Impact of spot reduction on the effectiveness of rescanning in pencil beam scanned proton therapy for mobile tumours.

Objective. In pencil beam scanning proton therapy, individually calculated and positioned proton pencil beams, also referred to as 'spots', are used to achieve a highly conformal dose distributions to the target. Recent work has shown that this number of spots can be substantially reduced, resulting in shorter delivery times without compromising dosimetric plan quality. However, the sensitivity of spot-reduced plans to tumour motion is unclear. Although previous work has shown that spot-reduced plans are slightly more sensitive to small positioning inaccuracies of the individual pencil beams, the resulting shorter delivery times may allow for more rescanning. The aim of this study was to assess the impact of tumour motion and the effectiveness of 3D volumetric rescanning for spot-reduced treatment plans.Approach.Three liver and two lung cancer patients with non-negligible motion amplitudes were analysed. Conventional and probabilistic internal target volume definitions were used for planning considering single or multiple breathing cycles respectively. For each patient, one clinical and two spot-reduced treatment plans were created using identical field geometries. 4D dynamic dose calculations were then performed and resulting target coverage (V95%), dose homogeneity (D5%-D95%) and hot spots (D2%) evaluated for 1-25 rescans.Main results. Over all patients investigated, spot reduction reduced the number of spots by 91% in comparison to the clinical plan, reducing field delivery times by approximately 50%. This reduction, together with the substantially increased dose per spot resulting from the spot reduction process, allowed for more rescans in the same amount of time as for clinical plans and typically improved dosimetric parameters, in some cases to values better than the reference static (3D calculated) plans. However, spot-reduced plans had an increased possibility of interference with the breathing cycle, especially for simulations of perfectly repeatable breathing.Significance.For the patients analysed in this study, spot-reduced plans were found to be a valuable option to increase the efficiency of 3D volumetric rescanning for motion mitigation, if attention is paid to possible interference patterns.

Treatment planning considerations for the development of FLASH proton therapy.

With increasing focus on the translation of the observed FLASH effect into clinical practice, this paper presents treatment planning considerations for its development using proton therapy. Potential requirements to induce a FLASH effect are discussed along with the properties of existing proton therapy delivery systems and the changes in planning and delivery approaches required to satisfy these prerequisites. For the exploration of treatment planning approaches for FLASH, developments in treatment planning systems are needed. Flexibility in adapting to new information will be important in such an evolving area. Variations in definitions, threshold values and assumptions can make it difficult to compare different published studies and to interpret previous studies in the context of new information. Together with the fact that much is left to be understood about the underlying mechanism behind the FLASH effect, a systematic and comprehensive approach to information storage is encouraged. Collecting and retaining more detailed information on planned and realised dose delivery as well as reporting the assumptions made in planning studies creates the potential for research to be revisited and re-evaluated in the light of future improvements in understanding. Forward thinking at the time of study development can help facilitate retrospective analysis. This, we hope, will increase the available evidence and accelerate the translation of the FLASH effect into clinical benefit.

Synthetic 4DCT(MRI) lung phantom generation for 4D radiotherapy and image guidance investigations.

PURPOSE: Respiratory motion is one of the major challenges in radiotherapy. In this work, a comprehensive and clinically plausible set of 4D numerical phantoms, together with their corresponding "ground truths," have been developed and validated for 4D radiotherapy applications. METHODS: The phantoms are based on CTs providing density information and motion from multi-breathing-cycle 4D Magnetic Resonance imagings (MRIs). Deformable image registration (DIR) has been utilized to extract motion fields from 4DMRIs and to establish inter-subject correspondence by registering binary lung masks between Computer Tomography (CT) and MRI. The established correspondence is then used to warp the CT according to the 4DMRI motion. The resulting synthetic 4DCTs are called 4DCT(MRI)s. Validation of the 4DCT(MRI) workflow was conducted by directly comparing conventional 4DCTs to derived synthetic 4D images using the motion of the 4DCTs themselves (referred to as 4DCT(CT)s). Digitally reconstructed radiographs (DRRs) as well as 4D pencil beam scanned (PBS) proton dose calculations were used for validation. RESULTS: Based on the CT image appearance of 13 lung cancer patients and deformable motion of five volunteer 4DMRIs, synthetic 4DCT(MRI)s with a total of 871 different breathing cycles have been generated. The 4DCT(MRI)s exhibit an average superior-inferior tumor motion amplitude of 7 ± 5 mm (min: 0.5 mm, max: 22.7 mm). The relative change of the DRR image intensities of the conventional 4DCTs and the corresponding synthetic 4DCT(CT)s inside the body is smaller than 5% for at least 81% of the pixels for all studied cases. Comparison of 4D dose distributions calculated on 4DCTs and the synthetic 4DCT(CT)s using the same motion achieved similar dose distributions with an average 2%/2 mm gamma pass rate of 90.8% (min: 77.8%, max: 97.2%). CONCLUSION: We developed a series of numerical 4D lung phantoms based on real imaging and motion data, which give realistic representations of both anatomy and motion scenarios and the accessible "ground truth" deformation vector fields of each 4DCT(MRI). The open-source code and motion data allow foreseen users to generate further 4D data by themselves. These numeric 4D phantoms can be used for the development of new 4D treatment strategies, 4D dose calculations, DIR algorithm validations, as well as simulations of motion mitigation and different online image guidance techniques for both proton and photon radiation therapy.

A quantitative FLASH effectiveness model to reveal potentials and pitfalls of high dose rate proton therapy.

PURPOSE: In ultrahigh dose rate radiotherapy, the FLASH effect can lead to substantially reduced healthy tissue damage without affecting tumor control. Although many studies show promising results, the underlying biological mechanisms and the relevant delivery parameters are still largely unknown. It is unclear, particularly for scanned proton therapy, how treatment plans could be optimized to maximally exploit this protective FLASH effect. MATERIALS AND METHODS: To investigate the potential of pencil beam scanned proton therapy for FLASH treatments, we present a phenomenological model, which is purely based on experimentally observed phenomena such as potential dose rate and dose thresholds, and which estimates the biologically effective dose during FLASH radiotherapy based on several parameters. We applied this model to a wide variety of patient geometries and proton treatment planning scenarios, including transmission and Bragg peak plans as well as single- and multifield plans. Moreover, we performed a sensitivity analysis to estimate the importance of each model parameter. RESULTS: Our results showed an increased plan-specific FLASH effect for transmission compared with Bragg peak plans (19.7% vs. 4.0%) and for single-field compared with multifield plans (14.7% vs. 3.7%), typically at the cost of increased integral dose compared to the clinical reference plan. Similar FLASH magnitudes were found across the different treatment sites, whereas the clinical benefits with respect to the clinical reference plan varied strongly. The sensitivity analysis revealed that the threshold dose as well as the dose per fraction strongly impacted the FLASH effect, whereas the persistence time only marginally affected FLASH. An intermediate dependence of the FLASH effect on the dose rate threshold was found. CONCLUSIONS: Our model provided a quantitative measure of the FLASH effect for various delivery and patient scenarios, supporting previous assumptions about potentially promising planning approaches for FLASH proton therapy. Positive clinical benefits compared to clinical plans were achieved using hypofractionated, single-field transmission plans. The dose threshold was found to be an important factor, which may require more investigation.

Combining rescanning and gating for a time-efficient treatment of mobile tumors using pencil beam scanning proton therapy.

BACKGROUND AND PURPOSE: Respiratory motion during proton therapy can severely degrade dose distributions, particularly due to interplay effects when using pencil beam scanning. Combined rescanning and gating treatments for moving tumors mitigates dose degradation, but at the cost of increased treatment delivery time. The objective of this study was to identify the time efficiency of these dose degradation-motion mitigation strategies for different range of motions. MATERIALS AND METHODS: Seventeen patients with thoracic or abdominal tumors were studied. Tumor motion amplitudes ranged from 2-30 mm. Deliveries using different combinations of rescanning and gating were simulated with a dense dose spot grid (4 × 4 × 2.5 mm3) for all patients and a sparse dose spot grid (8 × 8 × 5 mm3) for six patients with larger tumor movements (>8 mm). The resulting plans were evaluated in terms of CTV coverage and time efficiency. RESULTS: Based on the studied patient cohort, it has been shown that for amplitudes up to 5 mm, no motion mitigation is required with a dense spot grid. For amplitudes between 5 and 10 mm, volumetric rescanning should be applied while maintaining a 100% duty cycle when using a dense spot grid. Although gating could be envisaged to reduce the target volume for intermediate motion, it has been shown that the dose to normal tissues would only be reduced marginally. Moreover, the treatment time would increase. Finally, for larger motion amplitudes, both volumetric rescanning and respiratory gating should be applied with both spot grids. In addition, it has been shown that a dense spot grid delivers better CTV dose coverage than a sparse dose grid. CONCLUSION: Volumetric rescanning and/or respiratory gating can be used in order to effectively and efficiently mitigate dose degradation due to tumor movement.

Liver-ultrasound-guided lung tumour tracking for scanned proton therapy: a feasibility study.

Pencil beam scanned (PBS) proton therapy of lung tumours is hampered by respiratory motion and the motion-induced density changes along the beam path. In this simulation study, we aim to investigate the effectiveness of proton beam tracking for lung tumours both under ideal conditions and in conjunction with a respiratory motion model guided by real-time ultrasound imaging of the liver. Multiple-breathing-cycle 4DMRIs of the thorax and abdominal 2D ultrasound images were acquired simultaneously for five volunteers. Deformation vector fields extracted from the 4DMRI, referred to as ground truth motion, were used to generate 4DCT(MRI) data sets of two lung cancer patients, resulting in 10 data sets with variable motion patterns. Given the 4DCT(MRI) and the corresponding ultrasound images as surrogate data, a patient-specific motion model was built. The model consists of an autoregressive model and Gaussian process regression for the temporal and spatial prediction, respectively. Two-field PBS plans were optimised on the reference CTs, and 4D dose calculations (4DDC) were used to simulate dose delivery for (a) unmitigated motion, (b) ideal 2D and 3D tracking (both beam adaption and 4DDC based on ground truth motion), and (c) realistic 2D and 3D tracking (beam adaption based on motion predictions, 4DDC on ground truth motion). Model-guided tracking retrieved clinically acceptable target dose homogeneity, as seen in a substantial reduction of the D5%-D95% compared to the non-mitigated simulation. Tracking in 2D and 3D resulted in a similar improvement of the dose homogeneity, as did ideal and realistic tracking simulations. In some cases, however, the tracked deliveries resulted in a shift towards higher or lower dose levels, leading to unacceptable target over- or under-coverage. The presented motion modelling framework was shown to be an accurate motion prediction tool for the use in proton beam tracking. Tracking alone, however, may not always effectively mitigate motion effects, making it necessary to combine it with other techniques such as rescanning.

Liver-ultrasound based motion modelling to estimate 4D dose distributions for lung tumours in scanned proton therapy.

Motion mitigation strategies are crucial for scanned particle therapy of mobile tumours in order to prevent geometrical target miss and interplay effects. We developed a patient-specific respiratory motion model based on simultaneously acquired time-resolved volumetric MRI and 2D abdominal ultrasound images. We present its effects on 4D pencil beam scanned treatment planning and simulated dose distributions. Given an ultrasound image of the liver and the diaphragm, principal component analysis and Gaussian process regression were applied to infer dense motion information of the lungs. 4D dose calculations for scanned proton therapy were performed using the estimated and the corresponding ground truth respiratory motion; the differences were compared by dose difference volume metrics. We performed this simulation study on 10 combined CT and 4DMRI data sets where the motion characteristics were extracted from 5 healthy volunteers and fused with the anatomical CT data of two lung cancer patients. Median geometrical estimation errors below 2 mm for all data sets and maximum dose differences of [Formula: see text] = 43.2% and [Formula: see text] = 16.3% were found. Moreover, it was shown that abdominal ultrasound imaging allows to monitor organ drift. This study demonstrated the feasibility of the proposed ultrasound-based motion modelling approach for its application in scanned proton therapy of lung tumours.

Impact of internal target volume definition for pencil beam scanned proton treatment planning in the presence of respiratory motion variability for lung cancer: A proof of concept.

PURPOSE: Motion management is crucial in scanned proton therapy for mobile tumours. Current motion mitigation approaches rely on single 4DCTs before treatment, ignoring respiratory variability. We investigate the consequences of respiratory variations on internal target volumes (ITV) definition and motion mitigation efficacy, and propose a probabilistic ITV based on 4DMRI. MATERIALS AND METHODS: Four 4DCT(MRI) datasets, each containing 40 variable cycles of synthetic 4DCTs, were generated by warping single-phase CTs of two lung patients with motion fields extracted from two 4DMRI datasets. Two-field proton treatment plans were optimised on ITVs based on different parts of the 4DCT(MRI)s. 4D dose distributions were calculated by considering variable respiratory patterns. Different probabilistic ITVs were created by incorporating the voxels covered by the CTV in at least 25%, 50%, or 75% (ITV25, ITV50, ITV75) of the cycles, and compared with the conservative ITV encompassing all possible CTV positions. RESULTS: Depending on the selected planning 4DCT, ITV volumes vary up to 20%, resulting in significant variation in CTV coverage for 4D treatments. Target coverage and homogeneity improved with the conservative ITV, but was associated with significantly increased lung dose (~1%). ITV25 and ITV50 led to acceptable plan quality in most cases without lung dose increments. ITV75 best minimised lung dose, but was insufficient to ensure coverage under all motion scenarios. CONCLUSION: Irregular respiration significantly affects CTV coverage when ITVs are only defined by single 4DCTs. A probabilistic ITV50 provides an adequate compromise between target coverage and lung dose for most motion and patient scenarios investigated.

Anthropomorphic phantom for deformable lung and liver CT and MR imaging for radiotherapy.

In this study, a functioning and ventilated anthropomorphic phantom was further enhanced for the purpose of CT and MR imaging of the lung and liver. A deformable lung, including respiratory tract was 3D printed. Within the lung's inner structures is a solid region shaped from a patient's lung tumour and six nitro-glycerine capsules as reference landmarks. The full internal mesh was coated, and the tumour filled, with polyorganosiloxane based gel. A moulded liver was created with an external casing of silicon filled with polyorganosiloxane gel and flexible plastic internal structures. The liver, fitted to the inferior portion of the right lung, moves along with the lung's ventilation. In the contralateral side, a cavity is designed to host a dosimeter, whose motion is correlated to the lung pressure. A 4DCT of the phantom was performed along with static and 4D T1 weighted MR images. The CT Hounsfield units (HU) for the flexible 3D printed material were -600-100 HU (lung and liver structures), for the polyorganosiloxane gel 30-120 HU (lung coating and liver filling) and for the silicon 650-800 HU (liver casing). The MR image intensity units were 0-40, 210-280 and 80-130, respectively. The maximum range of motion in the 4D imaging for the superior lung was 1-3.5 mm and 3.5-8 mm in the inferior portion. The liver motion was 5.5-8.0 mm at the tip and 5.7-10.0 mm at the dome. No measurable drift in motion was observed over a 2 h session and motion was reproducible over three different sessions for sin2(t), sin4(t) and a patient-like breathing curve with the interquartile range of amplitudes for all breathing cycles within 0.5 mm. The addition of features within the lung and of a deformable liver will allow the phantom to be used for imaging studies such as validation of 4DMRI and pseudo CT methods.

The dosimetric effect of residual breath-hold motion in pencil beam scanned proton therapy - An experimental study.

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.

Experimental validation of a deforming grid 4D dose calculation for PBS proton therapy.

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.

Can decision biases improve insurance outcomes? An experiment on status quo bias in health insurance choice.

Rather than conforming to the assumption of perfect rationality in neoclassical economic theory, decision behavior has been shown to display a host of systematic biases. Properly understood, these patterns can be instrumentalized to improve outcomes in the public realm. We conducted a laboratory experiment to study whether decisions over health insurance policies are subject to status quo bias and, if so, whether experience mitigates this framing effect. Choices in two treatment groups with status quo defaults are compared to choices in a neutrally framed control group. A two-step design features sorting of subjects into the groups, allowing us to control for selection effects due to risk preferences. The results confirm the presence of a status quo bias in consumer choices over health insurance policies. However, this effect of the default framing does not persist as subjects repeat this decision in later periods of the experiment. Our results have implications for health care policy, for example suggesting that the use of non-binding defaults in health insurance can facilitate the spread of co-insurance policies and thereby help contain health care expenditure.