Background
At GSI Helmholtzzentrum für Schwerionenforschung (GSI) more than 430 patients with tumors mainly in the head and neck area were treated with a rasterscanned carbon beam [
1,
2]. For treatment of respiration-influenced tumors motion mitigation techniques will be required because the interference of target motion and scanned beam delivery potentially leads to mis-dosage, typically referred to as interplay [
3,
4]. Beam gating [
5], rescanning [
3], and beam tracking [
6,
7] have been proposed to adequately irradiate moving targets with scanned particle beams.
Tracking has been suggested in different technical ways and for different treatment modalities. For photon radiotherapy tracking is implemented clinically in the Cyberknife Synchrony system [
8]. Adaptations are primarily in the lateral dimensions and can therefore also be performed by dynamically adapting the multi-leaf collimator of a standard linear accelerator [
6]. In contrast to photon therapy, particle therapy requires modulation not only in the lateral direction but also in the radiological depth because organ motion potentially changes densities in the beam paths and therefore the particle ranges [
9].
A feasibility study at GSI showed that the rasterscan beam delivery system can be extended to treat moving tumours by beam tracking by adapting the position of rasterpoints [
10]. Lateral adaptation is performed by real-time changes of the scanning magnet settings. Compensation of changes in radiological depth is carried out by a passive energy modulation system installed proximal to the isocenter. The system consists of two opposing absorber wedges that are opened (closed) by fast linear motors when the radiological length has to be increased (decreased). Within the feasibility study, individual compensation components were tested independently. To allow simultaneous lateral and range adaptation the initial prototype system has been redesigned, fully integrated into the therapy control system (TCS), and technically commissioned [
7,
11].
The data in this report present a full set of dosimetric studies performed with the most recent version of the tracking system. Earlier investigations focused on individual components of the beam tracking system [
10], its technical performance [
11], as well as initial dosimetric measurements [
7]. We utilized our experience from previous, independent measurement series to determine the accuracy of 3D dose distributions as well as the RBE-effective dose, to investigate the implications of beam tracking for volumes proximal to the target volume, and to perform detailed measurements with respect to range adaptation. In order to examine the beam tracking performance independent from possible ambiguities of target motion detection an accurate industrial motion sensor was employed to monitor the motion trajectories of moving phantoms.
Discussion
Beam tracking is one of the options to treat tumors that are subject to respiratory motion with scanned ion beams. The presented data demonstrate that beam tracking is a feasible and accurate motion mitigation technique.
Small deviations between data from tracking and stationary reference irradiations most likely result from the experimental setup accuracy and the precision of the detector systems. In case of the cell survival experiments, the latter is dominating due to the complex cell processing procedure, including several cell handling steps, and the inherent biological variability. A large deviation in data points is observed in the survival points at +13.5 mm (Fig.
5), but this could be due to the limited statistical power of these experiments (3 independent experiments only). Concerning modeling of biological effects that have to be considered for heavy ion irradiation such as carbon beams the accuracy of the local-effect model for the primary beam and its fragments in the therapy relevant energy range has to be considered also for moving targets. Since our investigation focused on the impact of target motion and validation of the beam tracking system rather than validation of the biological modeling we did not include uncertainties of the model into the comparison between experimental and calculated data.
Additional uncertainties are related to induction and measurement of motion trajectories, discretization of the radiological depth compensation, and potentially the temporal response of the system. Since compensation parameters were determined relative to the voltage level measured by the displacement sensor, a shift of the motion table center (mean voltage level, i.e. compensation = 0) with respect to the isocenter leads to a small shift of the dose distribution. This effect is observable in the profiles of film measurements (fig.
2, distal film, beam tracking vs. stationary) and in the measurements with the pinpoint-ionization chambers (detected shift of 0.6 mm). The magnitude of each shift is comparable to the 0.75 mm shift reported previously [
7]. In principle this alignment uncertainty could be further reduced by a more precise motion phantom and improved alignment tools for the heavy water tank (~25 kg). Positioning accuracy of the MicroWell plates is estimated to be less than 1 mm and comprises both the alignment uncertainty of the container and the positioning precision of the plates within the container. Precision of the radiological depth compensation with the energy modulation system is currently limited by digitization to 0.16 mm water-equivalence for communication between therapy control system and controller of the energy modulation system [
11]. At least parts of the measured deviation in Bragg-peak depth (~250
μ m) can be attributed to this technical limitation. However, in comparison to typical range uncertainties [
17] this residual deviation is small; nonetheless it would be possible to decrease the step size by improving the communication if required by future applications. The temporal response of the system was studied in detail by Saito et al. [
11]. For lateral compensation the system response is below 1 ms which is much faster than typical irradiation times of 10 ms per spot and thus has a negligible impact on the experimental results. Range compensation is slower. A systematic communication delay of 16 ms plus a mechanical motion delay of for example 11 ms for 5 mm WE range change is required. Since we used motion prediction for the range adaptation component the limited response time of the range modulation device can be mitigated. The results of the depth dose distribution measurements shown in fig.
3 show the feasibility of accurate range adaptation.
Possible systematic uncertainties such as film developer conditions, differences between film batches, entrance position of the range telescope,
W- value, and positioning of ionization chambers within the water phantom are not relevant because beam tracking performance was compared to stationary reference measurements within the same experimental series. Random uncertainties are present in film analysis (1 mm pixel size in digitization process, 3 mm FWHM beam spot for coordinate system), in the positioning accuracy of the range telescope (10
μ m stepping motor step size) [
16], and due to accumulated background in the ionization chamber measurements which Karger et al. reported to be 0.5 - 1 mGy/min leading to ~ 0.1% uncertainty in our measurements (2 Gy in ~2.5 min) [
15]. In addition, the mechanical precision of the ramp-shaped absorber, the container of the cell samples as well as the wedge-system of the energy modulation system has to be considered which can be estimated to be in the range of 0.1-0.2 mm (each). Biological variability leads to mean standard errors of 4% and 5% for the moving and the stationary setup which is comparable to previous cell survival experiments [
14].
For future clinical use of a beam tracking system, larger uncertainties can be expected due to well-known deviations resulting from patient positioning [
23] range deviations [
17], and motion detection. The impact of these uncertainties on beam tracking will be subject of further research.
In the current status, the beam tracking system is capable to irradiate treatment plans of e.g. liver cancer patients that do not show large range variations. To further advance towards clinical use of ion beam tracking more work is required mainly concerning accurate and precise motion detection, robust treatment planning, and potentially with respect to an improved range modulation system as recently proposed by Chaudhri et al. [
24]. It has been reported by several authors that tumor motion characteristics change over the course of treatment [
9,
25]. Feasible mitigation strategies have to be developed because such changes might alter the dose distribution of dedicated 4D treatment plans applied by beam tracking. In the next step, serial 4DCT patient data will be analyzed and possible techniques to mitigate interfractional changes will be investigated. Besides adequate target dosage, effective doses deposited proximal of the target could be considered. As demonstrated with film experiments, if target motion is compensated by beam tracking inverse interplay effects in proximal regions can lead to over-dosage [
4] that should ideally be considered for dose distributions of proximal tissues or even organs-at-risk.
Adequate performance of the motion monitoring system will be as important as the technical precision of the beam tracking system. Several research groups are working on precise motion monitoring and motion prediction techniques; motion detection in the < 2 mm range has recently been reported [
26,
27]. Sawant et al. achieved a geometrical precision of < 1 mm for a multi-leaf collimator based tracking system that obtains motion information from a Calypso system [
26]. Lin et al. used principal component analysis to track lung tumors in fluoroscopic images and reported mean localization errors of less than 1 mm with a maximum of 2.5 mm in 12 patients [
27]. For systems that rely on implanted fiducials, like the electro-magnetic Calypso system [
28] or fluoroscopy tracking based on radio-opaque markers [
8], the compatibility with ion beams has to be evaluated with respect to functionality of the beacon transponders in high-LET fields and considering the dosimetric effect. Considering the data reported for motion detection, it seems feasible to detect, model, and predict target motion in quasi real-time sufficiently accurate to allow tracking with particle beams.
Competing interests
The Moving Targets project at GSI is in part funded by Siemens Healthcare, Particle Therapy. ER and AG are employees of Siemens Healthcare, Particle Therapy. ER has the status Guest researcher at GSI. All work was performed during the PhD-work of AG at GSI.
Authors' contributions
Experimental work: CB, AG, NS, NC, DS; Biological dosimetry: AG; Experimental design: CB, AG, NS, ER; Initial draft of manuscript: CB; consulting & supervision: DS, MD, GK, ER; all authors read and approved the final manuscript.