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INTRODUCTION Ocular biometry in Ocular Proton Therapy (OPT) currently relies on a generic geometrical eye model built by referencing surgically implanted markers. An alternative approach based on image fusion of volumetric Magnetic Resonance Imaging (MRI) and panoramic fundus photography was investigated. MATERIALS AND METHODS Eighteen non-consecutive uveal melanoma (UM) patients, who consented for an MRI and had their tumour base visible on panoramic fundus photography, were included in this comparative analysis. Through generating digitally-reconstructed projections from MRI images using the Lambert azimuthal equal-area projection, 2D-3D image fusion between fundus photography and an eye model delineated on MRI scans was achieved and allowed for a novel definition of the target base (MRI + FCTV). MRI + FCTV was compared with MRI-only delineation (MRIGTV) and the conventional (EyePlan) target definition (EPCTV). RESULTS The combined use of fundus photography and MRI to define tumour volumes reduced the average discrepancies by almost 65% with respect to the MRI only tumour definitions when comparing with the conventionally planned EPCTV. With the proposed method, shallow sub-retinal tumour infiltration, otherwise invisible on MRI, can be included in the target volume definition. Moreover, a novel definition of the fovea location improves the accuracy and personalisation of the 3D eye model. CONCLUSION MRI and fundus image fusion overcomes some of the limitations of ophthalmological MRI for tumour volume definition in OPT. This novel eye tumour modelling method might improve treatment planning personalisation, allowing to better anticipate which patients could benefit from prophylactic treatment protocols for radiation induced maculopathy.

Objective. 4D dose reconstruction in proton therapy with pencil beam scanning (PBS) typically relies on a single pre-treatment 4DCT (p4DCT). However, breathing motion during the fractionated treatment can vary considerably in both amplitude and frequency. We present a novel 4D dose reconstruction method combining delivery log files with patient-specific motion models, to account for the dosimetric effect of intra- and inter-fractional breathing variability. Approach. Correlation between an external breathing surrogate and anatomical deformations of the p4DCT is established using principal component analysis. Using motion trajectories of a surface marker acquired during the dose delivery by an optical tracking system, deformable motion fields are retrospectively reconstructed and used to generate time-resolved synthetic 4DCTs (‘5DCTs’) by warping a reference CT. For three abdominal/thoracic patients, treated with respiratory gating and rescanning, example fraction doses were reconstructed using the resulting 5DCTs and delivery log files. The motion model was validated beforehand using leave-one-out cross-validation (LOOCV) with subsequent 4D dose evaluations. Moreover, besides fractional motion, fractional anatomical changes were incorporated as proof of concept. Main results. For motion model validation, the comparison of 4D dose distributions for the original 4DCT and predicted LOOCV resulted in 3%/3 mm gamma pass rates above 96.2%. Prospective gating simulations on the p4DCT can overestimate the target dose coverage V95% by up to 2.1% compared to 4D dose reconstruction based on observed surrogate trajectories. Nevertheless, for the studied clinical cases treated with respiratory-gating and rescanning, an acceptable target coverage was maintained with V95% remaining above 98.8% for all studied fractions. For these gated treatments, larger dosimetric differences occurred due to CT changes than due to breathing variations. Significance. To gain a better estimate of the delivered dose, a retrospective 4D dose reconstruction workflow based on motion data acquired during PBS proton treatments was implemented and validated, thus considering both intra- and inter-fractional motion and anatomy changes., Physics in Medicine and Biology, 68 (11), ISSN:1361-6560, ISSN:0031-9155

PURPOSE/OBJECTIVES To develop a normal tissue complication probability (NTCP) model including clinical and dosimetric parameters for high-grade temporal lobe radionecroses (TRN) after pencil beam scanning (PBS) proton therapy (PT). MATERIALS/METHODS Data of 299 patients with skull base and Head and Neck tumors treated with PBS PT with a total dose of ���60 GyRBE from 05/2004-11/2018 were included. Patients with a ��� grade (G) 2 TRN (CTCAE v5.0 criteria) were considered as having a high-grade TRN. Nine clinical and 27 dosimetric parameters were considered for structure-wise modelling. After elimination of strongly cross-correlated variables, logistic regression models were generated using penalized LASSO regression. Bootstrapping was performed to assess parameter selection robustness. Model performance was evaluated via cross-correlation by assessing the area under the curve of receiver operating characteristic curves (AUC-ROC) and calibration with a Hosmer-Lemeshow test statistic. RESULTS After a median radiological follow-up of 51.5 months (range, 4-190), 27 (9%) patients developed a ��� G2 TRN. Eleven patients had bitemporal necrosis, resulting in 38 events in 598 temporal lobes for structure-wise analysis. During Bootstrapping analysis, the highest selection frequency was found for prescription dose (PD), followed by Age, V40Gy[%], Hypertension (HBP) and D1cc[Gy]. During cross validation Age*PD* D1cc[Gy]*HBP was superior in all described test statistics. Full cohort structure wise and patient wise models were built with a maximum AUC-ROC of 0.79 (structure-wise) and 0.76 (patient-wise). CONCLUSION While developing a logistic regression NTCP model to predict ��� G2 TRN, the best fit was found for the model containing Age, PD, D1cc[Gy] and HBP as risk factors. External validation will be the next step to improve generalizability and potential introduction into clinical routine.

Motion of the tumour during a radiotherapy treatment can compromise the clinical outcome for the cancer patient. To address this challenge the suitability and performance of the Intel RealSense™ D415 depth camera has been investigated as a tool for measuring the respiratory motion of the body surface. The precision of the camera depth data has been characterised as a function of the measurement distance up to 1.2 meters from a stationary and moving surface. The latency of the camera system was also measured. The average standard deviation of depth data in stationary measurements ranged from less than 0.2 mm for the shortest camera-surface distance of 400 mm to 3 mm for a distance of 1200 mm. Similar accuracy is reported for the acquisition of breathing motion with a discrepancy from nominal amplitudes of around 0.5 mm and 5 mm for the two extreme measurement distances. No dependence on the measurement precision has been observed as a function of the motion pattern. Finally, the camera was shown to be able to measure the more patient-like motion of a deformable respiratory motion phantom with an amplitude of surface motion varying from 1.5 – 2.5 mm. Although noisier, the camera data showed good agreement when compared with a NDI Polaris Spectra system. The latency of the Realsense™ system was measured to be 68.6 ms ± 9.6 ms. The results of this work indicate that the D415 RealSense™ depth camera is capable of measurement of external respiratory type motion of an irregular surface.

Purpose Radiation-induced optic neuropathy (RION) is a rare, yet severe complication following radiation therapy for brain, head and neck, or skull-base tumors. Although several risk factors, such as age, metabolic syndrome, and delivered dose, have been identified, we aimed at expanding the understanding of the mechanisms of interplay regarding dosimetry and patient variables leading to the onset of RION with a focus on proton therapy. Methods and Materials In this retrospective study, we have investigated proton-specific risk factors by comparing common phenomenological normal tissue complication probability models with a multivariate analysis that includes clinical features on a cohort of patients with skull-base and head and neck cancer treated with pencil beam scanning. Results Although predictive power of the Lyman-Kutcher-Burman and Poisson models was limited for this data set, the addition of clinical variables such as age, tumor involvement, hypertension, or sex remarkably increased model performance. Conclusions Based on our assessment, the maximum dose in the optical apparatus is confirmed the most intuitive risk factor. However, above a certain dose threshold, clinical patient characteristics are the deciding factors for the onset of RION. We observed a tendency toward a volume effect that, if confirmed, would imply a benefit for high precision radiation therapy techniques such as proton therapy for the treatment of patients with high clinical risk for RION.

Purpose Ocular proton therapy is an effective therapeutic option for patients affected with uveal melanomas. An optical eye-tracking system (ETS) aiming at noninvasive motion monitoring was developed and tested in a clinical scenario. Materials and methods The ETS estimates eye position and orientation at 25 frames per second using the three-dimensional position of pupil and cornea curvature centers identified, in the treatment room, through stereoscopic optical imaging and infrared eye illumination. Its capabilities for automatic detection of eye motion were retrospectively evaluated on 60 treatment fractions. Then, the ETS performance was benchmarked against the clinical standard based on visual control and manual beam interruption. Results Eye-tracking system detected eye position successfully in 97% of all available frames. Eye-tracking system-based eye monitoring during therapy guarantees quicker response to involuntary eye motions than manual beam interruptions and avoids unnecessary beam interruptions. Conclusions Eye-tracking system shows promise for on-line monitoring of eye motion. Its introduction in the clinical workflow will guarantee a swifter treatment course for the patient and the clinical personnel.

PURPOSE Energy changes in Pencil Beam Scanning (PBS) proton therapy can be a limiting factor in delivery time, hence limiting patient throughput and the effectiveness of motion mitigation techniques requiring fast irradiation. In this study, we investigate the feasibility of performing fast and continuous energy modulation within the momentum acceptance of a clinical beamline for proton therapy. METHODS The alternative use of a local beam degrader at the gantry coupling point has been compared with a more common upstream regulation. Focusing on clinically relevant parameters, a complete beam properties characterization has been carried out. In particular, the acquired empirical data allowed to model and parametrize the errors in range and beam current to deliver clinical treatment plans. RESULTS For both options, the local and the upstream degrader, depth-dose curves measured in water for off-momentum beams were only marginally distorted (��(1%,1mm) > 90%) and the errors in the spot position were within the clinical tolerance, even though increasing at the boundaries of the investigated scan range. The impact on the beam size was limited for the upstream degrader while dedicated strategies could be required to tackle the beam broadening through the local degrader. Range correction models were investigated for the upstream regulation. The impaired beam transport required a dedicated strategy for fine range control and compensation of beam intensity losses. Our current parametrization based on empirical data allowed energy modulation within acceptance with range errors (median 0.05 mm) and transmission (median -14%) compatible with clinical operation and remarkably low average 27 ms dead time for small energy changes. The technique, tested for the delivery of a skull glioma treatment, resulted in high gamma pass rates at 1%,1mm compared to conventional deliveries in experimental measurements with about 45% reduction of the energy switching time when regulation could be performed within acceptance. CONCLUSIONS Fast energy modulation within beamline acceptance has potential for clinical applications and, when realized with an upstream degrader, does not require modification in the beamline hardware, therefore being potentially applicable in any running facility. Centers with slow energy switching time can particularly profit from such a technique for reducing dead time during treatment delivery. This article is protected by copyright. All rights reserved.

Background and Purpose: To investigate the impact of organ motion on hypoxia-guided proton therapy treatments for non-small cell lung cancer (NSCLC) patients. Materials and Methods: Hypoxia PET and 4D imaging data of six NSCLC patients were used to simulate hypoxia-guided proton therapy with different motion mitigation strategies including rescanning, breath-hold, respiratory gating and tumour tracking. Motion-induced dose degradation was estimated for treatment plans with dose painting of hypoxic tumour sub-volumes at escalated dose levels. Tumour control probability (TCP) and dosimetry indices were assessed to weigh the clinical benefit of dose escalation and motion mitigation. In addition, the difference in normal tissue complication probability (NTCP) between escalated proton and photon VMAT treatments has been assessed. Results: Motion-induced dose degradation was found for target coverage (CTV V95% up to −4%) and quality of the dose-escalation-by-contour (QRMS up to 6%) as a function of motion amplitude and amount of dose escalation. The TCP benefit coming from dose escalation (+4–13%) outweighs the motion-induced losses (, Radiotherapy & Oncology, 176, ISSN:0167-8140, ISSN:1879-0887

Purpose/objective(s) Calculation of tumor control probability (TCP) and normal tissue complication probability (NTCP) is becoming increasingly relevant for optimizing treatment strategies, for example the selection of patients for proton therapy. While radiobiological models are typically built and evaluated on the planned treatment dose, no consensus exists for their evaluation in the context of varying patient anatomy during treatment. For example, different adaptive strategies can lead to different expected treatment outcomes for the same planned dose. This shows that TCP/NTCP needs to be calculated from the cumulative treatment dose resulting from multiple fraction doses and patient geometries. In this study, different methods of applying TCP and NTCP models to treatments with anatomical changes are developed and compared. These methods were evaluated on an example of locally advanced non-small cell lung cancer (NSCLC) patients using two extreme scenarios: no adaption vs online daily adaptive proton therapy (DAPT). Materials/methods Three methods to calculate TCP/NTCP in the context of anatomical changes were compared: (I) based on the accumulated treatment doses. Six different deformable image registration (DIR) algorithms were used to accumulate the dose, then the TCP/NTCP was calculated on all accumulated doses showing the variation due to the DIR. (II) based on the cumulative effective uniform dose (EUD) of each fraction. (III) based on each fraction dose directly, permitting an evaluation of the mean and variation of TCP/NTCP during treatment. To test and compare these methods, proton therapy treatment plans were generated on deep inspiration breath-hold (DIBH) planning CTs for 5 NSCLC patients (66 Gy-RBE, 33 fractions). Non-adapted and DAPT treatment doses were created by recalculating and reoptimizing these plans on nine repeated CTs. TCP/NTCP calculations were performed with all three methods. Results All methods showed consistent results between no adaption and DAPT. Two patients showed substantial TCP reductions up to 33% without adaption. Three patients, despite anatomical changes and dose differences, did not show a reduced calculated TCP with all methods. For most patients, NTCP differences between DAPT and no adaption were moderate, but one showed improvement in predicted 2-year survival based on heart toxicity with DAPT. Furthermore, the absolute NTCP calculated with method (I) showed variations of up to 7% depending on the DIR algorithm used for dose accumulation. Conclusion The three proposed methods of calculating clinical outcome based on treatment doses showed consistent result between DAPT and non-adapted treatments. Three patients showed benefits with DAPT, so the calculated NTCP could be reduced or calculated TCP maintained. For two patients the dose differences with adaption did not translate in clinically relevant effects. The proposed outcome calculation methods enable a more realistic quantification of TCP/NTCP of different adaptive strategies.

Optical eye tracking solutions can play a role in patient alignment and real-time monitoring of the eye movements during ocular proton therapy (OPT) and replace the current clinical standard based on radiographic imaging of surgical clips implanted in the patient's eye. The aim of this study is to compare the performance of an eye tracking solution specifically developed for OPT applications to this clinical standard. The eye tracking system (ETS) was used to pre-align the patient to the treatment position using information based solely on the pupil position before correction administered through X-ray imaging. As a result, we compared the geometrical accuracy achieved with the ETS to X-ray imaging of clips. In addition, we evaluated the ability of the ETS in determining the real position of the pupil through a comparison with a geometrical eye model. Pupil-based patient alignment performed, on average, worse than the conventional approach based on clips and a patient-specific bias was observed in the assessment of the pupil center position between ETS and the eye model. The limited accuracy of the ETS id due to the adoption of a simplified eye tracking approach and current investigation are focused into integrating gaze direction estimation in the process.

We present the commissioning and quality assurance of our clinical protocol for respiratory gating in pencil beam scanning proton therapy for cancer patients with moving targets. In a novel approach, optical tracking has been integrated in the therapy workflow and used to monitor respiratory motion from multiple surrogates, applied on the patients’ chest. The gating system was tested under a variety of experimental conditions, specific to proton therapy, to evaluate reaction time and reproducibility of dose delivery control. The system proved to be precise in the application of beam gating and allowed the mitigation of dose distortions even for large (1.4 cm) motion amplitudes, provided that adequate treatment windows were selected. The total delivered dose was not affected by the use of gating, with measured integral error within 0.15 cGy. Analysing high-resolution images of proton transmission, we observed negligible discrepancies in the geometric location of the dose as a function of the treatment window, with gamma pass rate greater than 95% (2%/2 mm) compared to stationary conditions. Similarly, pass rate for the latter metric at the 3%/3 mm level was observed above 97% for clinical treatment fields, limiting residual movement to 3 mm at end-exhale. These results were confirmed in realistic clinical conditions using an anthropomorphic breathing phantom, reporting a similarly high 3%/3 mm pass rate, above 98% and 94%, for regular and irregular breathing, respectively. Finally, early results from periodic QA tests of the optical tracker have shown a reliable system, with small variance observed in static and dynamic measurements. ISSN:0939-3889

PURPOSE Over the last four decades, Ocular Proton Therapy has been successfully used to treat patients affected by intraocular lesions. For this, treatment geometry verification is routinely performed using radiographic images to align a configuration of fiducial radiopaque markers implanted on the sclera outer surface. This paper describes the clinical application of an alternative approach based on optical eye tracking for three-dimensional non-invasive and automatic eye localization. An experimental protocol was designed to validate the optical-based eye referencing against both radiographic imaging system and the clinically used EYEPLAN treatment planning system. METHODS The eye tracking system (ETS) was installed in the OPTIS 2 treatment room at PSI to acquire eye motions during the treatment of nine patients. The pupil position and the cornea curvature centre were localized by segmenting the pupil contour and corneal light reflections on the images acquired by a pair of calibrated optical cameras. After calibration of the ETS, a direct comparison of radiopaque markers position, and consequentially eye position and orientation, provided by the ETS, radiographs and EYEPLAN was performed. RESULTS Nineteen out of thirty total monitored fractions were excluded from the study due to poor visibility of corneal reflection, resulting in a success rate of acquisition of 37%. For this data, overall median agreement between ETS-based and X-ray based markers position assessment were 0.29 mm and 0.94 degrees for translations and rotations respectively. Small discrepancies were also measured in the eye centre estimates of the ETS and EYEPLAN. Conversely, variations in measured eye orientation were higher, with inter-quartile range (IQR) between 4.39° and 7.58°. Nonetheless, dosimetric evaluation of the consequence of ETS uncertainties showed that the target volume would still be covered by more than 95% of the dose in all cases. CONCLUSION An ETS was successfully installed in a clinical ocular proton therapy treatment room and used to monitor eye position and orientation in a clinical scenario. First results show the potential of such a system as an eye localization device. However, the low success rate prevents straightforward clinical application and needs further improvements aimed at increasing corneal reflection visibility. This article is protected by copyright. All rights reserved.

Purpose/Objective(s) Radiation induced optic neuropathy (RION) is a rare but severe complication of radiotherapy that can lead to visual impairment or blindness. In this retrospective study, we report on RION incidence in a multi-institutional proton therapy cohort (median follow-up - 5.6 years), while determining risk factors that model the probability of this normal tissue complication (NTCP). Materials/Methods 292 chondrosarcoma (65%) and chordoma (35%) patients were included in the study, all treated with proton-only or combined photon-proton regimens at two institutions (50%/50%). Inclusion criteria were adults, absence of chemotherapy and at least 45 GyRBE dose planned to any part of the optic apparatus. Clinical variables and dosimetry were assessed in univariate and multivariate analyses including bootstrapping, cross-validation and stepwise logistic regression, to identify the most robust predictive factors and to develop a RION NTCP model. Results RION incidence grade ≥ 1 (mean 2.9, CTCAE 5.0) was observed in 12 patients (4.1%). Age (P = 0.008), arterial hypertension (P Conclusion Age and hypertension have been confirmed as significant risk factors for RION in a multi-institutional proton therapy cohort of patients receiving more than 45 GyRBE to the optic apparatus. While, in agreement with previous reporting, surgery and tumor abutment of the optic pathway emerged as potentially predictive factors, their statistical power was not sufficient for inclusion into the NTCP model. Author Disclosure A. Kothe: Research Grant; PHRT, ETH Domain. L. Feuvret: None. S. Safai: None. A. Lomax: None. D.C. Weber: None. G. Fattori: None.

The literature is controversial about the scan direction dependency of interplay effects in pencil beam scanning (PBS) treatment of moving targets. A directional effect is supported by many simulation studies, whereas the experimental data are mostly limited to simple geometries, not reflecting realistically clinical treatment plans. We have compared increasingly complex treatment fields, from a homogeneous single energy layer to a more modulated lung plan, under identical experimental settings, seeking evidence for differences in motion mitigation due to the selection of primary scanning direction. In total, 120 experimental samples were taken, combining two primary scan directions and three rescanning regimes with different motion scenarios. 4D dose distributions were measured in water with a moving ionisation chamber array and compared to those of a stationary delivery using 2D gamma analysis. Each plan has been verified twice for the same rescanning regime and motion scenario, changing the meandering direction in between to scan perpendicularly to, or along, the target motion. Additionally, machine log files of the lung plan, together with 4DCT data, were used to calculate the dose distribution that such deliveries would have produced in the patient. The primary meandering direction has a clear influence on measured dose distributions when considering a single energy layer. Introducing spot weight modulation and multiple energy layers however, makes the dynamic of interplay more complex and difficult to predict. Overall, gamma (3%/3 mm) differences between scanning along or orthogonal to the target motion follow a normal distribution [Formula: see text] when considering multiple motion scenarios and rescanning regimes. Nevertheless, data spread [Formula: see text] is significant enough such that, for individual experiments and set-ups, a dependency may be observed even if this is not a general result. Patient reconstructed doses follow the same trend, the two primary scan directions producing statistically insignificant differences in dose distributions in terms of conformity or homogeneity. Except for extremely simplified cases of mono-energetic and homogeneous treatment fields, the interplay effect has been found to be only marginally influenced by the choice of the primary scanning direction.

Therapeutic pencil beams are typically scanned using one of the following three techniques: spot scanning, raster scanning or line scanning. While providing similar dose distributions to the target, these three techniques can differ significantly in their delivery time sequence. Thus, we can expect differences in effectiveness and time efficiency when trying to mitigate interplay effects using rescanning. At the Paul Scherrer Institute, we are able to irradiate treatment plans using either of the three delivery techniques. Hence, we can compare them directly with identical underlying machine parameters such as energy switching time or minimum/maximum beam current. For this purpose, we selected three different liver targets, optimized plans for spots, and converted them to equivalent raster and line scanning plans. In addition to the scanning technique, we varied the underlying motion curve, starting phase, prescription dose and rescanning strategy, which resulted in a total of 1584 4D dose calculations and 49 measurements. They indicate that rescanning becomes effective when achieving a high number of rescans for every dose element. Fixed minimum spot weights for spot and raster scanning machines often hamper this. By introducing adaptive scaling of the beam current within iso-energy layers for line scanning, we can flexibly lower the minimum weight whenever required and achieve higher rescanning capability. Averaged over all scenarios studied, volumetric rescanning is significantly more effective than layered provided the same number of rescans are applied. Fast lateral scanning contributes to the efficiency of rescanning. We observed that in any given time window, we can always perform more rescans using raster or line scanning compared to spot scanning irradiations. Thus, we conclude that line scanning represents a promising technique for rescanning by combining both effectiveness and efficiency.

The aim of this study was to verify the temporal accuracy of the estimated dose distribution by a 4D dose calculation (4DDC) in comparison to measurements. A single-field plan (0.6 Gy), optimised for a liver patient case (CTV volume: 403cc), was delivered to a homogeneous PMMA phantom and measured by a high resolution scintillating-CCD system at two water equivalent depths. Various motion scenarios (no motion and motions with amplitude of 10 mm and two periods: 3.7 s and 4.4 s) were simulated using a 4D Quasar phantom and logged by an optical tracking system in real-time. Three motion mitigation approaches (single delivery, 6[Formula: see text] layered and volumetric rescanning) were applied, resulting in 10 individual measurements. 4D dose distributions were retrospectively calculated in water by taking into account the delivery log files (retrospective) containing information on the actually delivered spot positions, fluences, and time stamps. Moreover, in order to evaluate the sensitivity of the 4DDC inputs, the corresponding prospective 4DDCs were performed as a comparison, using the estimated time stamps of the spot delivery and repeated periodical motion patterns. 2D gamma analyses and dose-difference-histograms were used to quantify the agreement between measurements and calculations for all pixels with [Formula: see text]5% of the maximum calculated dose. The results show that a mean gamma score of 99.2% with standard deviation 1.0% can be achieved for 3%/3 mm criteria and all scenarios can reach a score of more than 95%. The average area with more than 5% dose difference was 6.2%. Deviations due to input uncertainties were obvious for single scan deliveries but could be smeared out once rescanning was applied. Thus, the deforming grid 4DDC has been demonstrated to be able to predict the complex patterns of 4D dose distributions for PBS proton therapy with high dosimetric and geometric accuracy, and it can be used as a valid clinical tool for 4D treatment planning, motion mitigation selection, and eventually 4D optimisation applications if the correct temporal information is available.

Purpose: External beam radiotherapy currently represents an important therapeutic strategy for the treatment of intraocular tumors. Accurate target localization and efficient compensation of involuntary eye movements are crucial to avoid deviations in dose distribution with respect to the treatment plan. This paper describes an eye tracking system (ETS) based on noninvasive infrared video imaging. The system was designed for capturing the tridimensional (3D) ocular motion and provides an on-line estimation of intraocular lesions position based on a priori knowledge coming from volumetric imaging. Methods: Eye tracking is performed by localizing cornea and pupil centers on stereo images captured by two calibrated video cameras, exploiting eye reflections produced by infrared illumination. Additionally, torsional eye movements are detected by template matching in the iris region of eye images. This information allows estimating the 3D position and orientation of the eye by means of an eye local reference system. By combining ETS measurements with volumetric imaging for treatment planning [computed tomography (CT) and magnetic resonance (MR)], one is able to map the position of the lesion to be treated in local eye coordinates, thus enabling real-time tumor referencing during treatment setup and irradiation. Experimental tests on an eye phantom and seven healthy subjectsmore » were performed to assess ETS tracking accuracy. Results: Measurements on phantom showed an overall median accuracy within 0.16 mm and 0.40° for translations and rotations, respectively. Torsional movements were affected by 0.28° median uncertainty. On healthy subjects, the gaze direction error ranged between 0.19° and 0.82° at a median working distance of 29 cm. The median processing time of the eye tracking algorithm was 18.60 ms, thus allowing eye monitoring up to 50 Hz. Conclusions: A noninvasive ETS prototype was designed to perform real-time target localization and eye movement monitoring during ocular radiotherapy treatments. The device aims at improving state-of-the-art invasive procedures based on surgical implantation of radiopaque clips and repeated acquisition of X-ray images, with expected positive effects on treatment quality and patient outcome.« less

Background and purpose Motion management in the treatment of lung cancer is necessary to assure highest quality of the delivered radiation therapy. In this study, the breath-hold technique is experimentally investigated for pencil beam scanned (PBS) proton therapy, with respect to the dosimetric effect of residual breath-hold motion. Material and methods Three-dimensional (3D)-printed tumours extracted from CT scans of three patients were inserted into a dynamic anthropomorphic breathing phantom. The target was set up to move with the individual patient’s tumour motion during breath-hold as previously assessed on fluoroscopy. Target dose was measured with radio-chromic film, and both single field uniform dose (SFUD) and intensity-modulated proton therapy (IMPT) plans were delivered. Experiments were repeated for each patient without any motion, to compute the relative dose deviation between static and breath-hold cases. Results SFUD plans showed small dose deviations between static and breath-hold cases, as evidenced by the gamma pass rate (3%, 3 mm) of 85% or higher. Dose deviation was more evident for IMPT plans, with gamma pass rate reduced to 50–70%. Conclusions The breath-hold technique is robust to residual intra-breath-hold motion for SFUD treatment plans, based on our experimental study. IMPT was less robust with larger detected dose deviations.

Purpose To investigate dose distribution variations due to setup errors and range uncertainties in image-guided carbon ion radiotherapy of head chordoma. Materials and methods Ten treatment plans were retrospectively tested with TRiP98 against ±1.0mm and ±1.0° setup errors, as observed in clinical routine, and 2.6% range uncertainty when 2mm CTV-to-PTV margins were applied. Single-fraction simulations were compared with the total treatment dose in terms of DVH bands, conformity and inhomogeneity. The contribution of image processing artifacts on reported results was also discussed, as a function of the imaging dataset resolution. Results Results showed that safety margins grant the conformal target coverage in presence of setup errors with D95 CTV variations below 10% in 7 patients out of 10. Instead, the inclusion of range uncertainty yielded to appreciable dose degradation, reporting larger effects for CTV and dose conformity, whereas reduced impact is found on the organ-at-risk. The fractionation scheme positively affects dose conformity and inhomogeneity; conversely its influence on DVH bands is strongly related to the patient anatomy. Conclusion Besides safety margins, setup and range uncertainties lead to non-negligible combined contribution. Systematical treatment plan robustness assessment against expected uncertainties is thus encouraged, selecting beam settings and fractionation schemes where homogeneity is preserved.

In an increasing number of clinical indications, radiotherapy with accelerated particles shows relevant advantages when compared with high energy X-ray irradiation. However, due to the finite range of ions, particle therapy can be severely compromised by setup errors and geometric uncertainties. The purpose of this work is to describe the commissioning and the design of the quality assurance procedures for patient positioning and setup verification systems at the Italian National Center for Oncological Hadrontherapy (CNAO). The accuracy of systems installed in CNAO and devoted to patient positioning and setup verification have been assessed using a laser tracking device. The accuracy in calibration and image based setup verification relying on in room X-ray imaging system was also quantified. Quality assurance tests to check the integration among all patient setup systems were designed, and records of daily QA tests since the start of clinical operation (2011) are presented. The overall accuracy of the patient positioning system and the patient verification system motion was proved to be below 0.5 mm under all the examined conditions, with median values below the 0.3 mm threshold. Image based registration in phantom studies exhibited sub-millimetric accuracy in setup verification at both cranial and extra-cranial sites. The calibration residuals of the OTS were found consistent with the expectations, with peak values below 0.3 mm. Quality assurance tests, daily performed before clinical operation, confirm adequate integration and sub-millimetric setup accuracy. Robotic patient positioning was successfully integrated with optical tracking and stereoscopic X-ray verification for patient setup in particle therapy. Sub-millimetric setup accuracy was achieved and consistently verified in daily clinical operation.

Accurate dose delivery to extra-cranial lesions requires tumor motion compensation. An effective compensation can be achieved by real-time tracking of the target position, either measured in fluoroscopy or estimated through correlation models as a function of external surrogate motion. In this work, we integrated two internal/external correlation models (a state space model and an artificial neural network-based model) into a custom infra-red optical tracking system (OTS). Dedicated experiments were designed and conducted at GSI (Helmholtzzentrum für Schwerionenforschung). A robotic breathing phantom was used to reproduce regular and irregular internal target motion as well as external thorax motion. The position of a set of markers placed on the phantom thorax was measured with the OTS and used by the correlation models to infer the internal target position in real-time. Finally, the estimated target position was provided as input for the dynamic steering of a carbon ion beam. Geometric results showed that the correlation models transversal (2D) targeting error was always lower than 1.3 mm (root mean square). A significant decrease of the dosimetric error with respect to the uncompensated irradiation was achieved in four out of six experiments, demonstrating that phase shifts are the most critical irregularity for external/internal correlation models. © 2013 Institute of Physics and Engineering in Medicine.

Background and purpose To investigate the intra-fraction breast motion during long-lasting treatments of breast cancer with Helical Tomotherapy by means of an optical tracking system. Materials and methods A set of seven radio-transparent passive markers was placed on the thoraco-abdominal surface of twenty breast cancer patients and tracked by an infrared tracking system. A continuous non-invasive monitoring of intra-fraction motion from patient setup verification and correction to the end of radiation delivery was thus obtained. The measured displacements were analysed in terms of cyclic respiratory motion and slow baseline drift. Results The average monitoring time per patient was 15.57 min. The breathing amplitude of the chest was less than 2 mm, on average, along all anatomical directions. The baseline drift of the body led to more significant setup uncertainties than the respiratory motion. The main intra-fraction baseline drifts were in posterior and inferior directions and occurred within the first eight minutes of monitoring. Considering the intra-fraction motion only, the resultant clinical-to-planning target volume safety margins are highly patient-specific and largely anisotropic. Conclusion The non-respiratory motion occurring during prolonged treatments induces notable uncertainties. Non-invasive continuous monitoring of patient setup variations including baseline drifts is recommended in order to minimize dosimetric deviations, which might jeopardize the therapeutic ratio between target coverage and the sparing of organs at risk.

Purpose We describe the interface developed at the National Center for Oncological Hadrontherapy in Pavia to provide the dose delivery systems with real time respiratory motion information captured with an optical tracking system. An experimental study is presented to assess the technical feasibility of the implemented organ motion compensation framework, by analyzing the film response when irradiated with proton beams. Methods The motion monitoring solution is based on a commercial hardware for motion capture running in-house developed software for respiratory signal processing. As part of the integration, the latency of data transmission to the dose delivery system was experimentally quantified and accounted for by signal time prediction. A respiratory breathing phantom is presented and used to test tumor tracking based either on the optical measurement of the target position or internal-external correlation models and beam gating, as driven by external surrogates. Beam tracking was tested considering the full target motion excursion (25×18 mm), whereas it is limited to 6×2 mm in the gating window. The different motion mitigation strategies were evaluated by comparing the experimental film responses with respect to static irradiation conditions. Dose inhomogeneity (IC) and conformity (CI) are provided as main indexes for dose quality assessment considering the irradiation in static condition as reference. Results We measured 20.6 ms overall latency for motion signal processing. Dose measurements showed that beam tracking largely preserved dose homogeneity and conformity, showing maximal IC and CI variations limited to +0.10 and −0.01 with respect to the static reference. Gating resulted in slightly larger discrepancies (ΔIC=+0.20, ΔCI=−0.13) due to uncompensated residual motion in the gating window. Conclusions The preliminary beam tracking and gating results verified the functionality of the prototypal solution for organ motion compensation based on optical monitoring.

We propose a novel method for radio-opaque external marker localization in CT scans for infrared (IR) patient set-up in radiotherapy. Efforts were focused on the quantification of uncertainties in marker localization in the CT dataset as a function of algorithm performance. We implemented a 3-D approach to fiducial localization based on surface extraction and marker recognition according to geometrical prior knowledge. The algorithm parameters were optimized on a clinical CT dataset coming from 35 cranial and extra-cranial patients; the localization accuracy was benchmarked at variable image resolution versus laser tracker measurements. The applicability of conventional IR optical tracking systems for localizing external surrogates in daily patient set-up procedures was also investigated in 121 proton therapy treatment sessions. Our study shows that the implemented algorithm features surrogates localization with uncertainties lower than 0.3 mm and with a true positive rate of 90.1%, being this latter mainly influenced by fiducial homogeneity in the CT images. The reported clinical validation in proton therapy confirmed the submillimetric accuracy and the expected algorithm sensitivity. Geometrical prior knowledge allows judging the reliability of the extracted fiducial coordinates, ensuring the highest accuracy in patient set-up.

The purpose of the study is to investigate a projection-based deformable registration method between the treatment planning CT and in-room ion-based tomographic imaging (iCT). The rationale of the study is to make use of iCT projections for treatment geometry verification and treatment planning CT image update. The hypothesis to be investigated is the possibility to register the treatment planning CT and the iCT images in the domain of projections, thus postponing iCT image reconstruction to registration. The iCT-CT image fusion in projection domain is expected to join the high spatial resolution of treatment planning CT images with the accurate tissue stopping power information provided by the ion beam projections. The strategy is tested on the anthropomorphic 4D CT NURBS-based cardiac-torso (NCAT) phantom, featuring the respiration induced organ motion. Specific features of the iCT imaging are also mimicked by applying piecewise linear gray level modification and ion (proton) scattering. Different imaging angular ranges (180°-135°-90°-45°) and number of projection views (180-135-90) are simulated. In order to assess the algorithm performance on measured carbon iCT data of the Alderson head phantom, the phantom CT image is rigidly transformed. The strategy suggests potential advantages for those in-beam/in-room imaging techniques where a complete 360° angle acquisition could be geometrically hampered but also when a limited number of projection angles are desirable for reduced dose or acquisition time.

In ion beam radiotherapy, PET-based treatment verification provides a consistency check of the delivered treatment with respect to a simulation based on the treatment planning. In this work the region-based MLEM reconstruction algorithm is proposed as a new evaluation strategy in PET-based treatment verification. The comparative evaluation is based on reconstructed PET images in selected regions, which are automatically identified on the expected PET images according to homogeneity in activity values. The strategy was tested on numerical and physical phantoms, simulating mismatches between the planned and measured β(+) activity distributions. The region-based MLEM reconstruction was demonstrated to be robust against noise and the sensitivity of the strategy results were comparable to three voxel units, corresponding to 6 mm in numerical phantoms. The robustness of the region-based MLEM evaluation outperformed the voxel-based strategies. The potential of the proposed strategy was also retrospectively assessed on patient data and further clinical validation is envisioned.

In this contribution we describe the implementation of a novel solution for image guided particle therapy, designed to ensure the maximal accuracy in patient setup. The presented system is installed in the central treatment room at Centro Nazionale di Adroterapia Oncologica (CNAO, Italy), featuring two fixed beam lines (horizontal and vertical) for proton and carbon ion therapy. Treatment geometry verification is based on robotic in-room imaging acquisitions, allowing for 2D/3D registration from double planar kV-images or 3D/3D alignment from cone beam image reconstruction. The calculated six degrees-of-freedom correction vector is transferred to the robotic patient positioning system, thus yielding automated setup error compensation. Sub-millimetre scale residual errors were measured in absolute positioning of rigid phantoms, in agreement with optical- and laser-based assessment. Sub-millimetre and sub-degree positioning accuracy was achieved when simulating setup errors with anthropomorphic head, thorax and pelvis phantoms. The in-house design and development allowed a high level of system customization, capable of replicating the clinical performance of commercially available products, as reported with preliminary clinical results in 10 patients.

Purpose This study applied automatic feature detection on cine–magnetic resonance imaging (MRI) liver images in order to provide a prospective comparison between MRI-guided and surrogate-based tracking methods for motion-compensated liver radiation therapy. Methods and Materials In a population of 30 subjects (5 volunteers plus 25 patients), 2 oblique sagittal slices were acquired across the liver at high temporal resolution. An algorithm based on scale invariant feature transform (SIFT) was used to extract and track multiple features throughout the image sequence. The position of abdominal markers was also measured directly from the image series, and the internal motion of each feature was quantified through multiparametric analysis. Surrogate-based tumor tracking with a state-of-the-art external/internal correlation model was simulated. The geometrical tracking error was measured, and its correlation with external motion parameters was also investigated. Finally, the potential gain in tracking accuracy relying on MRI guidance was quantified as a function of the maximum allowed tracking error. Results An average of 45 features was extracted for each subject across the whole liver. The multi-parametric motion analysis reported relevant inter- and intrasubject variability, highlighting the value of patient-specific and spatially-distributed measurements. Surrogate-based tracking errors (relative to the motion amplitude) were were in the range 7% to 23% (1.02-3.57mm) and were significantly influenced by external motion parameters. The gain of MRI guidance compared to surrogate-based motion tracking was larger than 30% in 50% of the subjects when considering a 1.5-mm tracking error tolerance. Conclusions Automatic feature detection applied to cine-MRI allows detailed liver motion description to be obtained. Such information was used to quantify the performance of surrogate-based tracking methods and to provide a prospective comparison with respect to MRI-guided radiation therapy, which could support the definition of patient-specific optimal treatment strategies.

The integrated use of optical technologies for patient monitoring is addressed in the framework of time-resolved treatment delivery for scanned ion beam therapy. A software application has been designed to provide the therapy control system (TCS) with a continuous geometrical feedback by processing the external surrogates tridimensional data, detected in real-time via optical tracking. Conventional procedures for phase-based respiratory phase detection were implemented, as well as the interface to patient specific correlation models, in order to estimate internal tumor motion from surface markers. In this paper, particular attention is dedicated to the quantification of time delays resulting from system integration and its compensation by means of polynomial interpolation in the time domain. Dedicated tests to assess the separate delay contributions due to optical signal processing, digital data transfer to the TCS and passive beam energy modulation actuation have been performed. We report the system technological commissioning activities reporting dose distribution errors in a phantom study, where the treatment of a lung lesion was simulated, with both lateral and range beam position compensation. The zero-delay systems integration with a specific active scanning delivery machine was achieved by tuning the amount of time prediction applied to lateral (14.61 ± 0.98 ms) and depth (34.1 ± 6.29 ms) beam position correction signals, featuring sub-millimeter accuracy in forward estimation. Direct optical target observation and motion phase (MPh) based tumor motion discretization strategies were tested, resulting in 20.3(2.3)% and 21.2(9.3)% median (IQR) percentual relative dose difference with respect to static irradiation, respectively. Results confirm the technical feasibility of the implemented strategy towards 4D treatment delivery, with negligible percentual dose deviations with respect to static irradiation. © Adenine Press (2014).

The synergy between in-room imaging and optical tracking, in co-operation with highly accurate robotic patient handling represents a concept for patient-set-up which has been implemented at CNAO (Centro Nazionale di Adroterapia Oncologica). In-room imaging is based on a double oblique X-ray projection system; optical tracking consists of the detection of the position of spherical markers placed directly on the patient's skin or on the immobilization devices. These markers are used as external fiducials during patient positioning and dose delivery. This study reports the results of a comparative analysis between in-room imaging and optical tracking data for patient positioning within the framework of high-precision particle therapy. Differences between the optical tracking system (OTS) and the imaging system (IS) were on average within the expected localization accuracy. On the first 633 fractions for head and neck (HN) set-up procedures, the corrections applied by the IS, after patient positioning using the OTS only, were for the mostly sub-millimetric regarding the translations (0.4 ± 1.1 mm) and sub-gradual regarding the rotations (0.0° ± 0.8°). On the first 236 fractions for pelvis localizations the amplitude of the corrections applied by the IS after preliminary optical set-up correction were moderately higher and more dispersed (translations: 1.3 ± 2.9 mm, rotations 0.1 ± 0.9°). Although the indication of the OTS cannot replace information provided by in-room imaging devices and 2D-3D image registration, the reported data show that OTS preliminary correction might greatly support image-based patient set-up refinement and also provide a secondary, independent verification system for patient positioning.

Purpose: We aim to compare the performance of discrete spot- or continuous line scanning combined with rescanning in mitigating residual organ motion during gated proton therapy treatments. Methods: The Quasar respiratory phantom was used to move a 2D scintillation detector on a linear trajectory with sinusoidal motion pattern (sin4), 20 mm peak-to-peak amplitude and 5 sec period. Its motion was monitored using a customized solution based on optical tracking technology. We compared spot and line scanning plans for a monoenergetic 150 MeV circular field, 50.4 mm radius at isocenter. Transverse dose distributions at 13 cm depth in PMMA (15.47 mm water equivalent) were measured to compare three options for motion mitigation: rescanning (10× factor), gating and their combination. The gating window was centered in the trajectory plateau to simulate end-exhale gated treatment in presence of 2 mm and 4 mm residual motion, parallel or perpendicular to the primary scanning direction. Results: When the target moves perpendicular to the primary scanning direction, large dose deviations are measured (γ3%/3mm=47%) without mitigation techniques. Beam gating combined with rescanning restores target coverage (γ3%/3mm=91%). For parallel target motion, observed dose distortions in the non-compensated irradiation are smaller (γ3%/3mm=77%). Beam gating alone recovers the 100% gamma pass-rate at 3%/3mm. Continuous line scanning reduces delivery time by up to 60% with respect to discrete spot scanning in presence of motion mitigation, and improves homogeneity when rescanning is applied (up to 20%, perpendicular motion, 4 mm residual motion). Conclusion: The direction of motion has a large impact on the target dose coverage. Nevertheless, even in the worst case scenario, gating combined with rescanning could mitigate the impact of motion on dose deposition. Moreover, continuous line rescanning improves the robustness against residual motion in the gating window. This study has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n.290605 (PSI-FELLOW/COFUND) and ‘Giuliana and Giorgio Stefanini Foundation’