Stopping power and range estimations in proton therapy based on prompt gamma timing: motion models and automated parameter optimization.

OBJECTIVE: Particle therapy treatments are currently limited by uncertainties of the delivered dose. Verification techniques like Prompt-Gamma-Timing-based Stopping Power Estimation (PGT-SPE) may allow for reduction of safety margins in treatment planning. Approach: From Prompt-Gamma-Timing measurements, we reconstruct the spatiotemporal distribution of prompt gamma emissions, which is linked to the average motion of the primary particles. The stopping power is determined by fitting a model of the average particle motion. Here, we compare a previously published implementation of the particle motion model with an alternative formulation and present two formulations to automatically select the hyperparameters of our procedure. The performance was assessed using Monte-Carlo simulations of proton beams (60 MeV to 219 MeV) impinging on a homogeneous PMMA phantom. Main results: The range was successfully determined within a standard deviation of 3 mm for proton beam energies from 70 MeV to 219 MeV. Stopping power estimates showed errors below 5 % for beam energies above 160 MeV. At lower energies, the estimation performance degraded to unsatisfactory levels due to the short range of the protons. The new motion model improved the estimation performance by up to 5 % for beam energies from 100 MeV to 150 MeV with mean errors ranging from 6 % to 18 %. The automated hyperparameter optimization matched the average error of previously reported manual selections, while significantly reducing the outliers. Significance: The data-driven hyperparameter optimization allowed for a reproducible and fast evaluation of our method. The updated motion model and evaluation at new beam energies bring us closer to applying PGT-SPE in more complex scenarios. Direct comparison of stopping power estimates between treatment planning and measurements during irradiation would offer a more direct verification than other secondary-particle-based techniques.

Using the gamma-index analysis for inter-fractional comparison of in-beam PET images for head-and-neck treatment monitoring in proton therapy: A Monte Carlo simulation study.

GOAL: In-beam Positron Emission Tomography (PET) is a technique for in-vivo non-invasive treatment monitoring for proton therapy. To detect anatomical changes in patients with PET, various analysis methods exist, but their clinical interpretation is problematic. The goal of this work is to investigate whether the gamma-index analysis, widely used for dose comparisons, is an appropriate tool for comparing in-beam PET distributions. Focusing on a head-and-neck patient, we investigate whether the gamma-index map and the passing rate are sensitive to progressive anatomical changes. METHODS/MATERIALS: We simulated a treatment course of a proton therapy patient using FLUKA Monte Carlo simulations. Gradual emptying of the sinonasal cavity was modeled through a series of artificially modified CT scans. The in-beam PET activity distributions from three fields were evaluated, simulating a planar dual head geometry. We applied the 3D-gamma evaluation method to compare the PET images with a reference image without changes. Various tolerance criteria and parameters were tested, and results were compared to the CT-scans. RESULTS: Based on 210 MC simulations we identified appropriate parameters for the gamma-index analysis. Tolerance values of 3 mm/3% and 2 mm/2% were suited for comparison of simulated in-beam PET distributions. The gamma passing rate decreased with increasing volume change for all fields. CONCLUSION: The gamma-index analysis was found to be a useful tool for comparing simulated in-beam PET images, sensitive to sinonasal cavity emptying. Monitoring the gamma passing rate behavior over the treatment course is useful to detect anatomical changes occurring during the treatment course.

Synthetic CT imaging for PET monitoring in proton therapy: a simulation study.

Objective.This study addresses a fundamental limitation of in-beam positron emission tomography (IB-PET) in proton therapy: the lack of direct anatomical representation in the images it produces. We aim to overcome this shortcoming by pioneering the application of deep learning techniques to create synthetic control CT images (sCT) from combining IB-PET and planning CT scan data.Approach.We conducted simulations involving six patients who underwent irradiation with proton beams. Leveraging the architecture of a visual transformer (ViT) neural network, we developed a model to generate sCT images of these patients using the planning CT scans and the inter-fractional simulated PET activity maps during irradiation. To evaluate the model's performance, a comparison was conducted between the sCT images produced by the ViT model and the authentic control CT images-serving as the benchmark.Main results.The structural similarity index was computed at a mean value across all patients of 0.91, while the mean absolute error measured 22 Hounsfield Units (HU). Root mean squared error and peak signal-to-noise ratio values were 56 HU and 30 dB, respectively. The Dice similarity coefficient exhibited a value of 0.98. These values are comparable to or exceed those found in the literature. More than 70% of the synthetic morphological changes were found to be geometrically compatible with the ones reported in the real control CT scan.Significance.Our study presents an innovative approach to surface the hidden anatomical information of IB-PET in proton therapy. Our ViT-based model successfully generates sCT images from inter-fractional PET data and planning CT scans. Our model's performance stands on par with existing models relying on input from cone beam CT or magnetic resonance imaging, which contain more anatomical information than activity maps.

Few-seconds range verification with short-lived positron emitters in carbon ion therapy.

In-beam PET (Positron Emission Tomography) is one of the most precise techniques for in-vivo range monitoring in hadron therapy. Our objective was to demonstrate the feasibility of a short irradiation run for range verification before a carbon-ion treatment. To do so a PMMA target was irradiated with a 220 MeV/u carbon-ion beam and annihilation coincidences from short-lived positron emitters were acquired after irradiations lasting 0.6 s. The experiments were performed at the synchrotron-based facility CNAO (Italian National Center of Oncological Hadrontherapy) by using the INSIDE in-beam PET detector. The results show that, with 3·107 carbon ions, the reconstructed positron emitting nuclei distribution is in good agreement with the predictions of a detailed FLUKA Monte Carlo study. Moreover, the radio-nuclei production is sufficiently abundant to determine the average ion beam range with a σ of 1 mm with a 6 s measurement of the activity distribution. Since the data were acquired when the beam was off, the proposed rapid calibration method can be applied to hadron beams extracted from accelerators with very different time structures.

Calibration method and performance of a time-of-flight detector to measure absolute beam energy in proton therapy.

BACKGROUND: The beam energy is one of the most significant parameters in particle therapy since it is directly correlated to the particles' penetration depth inside the patient. Nowadays, the range accuracy is guaranteed by offline routine quality control checks mainly performed with water phantoms, 2D detectors with PMMA wedges, or multi-layer ionization chambers. The latter feature low sensitivity, slow collection time, and response dependent on external parameters, which represent limiting factors for the quality controls of beams delivered with fast energy switching modalities, as foreseen in future treatments. In this context, a device based on solid-state detectors technology, able to perform a direct and absolute beam energy measurement, is proposed as a viable alternative for quality assurance measurements and beam commissioning, paving the way for online range monitoring and treatment verification. PURPOSE: This work follows the proof of concept of an energy monitoring system for clinical proton beams, based on Ultra Fast Silicon Detectors (featuring tenths of ps time resolution in 50 µm active thickness, and single particle detection capability) and time-of-flight techniques. An upgrade of such a system is presented here, together with the description of a dedicated self-calibration method, proving that this second prototype is able to assess the mean particles energy of a monoenergetic beam without any constraint on the beam temporal structure, neither any a priori knowledge of the beam energy for the calibration of the system. METHODS: A new detector geometry, consisting of sensors segmented in strips, has been designed and implemented in order to enhance the statistics of coincident protons, thus improving the accuracy of the measured time differences. The prototype was tested on the cyclotron proton beam of the Trento Protontherapy Center (TPC). In addition, a dedicated self-calibration method, exploiting the measurement of monoenergetic beams crossing the two telescope sensors for different flight distances, was introduced to remove the systematic uncertainties independently from any external reference. RESULTS: The novel calibration strategy was applied to the experimental data collected at TPC (Trento) and CNAO (Pavia). Deviations between measured and reference beam energies in the order of a few hundreds of keV with a maximum uncertainty of 0.5 MeV were found, in compliance with the clinically required water range accuracy of 1 mm. CONCLUSIONS: The presented version of the telescope system, minimally perturbative of the beam, relies on a few seconds of acquisition time to achieve the required clinical accuracy and therefore represents a feasible solution for beam commission, quality assurance checks, and online beam energy monitoring.

In-vivo range verification analysis with in-beam PET data for patients treated with proton therapy at CNAO.

Morphological changes that may arise through a treatment course are probably one of the most significant sources of range uncertainty in proton therapy. Non-invasive in-vivo treatment monitoring is useful to increase treatment quality. The INSIDE in-beam Positron Emission Tomography (PET) scanner performs in-vivo range monitoring in proton and carbon therapy treatments at the National Center of Oncological Hadrontherapy (CNAO). It is currently in a clinical trial (ID: NCT03662373) and has acquired in-beam PET data during the treatment of various patients. In this work we analyze the in-beam PET (IB-PET) data of eight patients treated with proton therapy at CNAO. The goal of the analysis is twofold. First, we assess the level of experimental fluctuations in inter-fractional range differences (sensitivity) of the INSIDE PET system by studying patients without morphological changes. Second, we use the obtained results to see whether we can observe anomalously large range variations in patients where morphological changes have occurred. The sensitivity of the INSIDE IB-PET scanner was quantified as the standard deviation of the range difference distributions observed for six patients that did not show morphological changes. Inter-fractional range variations with respect to a reference distribution were estimated using the Most-Likely-Shift (MLS) method. To establish the efficacy of this method, we made a comparison with the Beam's Eye View (BEV) method. For patients showing no morphological changes in the control CT the average range variation standard deviation was found to be 2.5 mm with the MLS method and 2.3 mm with the BEV method. On the other hand, for patients where some small anatomical changes occurred, we found larger standard deviation values. In these patients we evaluated where anomalous range differences were found and compared them with the CT. We found that the identified regions were mostly in agreement with the morphological changes seen in the CT scan.

Proton therapy monitoring: spatiotemporal emission reconstruction with prompt gamma timing and implementation with PET detectors.

Objective. In this study we introduce spatiotemporal emission reconstruction prompt gamma timing (SER-PGT), a new method to directly reconstruct the prompt photon emission in the space and time domains inside the patient in proton therapy.Approach. SER-PGT is based on the numerical optimisation of a multidimensional likelihood function, followed by a post-processing of the results. The current approach relies on a specific implementation of the maximum-likelihood expectation maximisation algorithm. The robustness of the method is guaranteed by the complete absence of any information about the target composition in the algorithm.Main results. Accurate Monte Carlo simulations indicate a range resolution of about 0.5 cm (standard deviation) when considering 107primary protons impinging on an homogeneous phantom. Preliminary results on an anthropomorphic phantom are also reported.Significance. By showing the feasibility for the reconstruction of the primary particle range using PET detectors, this study provides significant basis for the development of an hybrid in-beam PET and prompt photon device.

Localization of anatomical changes in patients during proton therapy with in-beam PET monitoring: A voxel-based morphometry approach exploiting Monte Carlo simulations.

PURPOSE: In-beam positron emission tomography (PET) is one of the modalities that can be used for in vivo noninvasive treatment monitoring in proton therapy. Although PET monitoring has been frequently applied for this purpose, there is still no straightforward method to translate the information obtained from the PET images into easy-to-interpret information for clinical personnel. The purpose of this work is to propose a statistical method for analyzing in-beam PET monitoring images that can be used to locate, quantify, and visualize regions with possible morphological changes occurring over the course of treatment. METHODS: We selected a patient treated for squamous cell carcinoma (SCC) with proton therapy, to perform multiple Monte Carlo (MC) simulations of the expected PET signal at the start of treatment, and to study how the PET signal may change along the treatment course due to morphological changes. We performed voxel-wise two-tailed statistical tests of the simulated PET images, resembling the voxel-based morphometry (VBM) method commonly used in neuroimaging data analysis, to locate regions with significant morphological changes and to quantify the change. RESULTS: The VBM resembling method has been successfully applied to the simulated in-beam PET images, despite the fact that such images suffer from image artifacts and limited statistics. Three dimensional probability maps were obtained, that allowed to identify interfractional morphological changes and to visualize them superimposed on the computed tomography (CT) scan. In particular, the characteristic color patterns resulting from the two-tailed statistical tests lend themselves to trigger alarms in case of morphological changes along the course of treatment. CONCLUSIONS: The statistical method presented in this work is a promising method to apply to PET monitoring data to reveal interfractional morphological changes in patients, occurring over the course of treatment. Based on simulated in-beam PET treatment monitoring images, we showed that with our method it was possible to correctly identify the regions that changed. Moreover we could quantify the changes, and visualize them superimposed on the CT scan. The proposed method can possibly help clinical personnel in the replanning procedure in adaptive proton therapy treatments.

Monitoring Carbon Ion Beams Transverse Position Detecting Charged Secondary Fragments: Results From Patient Treatment Performed at CNAO.

Particle therapy in which deep seated tumours are treated using 12C ions (Carbon Ions RadioTherapy or CIRT) exploits the high conformity in the dose release, the high relative biological effectiveness and low oxygen enhancement ratio of such projectiles. The advantages of CIRT are driving a rapid increase in the number of centres that are trying to implement such technique. To fully profit from the ballistic precision achievable in delivering the dose to the target volume an online range verification system would be needed, but currently missing. The 12C ions beams range could only be monitored by looking at the secondary radiation emitted by the primary beam interaction with the patient tissues and no technical solution capable of the needed precision has been adopted in the clinical centres yet. The detection of charged secondary fragments, mainly protons, emitted by the patient is a promising approach, and is currently being explored in clinical trials at CNAO. Charged particles are easy to detect and can be back-tracked to the emission point with high efficiency in an almost background-free environment. These fragments are the product of projectiles fragmentation, and are hence mainly produced along the beam path inside the patient. This experimental signature can be used to monitor the beam position in the plane orthogonal to its flight direction, providing an online feedback to the beam transverse position monitor chambers used in the clinical centres. This information could be used to cross-check, validate and calibrate, whenever needed, the information provided by the ion chambers already implemented in most clinical centres as beam control detectors. In this paper we study the feasibility of such strategy in the clinical routine, analysing the data collected during the clinical trial performed at the CNAO facility on patients treated using 12C ions and monitored using the Dose Profiler (DP) detector developed within the INSIDE project. On the basis of the data collected monitoring three patients, the technique potential and limitations will be discussed.

Carbon ions beam therapy monitoring with the INSIDE in-beam PET.

In vivo range monitoring techniques are necessary in order to fully take advantage of the high dose gradients deliverable in hadrontherapy treatments. Positron emission tomography (PET) scanners can be used to monitor beam-induced activation in tissues and hence measure the range. The INSIDE (Innovative Solutions for In-beam DosimEtry in Hadrontherapy) in-beam PET scanner, installed at the Italian National Center of Oncological Hadrontherapy (CNAO, Pavia, Italy) synchrotron facility, has already been successfully tested in vivo during a proton therapy treatment. We discuss here the system performance evaluation with carbon ion beams, in view of future in vivo tests. The work is focused on the analysis of activity images obtained with therapeutic treatments delivered to polymethyl methacrylate (PMMA) phantoms, as well as on the test of an innovative and robust Monte Carlo simulation technique for the production of reliable prior activity maps. Images are reconstructed using different integration intervals, so as to monitor the activity evolution during and after the treatment. Three procedures to compare activity images are presented, namely Pearson correlation coefficient, Beam's eye view and overall view. Images of repeated irradiations of the same treatments are compared to assess the integration time necessary to provide reproducible images. The range agreement between simulated and experimental images is also evaluated, so as to validate the simulation capability to provide sound prior information. The results indicate that at treatment end, or at most 20 s afterwards, the range measurement is reliable within 1-2 mm, when comparing both different experimental sessions and data with simulations. In conclusion, this work shows that the INSIDE in-beam PET scanner performance is promising towards its in vivo test with carbon ions.

Online proton therapy monitoring: clinical test of a Silicon-photodetector-based in-beam PET.

Particle therapy exploits the energy deposition pattern of hadron beams. The narrow Bragg Peak at the end of range is a major advantage but range uncertainties can cause severe damage and require online verification to maximise the effectiveness in clinics. In-beam Positron Emission Tomography (PET) is a non-invasive, promising in-vivo technique, which consists in the measurement of the ß+ activity induced by beam-tissue interactions during treatment, and presents the highest correlation of the measured activity distribution with the deposited dose, since it is not much influenced by biological washout. Here we report the first clinical results obtained with a state-of-the-art in-beam PET scanner, with on-the-fly reconstruction of the activity distribution during irradiation. An automated time-resolved quantitative analysis was tested on a lacrimal gland carcinoma case, monitored during two consecutive treatment sessions. The 3D activity map was reconstructed every 10 s, with an average delay between beam delivery and image availability of about 6 s. The correlation coefficient of 3D activity maps for the two sessions (above 0.9 after 120 s) and the range agreement (within 1 mm) prove the suitability of in-beam PET for online range verification during treatment, a crucial step towards adaptive strategies in particle therapy.

Targeted dose enhancement in radiotherapy for breast cancer using gold nanoparticles, part 1: A radiobiological model study.

PURPOSE: Gold nanoparticles (GNPs) are being proposed in combination with radiotherapy to improve tumor control. However, the exact mechanisms underlying GNP radiosensitization are yet to be understood, thus, we present a new approach to estimate the nanoparticle-driven increase in radiosensitivity. METHODS: A stochastic radiobiological model, derived from the Local Effect Model (LEM), was coupled with Monte Carlo simulations to estimate the increase in radiosensitivity produced by the interactions between photons and GNPs at nanometric scale. The model was validated using in vitro survival data of MDA-MB-231 breast cancer cells containing different concentrations of 2 nm diameter GNPs receiving different doses using 160 kVp, 6 MV, and 15 MV photons. A closed analytical formulation of the model was also derived and a study of RBE and TCP behavior was conducted. RESULTS: Results support the increased radiosensitivity due to GNP-driven dose inhomogeneities on a nanometric scale. The model is in good agreement with experimental clonogenic survival assays for 160 kVp, 6 MV, and 15 MV photons. The model suggests a RBE and TCP enhancement when lower energies and lower doses per fraction are used in the presence of GNPs. CONCLUSIONS: The evolution of the local effect model was implemented to assess cellular radiosensitization in the presence of GNPs and then validated with in vitro data. The model provides a useful framework to estimate the nanoparticle-driven radiosensitivity in treatment irradiations and could be applied to real clinical treatment predictions (described in a second part of this paper).

Targeted dose enhancement in radiotherapy for breast cancer using gold nanoparticles, part 2: A treatment planning study.

PURPOSE: In recent years, there has been growing interest in the use of gold nanoparticles (GNPs) combined with radiotherapy to improve tumor control. However, the complex interplay between GNP uptake and dose distribution in realistic clinical treatment are still somewhat unknown. METHODS: The effects of different concentrations of 2 nm diameter GNP, ranging from 0 to 5×105 nanoparticles per tumoral cell, were theoretically investigated. A parametrization of the GNP distribution outside the target was carried out using a Gaussian standard deviation σ, from a zero value, relative to a selective concentration of GNPs inside the tumor volume alone, to 50mm, when GNPs are spatially distributed also in the healthy tissues surrounding the tumor. Treatment simulations of five patients with breast cancer were performed with 6 and 15 MV photons assuming a partial breast irradiation. A closed analytical reformulation of the Local Effect Model coupled with the estimation of local dose deposited around a GNP was validated using an in vitro study for MDA-MB-231 tumoral cells. The expected treatment outcome was quantified in terms of tumor control probability (TCP) and normal tissue complication probability (NTCP) as a function of the spatially varying gold uptake. RESULTS: Breast cancer treatment planning simulations show improved treatment outcomes when GNPs are selectively concentrated in the tumor volume (i.e., σ = 0 mm). In particular, the TCP increases up to 18% for 5×105 nanoparticles per cell in the tumor region depending on the treatment schedules, whereas an improvement of the therapeutic index is observed only for concentrations of about 105 GNPs per tumoral cell and limited spatial distribution in the normal tissue. CONCLUSIONS: The model provides a useful framework to estimate the nanoparticle-driven radiosensitivity in breast cancer treatment irradiation, accounting for the complex interplay between dose and GNP uptake distributions.

INSIDE in-beam positron emission tomography system for particle range monitoring in hadrontherapy.

The quality assurance of particle therapy treatment is a fundamental issue that can be addressed by developing reliable monitoring techniques and indicators of the treatment plan correctness. Among the available imaging techniques, positron emission tomography (PET) has long been investigated and then clinically applied to proton and carbon beams. In 2013, the Innovative Solutions for Dosimetry in Hadrontherapy (INSIDE) collaboration proposed an innovative bimodal imaging concept that combines an in-beam PET scanner with a tracking system for charged particle imaging. This paper presents the general architecture of the INSIDE project but focuses on the in-beam PET scanner that has been designed to reconstruct the particles range with millimetric resolution within a fraction of the dose delivered in a treatment of head and neck tumors. The in-beam PET scanner has been recently installed at the Italian National Center of Oncologic Hadrontherapy (CNAO) in Pavia, Italy, and the commissioning phase has just started. The results of the first beam test with clinical proton beams on phantoms clearly show the capability of the in-beam PET to operate during the irradiation delivery and to reconstruct on-line the beam-induced activity map. The accuracy in the activity distal fall-off determination is millimetric for therapeutic doses.