Respiratory motion management in particle therapy.

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.

4D in-beam positron emission tomography for verification of motion-compensated ion beam therapy.

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 possibility to verify the correct functioning of beam tracking. Motion compensation of the imaged beta(+)-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.

Speed and accuracy of a beam tracking system for treatment of moving targets with scanned ion beams.

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 to < or =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.

Maximum-intensity volumes for fast contouring of lung tumors including respiratory motion in 4DCT planning.

PURPOSE: To assess the accuracy of maximum-intensity volumes (MIV) for fast contouring of lung tumors including respiratory motion. METHODS AND MATERIALS: 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. RESULTS: Visual comparison of GTVs demonstrated failure of the MIV technique for 5 of 10 patients. For adequate GTV(MIV)s, differences between PTVs were <1.0 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. CONCLUSION: 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.

Evaluation of deformable registration of patient lung 4DCT with subanatomical region segmentations.

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.

Quantification of interplay effects of scanned particle beams and moving targets.

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.

Target motion tracking with a scanned particle beam.

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.

Four-dimensional imaging and treatment planning of moving targets.

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.

Four-dimensional proton treatment planning for lung tumors.

PURPOSE: In proton radiotherapy, respiration-induced variations in density lead to changes in radiologic path lengths and will possibly result in geometric misses. We compared different treatment planning strategies for lung tumors that compensate for respiratory motion. METHODS AND MATERIALS: Particle-specific treatment planning margins were applied to standard helical computed tomography (CT) scans as well as to "representative" CT scans. Margins were incorporated beam specific laterally by aperture widening and longitudinally by compensator smearing. Furthermore, treatment plans using full time-resolved 4D-computed tomography data were generated. RESULTS: Four-dimensional treatment planning guaranteed target coverage throughout a respiratory cycle. Use of a standard helical CT data set resulted in underdosing the target volume to 36% of the prescribed dose. For CT data representing average target positions, coverage can be expected but not guaranteed. In comparison to this strategy, 4D planning decreased the mean lung dose by up to 16% and the lung volume receiving 20 Gy (prescribed target dose 72 Gy) by up to 15%. CONCLUSION: When the three planning strategies are compared, only 4D proton treatment planning guarantees delivery of the prescribed dose throughout a respiratory cycle. Furthermore, the 4D planning approach results in equal or reduced dose to critical structures; even the ipsilateral lung is spared.

Design of 4D treatment planning target volumes.

PURPOSE: When using non-patient-specific treatment planning margins, respiratory motion may lead to geometric miss of the target while unnecessarily irradiating normal tissue. Imaging different respiratory states of a patient allows patient-specific target design. We used four-dimensional computed tomography (4DCT) to characterize tumor motion and create treatment volumes in 10 patients with lung cancer. These were compared with standard treatment volumes. METHODS AND MATERIALS: Four-dimensional CT and free breathing helical CT data of 10 patients were acquired. Gross target volumes (GTV) were delineated on the helical scan as well as on each phase of the 4D data. Composite GTVs were defined on 4DCT. Planning target volumes (PTV) including clinical target volume, internal margin (IM), and setup margin were generated. 4DPTVs with different IMs and standard PTVs were compared by computing centroid positions, volumes, volumetric overlap, and bounding boxes. RESULTS: Four-dimensional PTVs and conventional PTVs differed in volume and centroid positions. Overlap between 4DPTVs generated from two extreme tumor positions only compared with 10 respiratory phases was 93.7%. Comparing PTVs with margins of 15 mm (IM 5 mm) on composite 4D target volumes to PTVs with 20 mm (IM 10 mm) on helical CT data resulted in a decrease in target volume sizes by 23% on average. CONCLUSION: With patient-specific characterization of tumor motion, it should be possible to decrease internal margins. Patient-specific treatment volumes can be generated using extreme tumor positions on 4DCT. To date, more than 150 patients have been treated using 4D target design.

Improving retrospective sorting of 4D computed tomography data.

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.

Deformable registration of 4D computed tomography data.

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.

Simulations to design an online motion compensation system for scanned particle beams.

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.

Four-dimensional image-based treatment planning: Target volume segmentation and dose calculation in the presence of respiratory motion.

PURPOSE: To describe approaches to four-dimensional (4D) treatment planning, including acquisition of 4D-CT scans, target delineation of spatio-temporal image data sets, 4D dose calculations, and their analysis. METHODS AND MATERIALS: The study included patients with thoracic and hepatocellular tumors. Specialized tools were developed to facilitate visualization, segmentation, and analysis of 4D-CT data: maximum intensity volume to define the extent of lung tumor motion, a 4D browser to examine and dynamically assess the 4D data sets, dose calculations, including respiratory motion, and deformable registration to combine the dose distributions at different points. RESULTS: Four-dimensional CT was used to visualize and quantitatively assess respiratory target motion. The gross target volume contours derived from light breathing scans showed significant differences compared with those extracted from 4D-CT. Evaluation of deformable registration using difference images of original and deformed anatomic maps suggested the algorithm is functionally useful. Thus, calculation of effective dose distributions, including respiratory motion, was implemented. CONCLUSION: Tools and methods to use 4D-CT data for treatment planning in the presence of respiratory motion have been developed and applied to several case studies. The process of 4D-CT-based treatment planning has been implemented, and technical barriers for its routine use have been identified.

Four-dimensional computed tomography: image formation and clinical protocol.

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.

A technique for respiratory-gated radiotherapy treatment verification with an EPID in cine mode.

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.

Temporo-spatial IMRT optimization: concepts, implementation and initial results.

With the recent availability of 4D-CT, the accuracy of information on internal organ motion during respiration has improved significantly. We investigate the utility of organ motion information in IMRT treatment planning, using an in-house prototype optimization system. Four approaches are compared: (1) planning with optimized margins, based on motion information; (2) the 'motion kernel' approach, in which a more accurate description of the dose deposit from a pencil beam to a moving target is achieved either through time-weighted averaging of influence matrices, calculated for different instances of anatomy (subsets of 4D-CT data, corresponding to various phases of motion) or through convolution of the pencil beam kernel with the probability density function describing the target motion; (3) optimal gating, or tracking with beam intensity maps optimized independently for each instance of anatomy; and (4) optimal tracking with beam intensity maps optimized simultaneously for all instances of anatomy. The optimization is based on a gradient technique and can handle both physical (dose-volume) and equivalent uniform dose constraints. Optimization requires voxel mapping from phase to phase in order to score the dose in individual voxels as they move. The results show that, compared to the other approaches, margin expansion has a significant disadvantage by substantially increasing the integral dose to patient. While gating or tracking result in the best dose conformation to the target, the former elongates treatment time, and the latter significantly complicates the delivery procedure. The 'motion kernel' approach does not provide a dosimetric advantage, compared to optimal tracking or gating, but might lead to more efficient delivery. A combination of gating with the 'motion kernel' or margin expansion approach will increase the duty cycle and may provide one with the most efficient solution, in terms of complexity of the delivery procedure and dose conformality to the target.

Effects of motion on the total dose distribution.

The success of highly target-conformal treatments such as intensity-modulated radiotherapy (IMRT) can be compromised by motion of the inner organs and random patient setup errors. This article gives an overview of different studies that looked at the effect of organ motion and setup errors on radiation therapy dose distributions, both from a qualitative and quantitative point of view. The qualitative findings are generally applicable (ie, case independent). It is found that motion always leads to a blurring of the dose distribution. In addition, there are so-called interplay effects if the treatment delivery involves moving parts, such as multileaf collimators. After a large number of fractions, the interplay effects lead to a normal distribution of the dose value around the average blurred value. Thirdly, organ motion can also cause a spatial deformation of the dose distribution. Quantitatively it has been found that both deformation and interplay effects appear to be small (in the order of 1%-2%) in many typical clinical cases. The dominant effect is the blurring of the dose distribution, which is, in essence, independent of the treatment technique, and is not more pronounced in IMRT than in more conventional treatment techniques. However, because in IMRT there is a tendency to reduce or compromise target margins, the blurring has potentially a bigger effect on the outcome of IMRT, unless precision dose delivery techniques (such as gated or motion-synchronized beams) are used. An alternative to the use of margins is to do the planning based on blurred dose distributions.

Monte Carlo simulations with time-dependent geometries to investigate effects of organ motion with high temporal resolution.

PURPOSE: To calculate the dose in time-dependent geometry, the results of three-dimensional calculations are usually performed separately and combined. This approach becomes cumbersome when high temporal resolution is required, if the geometry is complex, or if interplay effects between different, independently moving systems are to be studied. The purpose of this project was the implementation of continuous (four-dimensional [4D]) Monte Carlo simulation to study the irradiation of tumors under respiratory motion. METHODS AND MATERIALS: In taking advantage of object-oriented programming, we implemented 4D Monte Carlo dose calculation. Local dose depositions in the patient are calculated while beam configuration and organ positions are changed continuously. Deformable image registration is used to describe the CT voxel displacement over time. RESULTS: The 4D Monte Carlo technique is applied to a lung cancer case planned for proton therapy. We show that the effect of motion on the dose distribution can be simulated effectively based on statistical motion parameterizations acting on the geometry or based on patient-specific 4D CT information. CONCLUSION: We present a novel method able to calculate dose with underlying time-dependent geometry. The technique allows 4D dose calculation in arbitrary time scales in a single simulation even for double-dynamic systems (e.g., time-dependent beam delivery under organ motion).