Technical note: Measurement of the bunch structure of a clinical proton beam using a SiPM coupled to a plastic scintillator with an optical fiber.

BACKGROUND: Recent proposals of high dose rate plans in protontherapy as well as very short proton bunches may pose problems to current beam monitor systems. There is an increasing demand for real-time proton beam monitoring with high temporal resolution, extended dynamic range and radiation hardness. Plastic scintillators coupled to optical fiber sensors have great potential in this context to become a practical solution towards clinical implementation. PURPOSE: In this work, we evaluate the capabilities of a very compact fast plastic scintillator with an optical fiber readout by a SiPM and electronics sensor which has been used to provide information on the time structure at the nanosecond level of a clinical proton beam. MATERIALS AND METHODS: A 3 × 3 × 3 mm3 plastic scintillator (EJ-232Q Eljen Technology) coupled to a 3 × 3 mm2 SiPM (MicroFJ-SMA-30035, Onsemi) has been characterized with a 70 MeV clinical proton beam accelerated in a Proteus One synchrocyclotron. The signal was read out by a high sampling rate oscilloscope (5 GS/s). By exposing the sensor directly to the proton beam, the time beam profile of individual spots was recorded. RESULTS: Measurements of detector signal have been obtained with a time sampling period of 0.8 ns. Proton bunch period (16 ns), spot (10 µs) and interspot (1 ms) time structures could be observed in the time profile of the detector signal amplitude. From this, the RF frequency of the accelerator has been extracted, which is found to be 64 MHz. CONCLUSIONS: The proposed system was able to measure the fine time structure of a clinical proton accelerator online and with ns time resolution.

Radical Production with Pulsed Beams: Understanding the Transition to FLASH.

Ultra-high dose rate (UHDR) irradiation regimes have the potential to spare normal tissue while keeping equivalent tumoricidal capacity than conventional dose rate radiotherapy (CONV-RT). This has been called the FLASH effect. In this work, we present a new simulation framework aiming to study the production of radical species in water and biological media under different irradiation patterns. The chemical stage (heterogeneous phase) is based on a nonlinear reaction-diffusion model, implemented in GPU. After the first 1 µs, no further radical diffusion is assumed, and radical evolution may be simulated over long periods of hundreds of seconds. Our approach was first validated against previous results in the literature and then employed to assess the influence of different temporal microstructures of dose deposition in the expected biological damage. The variation of the Normal Tissue Complication Probability (NTCP), assuming the model of Labarbe et al., where the integral of the peroxyl radical concentration over time (AUC-ROO) is taken as surrogate for biological damage, is presented for different intra-pulse dose rate and pulse frequency configurations, relevant in the clinical scenario. These simulations yield that overall, mean dose rate and the dose per pulse are the best predictors of biological effects at UHDR.

In vivo production of fluorine-18 in a chicken egg tumor model of breast cancer for proton therapy range verification.

Range verification of clinical protontherapy systems via positron-emission tomography (PET) is not a mature technology, suffering from two major issues: insufficient signal from low-energy protons in the Bragg peak area and biological washout of PET emitters. The use of contrast agents including 18O, 68Zn or 63Cu, isotopes with a high cross section for low-energy protons in nuclear reactions producing PET emitters, has been proposed to enhance the PET signal in the last millimeters of the proton path. However, it remains a challenge to achieve sufficient concentrations of these isotopes in the target volume. Here we investigate the possibilities of 18O-enriched water (18-W), a potential contrast agent that could be incorporated in large proportions in live tissues by replacing regular water. We hypothesize that 18-W could also mitigate the problem of biological washout, as PET (18F) isotopes created inside live cells would remain trapped in the form of fluoride anions (F-), allowing its signal to be detected even hours after irradiation. To test our hypothesis, we designed an experiment with two main goals: first, prove that 18-W can incorporate enough 18O into a living organism to produce a detectable signal from 18F after proton irradiation, and second, determine the amount of activity that remains trapped inside the cells. The experiment was performed on a chicken embryo chorioallantoic membrane tumor model of head and neck cancer. Seven eggs with visible tumors were infused with 18-W and irradiated with 8-MeV protons (range in water: 0.74 mm), equivalent to clinical protons at the end of particle range. The activity produced after irradiation was detected and quantified in a small-animal PET-CT scanner, and further studied by placing ex-vivo tumours in a gamma radiation detector. In the acquired images, specific activity of 18F (originating from 18-W) could be detected in the tumour area of the alive chicken embryo up to 9 h after irradiation, which confirms that low-energy protons can indeed produce a detectable PET signal if a suitable contrast agent is employed. Moreover, dynamic PET studies in two of the eggs evidenced a minimal effect of biological washout, with 68% retained specific 18F activity at 8 h after irradiation. Furthermore, ex-vivo analysis of 4 irradiated tumours showed that up to 3% of oxygen atoms in the targets were replaced by 18O from infused 18-W, and evidenced an entrapment of 59% for specific activity of 18F after washing, supporting our hypothesis that F- ions remain trapped within the cells. An infusion of 18-W can incorporate 18O in animal tissues by replacing regular water inside cells, producing a PET signal when irradiated with low-energy protons that could be used for range verification in protontherapy. 18F produced inside cells remains entrapped and suffers from minimal biological washout, allowing for a sharper localization with longer PET acquisitions. Further studies must evaluate the feasibility of this technique in dosimetric conditions closer to clinical practice, in order to define potential protocols for its use in patients.

Radiochromic film dosimetry for protons up to 10 MeV with EBT2, EBT3 and unlaminated EBT3 films.

Passive dosimetry with radiochromic films is widely used in proton radiotherapy, both in clinical and scientific environments, thanks to its simplicity, high spatial resolution and dose-rate independence. However, film under-response for low-energy protons, the so-called linear-energy transfer (LET) quenching, must be accounted and corrected for. We perform a meta-analysis on existing film under-response data with EBT, EBT2 and EBT3 GAFchromic™ films and provide a common framework to integrate it, based on the calculation of dose-averaged LET in the active layer of the films. We also report on direct measurements with the 10 MeV proton beam at the Center for Microanalysis of Materials (CMAM) for EBT2, EBT3 and unlaminated EBT3 films, focusing on the 20-80 keVµm-1LET range, where previous data was scarce. Measured film relative efficiency (RE) values are in agreement with previously reported data from the literature. A model on film RE constructed with combined literature and own experimental values in the 5-80 keVµm-1LET range is presented, supporting the hypothesis of a linear decrease of RE with LET, with no remarkable differences between the three types of films analyzed.

Dictionary-based protoacoustic dose map imaging for proton range verification.

Proton radiotherapy has the potential to provide state-of-the-art dose conformality in the tumor area, reducing possible adverse effects on surrounding organs at risk. However, uncertainties in the exact location of the proton Bragg peak inside the patient prevent this technique from achieving full clinical potential. In this context, in vivo verification of the range of protons in patients is key to reduce uncertainty margins. Protoacoustic range verification employs acoustic pressure waves generated by protons due to the radio-induced thermoacoustic effect to reconstruct the dose deposited in a patient during proton therapy. In this paper, we propose to use the a priori knowledge of the shape of the proton dose distribution to create a dictionary with the expected ultrasonic signals at predetermined detector locations. Using this dictionary, the reconstruction of deposited dose is performed by matching pre-calculated dictionary acoustic signals with data acquired online during treatment. The dictionary method was evaluated on a single-field proton plan for a prostate cancer patient. Dose calculation was performed with the open-source treatment planning system matRad, while acoustic wave propagation was carried out with k-Wave. We studied the ability of the proposed dictionary method to detect range variations caused by anatomical changes in tissue density, and alterations of lateral and longitudinal beam position. Our results show that the dictionary-based protoacoustic method was able to identify the changes in range originated by all the alterations introduced, with an average accuracy of 1.4 mm. This procedure could be used for in vivo verification, comparing the measured signals with the precalculated dictionary.

Biological and Mechanical Synergies to Deal With Proton Therapy Pitfalls: Minibeams, FLASH, Arcs, and Gantryless Rooms.

Proton therapy has advantages and pitfalls comparing with photon therapy in radiation therapy. Among the limitations of protons in clinical practice we can selectively mention: uncertainties in range, lateral penumbra, deposition of higher LET outside the target, entrance dose, dose in the beam path, dose constraints in critical organs close to the target volume, organ movements and cost. In this review, we combine proposals under study to mitigate those pitfalls by using individually or in combination: (a) biological approaches of beam management in time (very high dose rate "FLASH" irradiations in the order of 100 Gy/s) and (b) modulation in space (a combination of mini-beams of millimetric extent), together with mechanical approaches such as (c) rotational techniques (optimized in partial arcs) and, in an effort to reduce cost, (d) gantry-less delivery systems. In some cases, these proposals are synergic (e.g., FLASH and minibeams), in others they are hardly compatible (mini-beam and rotation). Fixed lines have been used in pioneer centers, or for specific indications (ophthalmic, radiosurgery,…), they logically evolved to isocentric gantries. The present proposals to produce fixed lines are somewhat controversial. Rotational techniques, minibeams and FLASH in proton therapy are making their way, with an increasing degree of complexity in these three approaches, but with a high interest in the basic science and clinical communities. All of them must be proven in clinical applications.

MultiRBE: Treatment planning for protons with selective radiobiological effectiveness.

PURPOSE: Clinical treatment planning protocols for protons recommend a uniform value radiobiological effectiveness (RBE) of protons of 1.1 throughout the treatment field, despite evidence from in-vitro and animal studies that proton RBE increases with linear energy transfer (LET), causing tissues placed distally to the target location to receive a presumably higher biological dose than estimated. While several voices in the medical physics community have advocated for variable RBE-based optimization, the uncertainties in RBE models have prevented its implementation in clinical practice, since an overestimation of RBE could cause significant target underdosage. METHODS: We propose a mixed RBE model (MultiRBE), where a uniform RBE is used in the target contours to ensure an adequate tumor coverage in terms of physical dose, but a variable RBE is used elsewhere. Our model was implemented in the open-source treatment planning system matRad and three example cases were planned: a homogeneous phantom, a prostate tumor and a head-and-neck case. MultiRBE was used for plan optimization, and the produced plans were subsequently evaluated in terms of physical dose coverage (V95% ) and variable RBE-weighted dose in organs at risk and normal tissue complication probabilities (NTCP), where prediction models were available. RESULTS: The planning algorithm showed potential for reducing the biological dose in organs surrounding the planning target and thus decreasing the probability for complications in normal tissue (by up to 62% in the prostate case and 37% in the head-and-neck patient). This was achieved without compromising the target coverage or homogeneity in terms of physical dose, as a result of a smarter redistribution of dose among the surrounding tissues with regard to the optimization constraints. CONCLUSIONS: The results prove the ability of the MultiRBE model to reduce biological dose at healthy tissues without compromising the dose coverage of the tumor, with independence of the variable RBE models used.

Teaching treatment planning for protons with educational open-source software: experience with FoCa and matRad.

Open-source, MATLAB-based treatment planning systems FoCa and matRAD were used in a pilot project for training prospective medical physicists and postgraduate physics students in treatment planning and beam modeling techniques for proton therapy. In the four exercises designed, students learnt how proton pencil beams are modeled and how dose is calculated in three-dimensional voxelized geometries, how pencil beam scanning plans (PBS) are constructed, the rationale behind the choice of spot spacing in patient plans, and the dosimetric differences between photon IMRT and proton PBS plans. Sixty students of two courses participated in the pilot project, with over 90% of satisfactory rating from student surveys. The pilot experience will certainly be continued.

Performance of a hybrid Monte Carlo-Pencil Beam dose algorithm for proton therapy inverse planning.

PURPOSE: Analytical algorithms have a limited accuracy when modeling very heterogeneous tumor sites. This work addresses the performance of a hybrid dose optimizer that combines both Monte Carlo (MC) and pencil beam (PB) dose engines to get the best trade-off between speed and accuracy for proton therapy plans. METHODS: The hybrid algorithm calculates the optimal spot weights (w) by means of an iterative optimization process where the dose at each iteration is computed by using a precomputed dose influence matrix based on the conventional PB plus a correction term c obtained from a MC simulation. Updates of c can be triggered as often as necessary by calling the MC dose engine with the last corrected values of w as input. In order to analyze the performance of the hybrid algorithm against dose calculation errors, it was applied to a simplistic water phantom for which several test cases with different errors were simulated, including proton range uncertainties. Afterwards, the algorithm was used in three clinical cases (prostate, lung, and brain) and benchmarked against full MC-based optimization. The influence of different stopping criteria in the final results was also investigated. RESULTS: The hybrid algorithm achieved excellent results provided that the estimated range in a homogeneous material is the same for the two dose engines involved, i.e., PB and MC. For the three patient cases, the hybrid plans were clinically equivalent to those obtained with full MC-based optimization. Only a single update of c was needed in the hybrid algorithm to fulfill the clinical dose constraints, which represents an extra computation time to obtain c that ranged from 1 (brain) to 4 min (lung) with respect to the conventional PB-based optimization, and an estimated average gain factor of 14 with respect to full MC-based optimization. CONCLUSION: The hybrid algorithm provides an improved trade-off between accuracy and speed. This algorithm can be immediately considered as an option for improving dose calculation accuracy of commercial analytical treatment planning systems, without a significant increase in the computation time (≪5 min) with respect to current PB-based optimization.

Range optimization for mono- and bi-energetic proton modulated arc therapy with pencil beam scanning.

The development of rotational proton therapy plans based on a pencil-beam-scanning (PBS) system has been limited, among several other factors, by the energy-switching time between layers, a system-dependent parameter that ranges between a fraction of a second and several seconds. We are investigating mono- and bi-energetic rotational proton modulated arc therapy (PMAT) solutions that would not be affected by long energy switching times. In this context, a systematic selection of the optimal proton energy for each arc is vital. We present a treatment planning comparison of four different range selection methods, analyzing the dosimetric outcomes of the resulting treatment plans created with the ranges obtained. Given the patient geometry and arc definition (gantry and couch trajectories, snout elevation) our in-house treatment planning system (TPS) FoCa was used to find the maximum, medial and minimum water-equivalent thicknesses (WETs) of the target viewed from all possible field orientations. Optimal ranges were subsequently determined using four methods: (1) by dividing the max/min WET interval into equal steps, (2) by taking the average target midpoints from each field, (3) by taking the average WET of all voxels from all field orientations, and (4) by minimizing the fraction of the target which cannot be reached from any of the available angles. After the range (for mono-energetic plans) or ranges (for bi-energetic plans) were selected, the commercial clinical TPS in use in our institution (Varian Eclipse™) was used to produce the PMAT plans using multifield optimization. Linear energy transfer (LET) distributions of all plans were also calculated using FoCa and compared among the different methods. Mono- and bi-energetic PMAT plans, composed of a single 180° arc, were created for two patient geometries: a C-shaped target located in the mediastinal area of a thoracic tissue-equivalent phantom and a small brain tumor located directly above the brainstem. All plans were optimized using the same procedure to (1) achieve target coverage, (2) reduce dose to OAR and (3) limit dose hot spots in the target. Final outcomes were compared in terms of the resulting dose and LET distributions. Data shows little significant differences among the four studied methods, with superior results obtained with mono-energetic plans. A streamlined systematic method has been implemented in an in-house TPS to find the optimal range to maximize target coverage with rotational mono- or bi-energetic PBS rotational plans by minimizing the fraction of the target that cannot be reached by any direction.