intensity-modulated beams (IMBs) to intrafraction deformable organ motion and assessed whether smoothing of the IMBs at the treatment-planning stage can reduce this sensitivity. The study was performed with a 4D computed tomography (CT) data set for an IMRT treatment of a patient with liver cancer. Fluence profiles obtained from inverse-planning calculations on a standard reference CT scan were redelivered on a CT scan from the 4D data set at a different part of the breathing cycle. The use of a nonrigid registration model on the 4D data set additionally enabled detailed analysis of the overall intrafraction motion effects on the IMRT delivery during free breathing. Smoothing filters were then applied to the beam profiles within the optimization process to investigate whether this could reduce the sensitivity of IMBs to intrafraction organ motion. In addition, optimal fluence profiles from calculations on each individual phase of the breathing cycle were averaged to mimic the convolution of a static dose distribution with a motion probability kernel and assess its usefulness. Results from nonrigid registrations of the CT scan data showed a maximum liver motion of 7 mm in superior-inferior direction for this patient. Dose-volume histogram (DVH) comparison indicated a systematic shift when planning treatment on a motion-frozen, standard CT scan but delivering over a full breathing cycle. The ratio of the dose to 50% of the normal liver to 50% of the planning target volume (PTV) changed up to 28% between different phases. Smoothing beam profiles with a median-window filter did not overcome the substantial shift in dose due to a difference in breathing phase between planning and delivery of treatment. Averaging of optimal beam profiles at different phases of the breathing cycle mainly resulted in an increase in dose to the organs at risk (OAR) and did not seem beneficial to compensate for organ motion compared with using a large margin. Additionally, the results emphasized the need for 4D CT scans when aiming to reduce the internal margin (IM). Using only a single planning scan introduces a systematic shift in the dose distribution during delivery. Smoothing beam profiles either based on a single scan or over the different breathing phases was not beneficial for reducing this shift.

Respiratory correlated CT is commercially available, and we have implemented its routine clinical use in planning lung tumor patients. Its value is determined by the fidelity of the spatiotemporal data set after processing the acquired reconstructed slices. Retrospective sorting of reconstructed slices is based on respiratory phase. However, the existing commercial software inadequately models respiratory phase for about 30% of the patients, mainly due to irregularities in the respiratory cycle. We have developed software that improves phase determination and consequently leads to an improvement of retrospective data sorting to make 4DCT data acquisition feasible for routine clinical use. Peak inhalation and exhalation respiratory states are selected manually; intermediate phases are interpolated. Residual motion artifacts in the resulting 4DCT volumes are reduced and allow use of the 4D imaging studies for treatment planning.