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Purpose In proton therapy, the potential of using high-dose rates in the cancer treatment is being explored. High-dose rates could improve efficiency and throughput in standard clinical practice, allow efficient utilization of motion mitigation techniques for moving targets, and potentially enhance normal tissue sparing due to the so-called FLASH effect. However, high-dose rates are difficult to reach when lower energy beams are applied in cyclotron-based proton therapy facilities, because they result in large beam sizes and divergences downstream of the degrader, incurring large losses from the cyclotron to the patient position (isocenter). In current facilities, the emittance after the degrader is reduced using circular collimators; however, this does not provide an optimal matching to the acceptance of the following beamline, causing a low transmission for these energies. We, therefore, propose to use a collimation system, asymmetric in both beam size and divergence, resulting in symmetric emittance in both beam transverse planes as required for a gantry system. This new emittance selection, together with a new optics design for the following beamline and gantry, allows a better matching to the beamline acceptance and an improvement of the transmission. Methods We implemented a custom method to design the collimator sizes and shape required to select high emittance, to be transported by the following beamline using new beam optics (designed with TRANSPORT) to maximize acceptance matching. For predicting the transmission in the new configuration (new collimators + optics), we used Monte Carlo simulations implemented in BDSIM, implementing a model of PSI Gantry 2 which we benchmarked against measurements taken in the current clinical scenario (circular collimators + clinical optics). Results From the BDSIM simulations, we found that the new collimator system and matching beam optics results in an overall transmission from the cyclotron to the isocenter for a 70 MeV beam of 0.72%. This is an improvement of almost a factor of 6 over the current clinical performance (0.13% transmission). The new optics satisfies clinical beam requirements at the isocenter. Conclusions We developed a new emittance collimation system for PSI's PROSCAN beamline which, by carefully selecting beam size and divergence asymmetrically, increases the beam transmission for low-energy beams in current state-of-the-art cyclotron-based proton therapy gantries. With these improvements, we could predict almost 1% transmission for low-energy beams at PSI's Gantry 2. Such a system could easily be implemented in facilities interested in increasing dose rates for efficient motion mitigation and FLASH experiments alike., Medical Physics, 48 (12), ISSN:0094-2405, ISSN:2473-4209, ISSN:1522-8541

Purpose: The purpose of this work was to provide a flexible platform for FLASH research with protons by adapting a former clinical pencil beam scanning gantry to irradiations with ultrahigh dose rates. Methods: PSI Gantry 1 treated patients until December 2018. We optimized the beamline parameters to transport the 250 MeV beam extracted from the PSI COMET accelerator to the treatment room, maximizing the transmission of beam intensity to the sample. We characterized a dose monitor on the gantry to ensure good control of the dose, delivered in spot-scanning mode. We characterized the beam for different dose rates and field sizes for transmission irradiations. We explored scanning possibilities in order to enable conformal irradiations or transmission irradiations of large targets (with transverse scanning). Results: We achieved a transmission of 86 % from the cyclotron to the treatment room. We reached a peak dose rate of 9000 Gy/s at 3 mm water equivalent depth, along the central axis of a single pencil beam. Field sizes of up to 5x5 mm$^{2}$ were achieved for single spot FLASH irradiations. Fast transverse scanning allowed to cover a field of 16x1.2 cm$^{2}$. With the use of a nozzle-mounted range shifter we are able to span depths in water ranging from 19.6 to 37.9 cm. Various dose levels were delivered with a precision within less than 1 %. Conclusions: We have realized a proton FLASH irradiation setup able to investigate continuously a wide dose rate spectrum, from 1 to 9000 Gy/s in a single spot irradiation as well as in the pencil beam scanning mode. As such, we have developed a versatile test bench for FLASH research., Comment: Submitted to Medical Physics

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 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 A detailed analysis of 2728 intensity modulated proton therapy (IMPT) fields that were clinically delivered to patients between 2007 and 2013 at Paul Scherrer Institute (PSI) was performed. The aim of this study was to analyze the results of patient specific dosimetric verifications and to assess possible correlation between the quality assurance (QA) results and specific field metrics. METHODS Dosimetric verifications were performed for every IMPT field prior to patient treatment. For every field, a steering file was generated containing all the treatment unit information necessary for treatment delivery: beam energy, beam angle, dose, size of air gap, nuclear interaction (NI) correction factor, number of range shifter plates, number of Bragg peaks (BPs) with their position and weight. This information was extracted and correlated to the results of dosimetric verification of each field which was a measurement of two orthogonal profiles using an orthogonal ionization chamber array in a movable water column. RESULTS The data analysis has shown more than 94% of all verified plans were within defined clinical tolerances. The differences between measured and calculated dose depend critically on the number of BPs, total thickness of all range shifter plates inserted in the beam path, and maximal range. An increase of the dose difference was observed with smaller number of BPs (i.e., smaller tumor) and smaller ranges (i.e., superficial tumors). The results of the verification do not depend, however, on the prescribed dose, NI correction, or the size of the air gap. There is no dependency of the transversal and longitudinal spot position precision on the beam angle. The value of NI correction depends on the number of spots and number of range shifter plates. CONCLUSIONS The presented study has shown that the verification method used at Centre for Proton Therapy at Paul Scherrer Institute is accurate and reproducible for performing patient specific QA. The results confirmed that the dose discrepancy is dependent on the size and location of the tumor.

Despite growing rapidly, proton therapy is still a relatively immature treatment modality, at least in comparison to conventional radiotherapy using photons. As such, in this article, the author gives a very personal view of some of the potential areas for development in medical physics for proton therapy in the next 10 yr by identifying six topics for detailed discussion. The first of these are all related to reducing various "parameters" of proton therapy treatments (size and cost, treatment times, penumbras, and margins), while the second group are related to providing more quantitative "knowledge" about the quality of the treatments we are delivering. In conclusion, there is much interesting and important work still to be done in many areas of medical physics related to proton therapy, of which, the topics selected here are just the tip of the iceberg.

Purpose: Prospective respiratory-gated 4D CT has been shown to reduce tumor image artifacts by up to 50% compared to conventional 4D CT. However, to date no studies have quantified the impact of gated 4D CT on normal lung tissue imaging, which is important in performing dose calculations based on accurate estimates of lung volume and structure. To determine the impact of gated 4D CT on thoracic image quality, the authors developed a novel simulation framework incorporating a realistic deformable digital phantom driven by patient tumor motion patterns. Based on this framework, the authors test the hypothesis that respiratory-gated 4D CT can significantly reduce lung imaging artifacts. Methods: Our simulation framework synchronizes the 4D extended cardiac torso (XCAT) phantom with tumor motion data in a quasi real-time fashion, allowing simulation of three 4D CT acquisition modes featuring different levels of respiratory feedback: (i) “conventional” 4D CT that uses a constant imaging and couch-shift frequency, (ii) “beam paused” 4D CT that interrupts imaging to avoid oversampling at a given couch position and respiratory phase, and (iii) “respiratory-gated” 4D CT that triggers acquisition only when the respiratory motion fulfills phase-specific displacement gating windows based on prescan breathing data. Our framework generates a setmore » of ground truth comparators, representing the average XCAT anatomy during beam-on for each of ten respiratory phase bins. Based on this framework, the authors simulated conventional, beam-paused, and respiratory-gated 4D CT images using tumor motion patterns from seven lung cancer patients across 13 treatment fractions, with a simulated 5.5 cm{sup 3} spherical lesion. Normal lung tissue image quality was quantified by comparing simulated and ground truth images in terms of overall mean square error (MSE) intensity difference, threshold-based lung volume error, and fractional false positive/false negative rates. Results: Averaged across all simulations and phase bins, respiratory-gating reduced overall thoracic MSE by 46% compared to conventional 4D CT (p ∼ 10{sup −19}). Gating leads to small but significant (p < 0.02) reductions in lung volume errors (1.8%–1.4%), false positives (4.0%–2.6%), and false negatives (2.7%–1.3%). These percentage reductions correspond to gating reducing image artifacts by 24–90 cm{sup 3} of lung tissue. Similar to earlier studies, gating reduced patient image dose by up to 22%, but with scan time increased by up to 135%. Beam paused 4D CT did not significantly impact normal lung tissue image quality, but did yield similar dose reductions as for respiratory-gating, without the added cost in scanning time. Conclusions: For a typical 6 L lung, respiratory-gated 4D CT can reduce image artifacts affecting up to 90 cm{sup 3} of normal lung tissue compared to conventional acquisition. This image improvement could have important implications for dose calculations based on 4D CT. Where image quality is less critical, beam paused 4D CT is a simple strategy to reduce imaging dose without sacrificing acquisition time.« less

A detailed analysis of 2728 intensity modulated proton therapy (IMPT) fields that were clinically delivered to patients between 2007 and 2013 at Paul Scherrer Institute (PSI) was performed. The aim of this study was to analyze the results of patient specific dosimetric verifications and to assess possible correlation between the quality assurance (QA) results and specific field metrics.Dosimetric verifications were performed for every IMPT field prior to patient treatment. For every field, a steering file was generated containing all the treatment unit information necessary for treatment delivery: beam energy, beam angle, dose, size of air gap, nuclear interaction (NI) correction factor, number of range shifter plates, number of Bragg peaks (BPs) with their position and weight. This information was extracted and correlated to the results of dosimetric verification of each field which was a measurement of two orthogonal profiles using an orthogonal ionization chamber array in a movable water column.The data analysis has shown more than 94% of all verified plans were within defined clinical tolerances. The differences between measured and calculated dose depend critically on the number of BPs, total thickness of all range shifter plates inserted in the beam path, and maximal range. An increase of the dose difference was observed with smaller number of BPs (i.e., smaller tumor) and smaller ranges (i.e., superficial tumors). The results of the verification do not depend, however, on the prescribed dose, NI correction, or the size of the air gap. There is no dependency of the transversal and longitudinal spot position precision on the beam angle. The value of NI correction depends on the number of spots and number of range shifter plates.The presented study has shown that the verification method used at Centre for Proton Therapy at Paul Scherrer Institute is accurate and reproducible for performing patient specific QA. The results confirmed that the dose discrepancy is dependent on the size and location of the tumor.

Purpose To assess the quality of dose distributions in real clinical cases for different dimensions of scanned proton pencil beams. The distance between spots (i.e., the grid of delivery) is optimized for each dimension of the pencil beam. Methods The authors vary the σ of the initial Gaussian size of the spot, from σ(x) = σ(y) = 3 mm to σ(x) = σ(y) = 8 mm, to evaluate the impact of the proton beam size on the quality of intensity modulated proton therapy (IMPT) plans. The distance between spots, Δx and Δy, is optimized on the spot plane, ranging from 4 to 12 mm (i.e., each spot size is coupled with the best spot grid resolution). In our Hyperion treatment planning system (TPS), constrained optimization is applied with respect to the organs at risk (OARs), i.e., the optimization tries to satisfy the dose objectives in the planning target volume (PTV) as long as all planning objectives for the OARs are met. Three-field plans for a nasopharynx case, two-field plans for a prostate case, and two-field plans for a malignant pleural mesothelioma case are considered in our analysis. Results For the head and neck tumor, the best grids (i.e., distance between spots) are 5, 4, 6, 6, and 8 mm for σ = 3, 4, 5, 6, and 8 mm, respectively. σ ≤ 5 mm is required for tumor volumes with low dose and σ ≤ 4 mm for tumor volumes with high dose. For the prostate patient, the best grid is 4, 4, 5, 5, and 5 mm for σ = 3, 4, 5, 6, and 8 mm, respectively. Beams with σ > 3 mm did not satisfy our first clinical requirement that 95% of the prescribed dose is delivered to more than 95% of prostate and proximal seminal vesicles PTV. Our second clinical requirement, to cover the distal seminal vesicles PTV, is satisfied for beams as wide as σ = 6 mm. For the mesothelioma case, the low dose PTV prescription is well respected for all values of σ, while there is loss of high dose PTV coverage for σ > 5 mm. The best grids have a spacing of 6, 7, 8, 9, and 12 mm for σ = 3, 4, 5, 6, and 8 mm, respectively. Conclusions The maximum acceptable proton pencil beam σ depends on the volume treated, the protocol of delivery, and optimization of the plan. For the clinical cases, protocol and optimization used in this analysis, acceptable σs are ≤ 4 mm for the head and neck tumor, ≤ 3 mm for the prostate tumor and ≤ 6 mm for the malignant pleural mesothelioma. One can apply the same procedure used in this analysis when given a "class" of patients, a σ and a clinical protocol to determine the optimal grid spacing.

This article reports on a 4D-treatment planning workshop (4DTPW), held on 7–8 December 2009 at the Paul Scherrer Institut (PSI) in Villigen, Switzerland. The participants were all members of institutions actively involved in particle therapy delivery and research. The purpose of the 4DTPW was to discuss current approaches, challenges, and future research directions in 4D-treatment planning in the context of actively scanned particle radiotherapy. Key aspects were addressed in plenary sessions, in which leaders of the field summarized the state-of-the-art. Each plenary session was followed by an extensive discussion. As a result, this article presents a summary of recommendations for the treatment of mobile targets (intrafractional changes) with actively scanned particles and a list of requirements to elaborate and apply these guidelines clinically.

Prospective respiratory-gated 4D CT has been shown to reduce tumor image artifacts by up to 50% compared to conventional 4D CT. However, to date no studies have quantified the impact of gated 4D CT on normal lung tissue imaging, which is important in performing dose calculations based on accurate estimates of lung volume and structure. To determine the impact of gated 4D CT on thoracic image quality, the authors developed a novel simulation framework incorporating a realistic deformable digital phantom driven by patient tumor motion patterns. Based on this framework, the authors test the hypothesis that respiratory-gated 4D CT can significantly reduce lung imaging artifacts.Our simulation framework synchronizes the 4D extended cardiac torso (XCAT) phantom with tumor motion data in a quasi real-time fashion, allowing simulation of three 4D CT acquisition modes featuring different levels of respiratory feedback: (i) "conventional" 4D CT that uses a constant imaging and couch-shift frequency, (ii) "beam paused" 4D CT that interrupts imaging to avoid oversampling at a given couch position and respiratory phase, and (iii) "respiratory-gated" 4D CT that triggers acquisition only when the respiratory motion fulfills phase-specific displacement gating windows based on prescan breathing data. Our framework generates a set of ground truth comparators, representing the average XCAT anatomy during beam-on for each of ten respiratory phase bins. Based on this framework, the authors simulated conventional, beam-paused, and respiratory-gated 4D CT images using tumor motion patterns from seven lung cancer patients across 13 treatment fractions, with a simulated 5.5 cm(3) spherical lesion. Normal lung tissue image quality was quantified by comparing simulated and ground truth images in terms of overall mean square error (MSE) intensity difference, threshold-based lung volume error, and fractional false positive/false negative rates.Averaged across all simulations and phase bins, respiratory-gating reduced overall thoracic MSE by 46% compared to conventional 4D CT (p ∼ 10(-19)). Gating leads to small but significant (p0.02) reductions in lung volume errors (1.8%-1.4%), false positives (4.0%-2.6%), and false negatives (2.7%-1.3%). These percentage reductions correspond to gating reducing image artifacts by 24-90 cm(3) of lung tissue. Similar to earlier studies, gating reduced patient image dose by up to 22%, but with scan time increased by up to 135%. Beam paused 4D CT did not significantly impact normal lung tissue image quality, but did yield similar dose reductions as for respiratory-gating, without the added cost in scanning time.For a typical 6 L lung, respiratory-gated 4D CT can reduce image artifacts affecting up to 90 cm(3) of normal lung tissue compared to conventional acquisition. This image improvement could have important implications for dose calculations based on 4D CT. Where image quality is less critical, beam paused 4D CT is a simple strategy to reduce imaging dose without sacrificing acquisition time.

The purpose of this work is to show the feasibility of using in vivo proton radiography of a radiotherapy patient for the patient individual optimization of the calibration from CT-Hounsfield units to relative proton stopping power. Water equivalent tissue (WET) calibrated proton radiographs of a dog patient treated for a nasal tumor were used as baseline in comparison with integrated proton stopping power through the calibrated CT of the dog. In an optimization procedure starting with a stoichiometric calibration curve, the calibration was modified randomly. The result of this iteration is an optimized calibration curve which was used to recalculate the dose distribution of the patient. One result of this experiment was that the mean value of the deviations between WET calculations based on the stoichiometric calibration curve and the measurements was shifted systematically away from zero. The calibration produced by the optimization procedure reduced this shift to around 0.4 mm. Another result was that the precision of the calibration, reflected as the standard deviation of the normally distributed deviations between WET calculation and measurement, could be reduced from 7.9 to 6.7 mm with the optimized calibration. The dose distributions based on the two calibration curves showed major deviations at the distal end of the target volume.

Base of skull meningioma can be treated with both intensity modulated radiation therapy (IMRT) and spot scanned proton therapy (PT). One of the main benefits of PT is better sparing of organs at risk, but due to the physical and dosimetric characteristics of protons, spot scanned PT can be more sensitive to the uncertainties encountered in the treatment process compared with photon treatment. Therefore, robustness analysis should be part of a comprehensive comparison between these two treatment methods in order to quantify and understand the sensitivity of the treatment techniques to uncertainties. The aim of this work was to benchmark a spot scanning treatment planning system for planning of base of skull meningioma and to compare the created plans and analyze their robustness to setup errors against the IMRT technique.Plans were produced for three base of skull meningioma cases: IMRT planned with a commercial TPS [Monaco (Elekta AB, Sweden)]; single field uniform dose (SFUD) spot scanning PT produced with an in-house TPS (PSI-plan); and SFUD spot scanning PT plan created with a commercial TPS [XiO (Elekta AB, Sweden)]. A tool for evaluating robustness to random setup errors was created and, for each plan, both a dosimetric evaluation and a robustness analysis to setup errors were performed.It was possible to create clinically acceptable treatment plans for spot scanning proton therapy of meningioma with a commercially available TPS. However, since each treatment planning system uses different methods, this comparison showed different dosimetric results as well as different sensitivities to setup uncertainties. The results confirmed the necessity of an analysis tool for assessing plan robustness to provide a fair comparison of photon and proton plans.Robustness analysis is a critical part of plan evaluation when comparing IMRT plans with spot scanned proton therapy plans.

In this paper, we report on the clinical application of fully automated three-dimensional intensity modulated proton therapy, as applied to a 34-year-old patient presenting with a thoracic chordoma. Due to the anatomically challenging position of the lesion, a three-field technique was adopted in which fields incident through the lungs and heart, as well as beams directed directly at the spinal cord, could be avoided. A homogeneous target dose and sparing of the spinal cord was achieved through field patching and computer optimization of the 3D fluence of each field. Sensitivity of the resultant plan to delivery and calculational errors was determined through both the assessment of the potential effects of range and patient setup errors, and by the application of Monte Carlo dose calculation methods. Ionization chamber profile measurements and 2D dosimetry using a scintillator/CCD camera arrangement were performed to verify the calculated fields in water. Modeling of a 10% overshoot of proton range showed that the maximum dose to the spinal cord remained unchanged, but setup error analysis showed that dose homogeneity in the target volume could be sensitive to offsets in the AP direction. No significant difference between the MC and analytic dose calculations was found and the measured dosimetry for all fields was accurate to 3% for all measured points. Over the course of the treatment, a setup accuracy of +/-4 mm (2 s.d.) could be achieved, with a mean offset in the AP direction of 0.1 mm. Inhalation/exhalation CT scans indicated that organ motion in the region of the target volume was negligible. We conclude that 3D IMPT plans can be applied clinically and safely without modification to our existing delivery system. However, analysis of the calculated intensity matrices should be performed to assess the practicality, or otherwise, of the plan.

A two-dimensionally position sensitive dosimetry system has been tested for different dosimetric applications in a radiation therapy facility with a scanning proton beam. The system consists of a scintillating (fluorescent) screen, mounted at the beam-exit side of a phantom and it is observed by a charge coupled device (CCD) camera. The observed light distribution at the screen is equivalent to the two-dimensional (2D)-dose distribution at the screen position. It has been found that the dosimetric properties of the system, measured in a scanning proton beam, are equal to those measured in a proton beam broadened by a scattering system. Measurements of the transversal dose distribution of a single pencil beam are consistent with dose measurements as well as with dose calculations in clinically relevant fields made with multiple pencil beams. Measurements of inhomogeneous dose distributions have shown to be of sufficient accuracy to be suitable for the verification of dose calculation algorithms. The good sensitivity and sub-mm spatial resolution of the system allows for the detection of deviations of a few percent in dose from the expected (intended or calculated) dose distribution. Its dosimetric properties and the immediate availability of the data make this device a useful tool in the quality control of scanning proton beams. (C) 2000 American Association of Physicists in Medicine. [S0094-2405(00)01909-X].

Purpose: To evaluate the effectiveness of image guided beam gating for PBS liver treatments under realistic breathing conditions. Methods: We have previously proposed a Beams’ Eye View (BEV) X-ray image system as an online motion monitoring device for deriving a gating signal for PBS proton therapy. Using dedicated 4D dose calculations (4DDC), in this work we have simulated gated liver treatments using three amplitude-based gating windows (10/5/3mm) based on motion extracted from BEV imaging of fiducial markers or the diaphragm. In order to improve motion mitigation, BEV guided gating has also been combined with either volumetric (VS) or layered (LS) rescanning. Nine 4DCT(MRI) liver data-sets have been used for the investigation, which not only consider realistic patient geometries but also motion variations between different breathing cycles. All 4D plans have been quantified in terms of plan homogeneity in the PTV (D5-D95), the total estimated treatment time and the beam-on duty cycle. Results: Neither gating nor rescanning can fully retrieve a comparable plan homogeneity to the static case, and considerable reductions of the duty cycle (

Target sites affected by organ motion require a time resolved (4D) dose calculation. Typical 4D dose calculations use 4D-CT as a basis. Unfortunately, 4D-CT images have the disadvantage of being a "snap-shot" of the motion during acquisition and of assuming regularity of breathing. In addition, 4D-CT acquisitions involve a substantial additional dose burden to the patient making many, repeated 4D-CT acquisitions undesirable. Here the authors test the feasibility of an alternative approach to generate patient specific 4D-CT data sets.In this approach motion information is extracted from 4D-MRI. Simulated 4D-CT data sets [which the authors call 4D-CT(MRI)] are created by warping extracted deformation fields to a static 3D-CT data set. The employment of 4D-MRI sequences for this has the advantage that no assumptions on breathing regularity are made, irregularities in breathing can be studied and, if necessary, many repeat imaging studies (and consequently simulated 4D-CT data sets) can be performed on patients and/or volunteers. The accuracy of 4D-CT(MRI)s has been validated by 4D proton dose calculations. Our 4D dose algorithm takes into account displacements as well as deformations on the originating 4D-CT/4D-CT(MRI) by calculating the dose of each pencil beam based on an individual time stamp of when that pencil beam is applied. According to corresponding displacement and density-variation-maps the position and the water equivalent range of the dose grid points is adjusted at each time instance.4D dose distributions, using 4D-CT(MRI) data sets as input were compared to results based on a reference conventional 4D-CT data set capturing similar motion characteristics. Almost identical 4D dose distributions could be achieved, even though scanned proton beams are very sensitive to small differences in the patient geometry. In addition, 4D dose calculations have been performed on the same patient, but using 4D-CT(MRI) data sets based on variable breathing patterns to show the effect of possible irregular breathing on active scanned proton therapy. Using a 4D-CT(MRI), including motion irregularities, resulted in significantly different proton dose distributions.The authors have demonstrated that motion information from 4D-MRI can be used to generate realistic 4D-CT data sets on the basis of a single static 3D-CT data set. 4D-CT(MRI) presents a novel approach to test the robustness of treatment plans in the circumstance of patient motion.

Purpose: The breath-hold (BH) technique has been suggested to mitigate motion and reduce target coverage degradation due to motion effects. The aim of this study was to investigate the effect of inter-BH residual motion on the dose distribution for pencil beam scanned (PBS) proton therapy of locally-advanced lung cancer patients. Methods: A dataset of visually-guided BH CT scans was acquired (10 scans per patient) taken from five lung cancer patients: three intra-fractionally repeated CT scans on treatment days 2,16 and 31, in addition to the day 0 planning CT scan. Three field intensity-modulated proton therapy (IMPT) plans were constructed on the planning CT scan. Dose delivery on fraction 2, 16 and 31 were simulated on the three consecutive CT scans, assuming BH duration of 20s and soft tissue match. The dose was accumulated in the planning CT using deformable image registration, and scaled to simulate the full treatment of 66Gy(RBE) in 33 fractions. Results: The mean dose to the lungs and heart, and maximum dose to the spinal cord and esophagus were within 1% of the planned dose. The CTV V95% decreased and the inhomogeneity (D5%–D95%) increased on average 4.1% (0.4–12.2%) and 5.8% (2.2–13.4%), respectively, over the five patient cases. Conclusion: The results showed that the BH technique seems to spare the OARs in spite of inter-BH residual motion. However, small degradation of target coverage occurred for all patients, with 3/5 patients having a decrease in V95% ≤1%. For the remaining two patients, where V95% decreased up to 12%, the cause could be related to treatment related anatomical changes and, as in photon therapy, plan adaptation may be necessary to ensure target coverage. This study showed that BH could be a potential treatment option to reliably mitigate motion for the treatment of locally-advanced lung cancer using PBS proton therapy.

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’

Purpose: In clinical pencil-beam-scanned (PBS) proton therapy, the advantage of the characteristic sharp dose fall-off after the Bragg Peak (BP) becomes a disadvantage if the BP positions of a plan's constituent pencil beams are shifted, eg.due to anatomical changes. Thus, for fractionated PBS proton therapy, accurate knowledge of the water equivalent path length (WEPL) of the traversed anatomy is critical. In this work we investigate the feasibility of using 2D proton range maps (proton radiography, PR) with the active-scanning gantry at PSI. Methods: We simulated our approach using Monte Carlo methods (MC) to simulate proton beam interactions in patients using clinical imaging data. We selected six head and neck cases having significant anatomical changes detected in per-treatment CTs.PRs (two at 0°/90°) were generated from MC simulations of low-dose pencil beams at 230MeV. Each beam's residual depth-dose was propagated through the patient geometry (from CT) and detected on exiting the patient anatomy in an ideal depth-resolved detector (eg. range telescope). Firstly, to validate the technique, proton radiographs were compared to the ground truth, which was the WEPL from ray-tracing in the patient CT at the pencil beam location. Secondly, WEPL difference maps (per-treatment – planning imaging timepoints) were then generated to locate the anatomical changes, both in the CT (ground truth) and in the PRs. Binomial classification was performed to evaluate the efficacy of the technique relative to CT. Results: Over the projections simulated over all six patients, 70%, 79% and 95% of the grid points agreed with the ground truth proton range to within ±0.5%, ±1%, and ±3% respectively. The sensitivity, specificity, precision and accuracy were high (mean±1σ, 83±8%, 87±13%, 95±10%, 83±7% respectively). Conclusion: We show that proton-based radiographic images can accurately monitor patient positioning and in vivo range verification, while providing equivalent WEPL information to a CT scan, with the advantage of a much lower imaging dose.

The new proton therapy facility is being assembled at the Paul Scherrer Institute (PSI). The beam delivered by the PSI sector cyclotron can be split and brought into a new hall where it is degraded from 590 MeV down to an energy in the range of 85-270 MeV. A new beam line following the degrader is used to clean the low-energetic beam in phase space and momentum band. The analyzed beam is then injected into a compact isocentric gantry, where it is applied to the patient using a new dynamic treatment modality, the so-called spot-scanning technique. This technique will permit full three-dimensional conformation of the dose to the target volume to be realized in a routine way without the need for individualized patient hardware like collimators and compensators. By combining the scanning of the focused pencil beam within the beam optics of the gantry and by mounting the patient table eccentrically on the gantry, the diameter of the rotating structure has been reduced to only 4 m. In the article the degrees of freedom available on the gantry to apply the beam to the patient (with two rotations for head treatments) are also discussed. The devices for the positioning of the patient on the gantry (x rays and proton radiography) and outside the treatment room (the patient transporter system and the modified mechanics of the computer tomograph unit) are briefly presented. The status of the facility and first experimental results are introduced for later reference.

This article shows the limitations of respiratory gating due to intrafraction deformations of the right liver lobe. The variability of organ shape and motion over tens of minutes was taken into account for this evaluation, which closes the gap between short-term analysis of a few regular cycles, as it is possible with 4DCT, and long-term analysis of interfraction motion. Time resolved MR volumes (4D MR sequences) were reconstructed for 12 volunteers and subsequent non-rigid registration provided estimates of the 3D trajectories of points within the liver over time. The full motion during free breathing and its distribution over the liver were quantified and respiratory gating was simulated to determine the gating accuracy for different gating signals, duty cycles, and different intervals between patient setup and treatment. Gating effectively compensated for the respiratory motion within short sequences (3 min), but deformations, mainly in the anterior inferior part (Couinaud segments IVb and V), led to systematic deviations from the setup position of more than 5 mm in 7 of 12 subjects after 20 min. We conclude that measurements over a few breathing cycles should not be used as a proof of accurate reproducibility of motion, not even within the same fraction, if it is longer than a few minutes. Although the diaphragm shows the largest magnitude of motion, it should not be used to assess the gating accuracy over the entire liver because the reproducibility is typically much more limited in inferior parts. Simple gating signals, such as the trajectory of skin motion, can detect the exhalation phase, but do not allow for an absolute localization of the complete liver over longer periods because the drift of these signals does not necessarily correlate with the internal drift.

Purpose: To develop a 4D treatment optimization approach for Pencil Beam Scanned (PBS) proton therapy that includes breathing variability. Method: PBS proton therapy delivers a pattern of proton pencil beams (PBs), distributed to cover the target volume and optimized such as to achieve a homogenous dose distribution across the target. In this work, this optimization step has been enhanced to include advanced 4D dose calculations of liver tumors based on motion extracted from either 4D-CT (representing a single and averaged respiratory cycle) or 4D-CT(MRI) (including breathing variability). The 4D dose calculation is performed per PB on deforming dose grid, and according to the timestamp of each PB, a displacement due to patient’s motion and a change in radiological depth.Three different treatment fields have been optimized in 3D on the end-exhale phase of a 4D-CT liver data set (3D-opt) and then in 4D using the motion extracted from either 4D-CT or 4D-CT(MRI) using deformable image registration. All plans were calculated directly on the PTV without the use of an ITV. The delivery characteristics of the PSI Gantry 2 have been assumed for all calculations. Results: Dose inhomogeneities (D5-D95) in the CTV for the 3D optimized plans recalculated under conditions of variable motion were increased by on average 19.8% compared to the static case. These differences could be reduced by 4D-CT based 4D optimization to 10.5% and by 4D-CT(MRI) based optimization to only 2.3% of the static value. Liver V25 increased by less than 1% using 4D optimization. Conclusion: 4D optimized PBS treatment plans taking into account breathing variability provide for significantly improved robustness against motion and motion variability than those based on 4D-CT alone, and may negate the need of motion specific target expansions. Swiss National Fund Grant (320030_1493942-1)

The purpose of this work is to show the feasibility of using in vivo proton radiography of a radiotherapy patient for the patient individual optimization of the calibration from CT-Hounsfield units to relative proton stopping power. Water equivalent tissue (WET) calibrated proton radiographs of a dog patient treated for a nasal tumor were used as baseline in comparison with integrated proton stopping power through the calibrated CT of the dog. In an optimization procedure starting with a stoichiometric calibration curve, the calibration was modified randomly. The result of this iteration is an optimized calibration curve which was used to recalculate the dose distribution of the patient. One result of this experiment was that the mean value of the deviations between WET calculations based on the stoichiometric calibration curve and the measurements was shifted systematically away from zero. The calibration produced by the optimization procedure reduced this shift to around 0.4 mm. Another result was that the precision of the calibration, reflected as the standard deviation of the normally distributed deviations between WET calculation and measurement, could be reduced from 7.9 to 6.7 mm with the optimized calibration. The dose distributions based on the two calibration curves showed major deviations at the distal end of the target volume.

Since the end of 1996, we have treated more than 160 patients at PSI using spot-scanned protons. The range of indications treated has been quite wide and includes, in the head region, base-of-skull sarcomas, low-grade gliomas, meningiomas, and para-nasal sinus tumors. In addition, we have treated bone sarcomas in the neck and trunk--mainly in the sacral area--as well as prostate cases and some soft tissue sarcomas. PTV volumes for our treated cases are in the range 20-4500 ml, indicating the flexibility of the spot scanning system for treating lesions of all types and sizes. The number of fields per applied plan ranges from between 1 and 4, with a mean of just under 3 beams per plan, and the number of fluence modulated Bragg peaks delivered per field has ranged from 200 to 45 000. With the current delivery rate of roughly 3000 Bragg peaks per minute, this translates into delivery times per field of between a few seconds to 20-25 min. Bragg peak weight analysis of these spots has shown that over all fields, only about 10% of delivered spots have a weight of more than 10% of the maximum in any given field, indicating that there is some scope for optimizing the number of spots delivered per field. Field specific dosimetry shows that these treatments can be delivered accurately and precisely to within +/-1 mm (1 SD) orthogonal to the field direction and to within 1.5 mm in range. With our current delivery system the mean widths of delivered pencil beams at the Bragg peak is about 8 mm (sigma) for all energies, indicating that this is an area where some improvements can be made. In addition, an analysis of the spot weights and energies of individual Bragg peaks shows a relatively broad spread of low and high weighted Bragg peaks over all energy steps, indicating that there is at best only a limited relationship between pencil beam weighting and depth of penetration. This latter observation may have some consequences when considering strategies for fast re-scanning on second generation scanning gantries.