LIDAL, a Time-of-Flight Radiation Detector for the International Space Station: Description and Ground Calibration.

LIDAL (Light Ion Detector for ALTEA, Anomalous Long-Term Effects on Astronauts) is a radiation detector designed to measure the flux, the energy spectra and, for the first time, the time-of-flight of ions in a space habitat. It features a combination of striped silicon sensors for the measurement of deposited energy (using the ALTEA device, which operated from 2006 to 2012 in the International Space Station) and fast scintillators for the time-of-flight measurement. LIDAL was tested and calibrated using the proton beam line at TIFPA (Trento Institute for Fundamental Physics Application) and the carbon beam line at CNAO (National Center for Oncology Hadron-therapy) in 2019. The performance of the time-of-flight system featured a time resolution (sigma) less than 100 ps. Here, we describe the detector and the results of these tests, providing ground calibration curves along with the methodology established for processing the detector's data. LIDAL was uploaded in the International Space Station in November 2019 and it has been operative in the Columbus module since January 2020.

Potential skin morbidity reduction with intensity-modulated proton therapy for breast cancer with nodal involvement.

Background: Different modern radiation therapy treatment solutions for breast cancer (BC) and regional nodal irradiation (RNI) have been proposed. In this study, we evaluate the potential reduction in radiation-induced skin morbidity obtained by intensity modulated proton therapy (IMPT) compared with intensity modulated photon therapy (IMXT) for left-side BC and RNI. Material and Methods: Using CT scans from 10 left-side BC patients, treatment plans were generated using IMXT and IMPT techniques. A dose of 50 Gy (or Gy [RBE] for IMPT) was prescribed to the target volume (involved breast, the internal mammary, supraclavicular, and infraclavicular nodes). Two single filed optimization IMPT (IMPT1 and IMPT2) plans were calculated without and with skin optimization. For each technique, skin dose-metrics were extracted and normal tissue complication probability (NTCP) models from the literature were employed to estimate the risk of radiation-induced skin morbidity. NTCPs for relevant organs-at-risk (OARs) were also considered for reference. The non-parametric Anova (Friedman matched-pairs signed-rank test) was used for comparative analyses. Results: IMPT improved target coverage and dose homogeneity even if the skin was included into optimization strategy (HIIMPT2 = 0.11 vs. HIIMXT = 0.22 and CIIMPT2 = 0.96 vs. CIIMXT = 0.82, p < .05). A significant relative skin risk reduction (RR = NTCPIMPT/NTCPIMXT) was obtained with IMPT2 including the skin in the optimization with a RR reduction ranging from 0.3 to 0.9 depending on the analyzed skin toxicity endpoint/model. Both IMPT plans attained significant OARs dose sparing compared with IMXT. As expected, the heart and lung doses were significantly reduced using IMPT. Accordingly, IMPT always provided lower NTCP values. Conclusions: IMPT guarantees optimal target coverage, OARs sparing, and simultaneously minimizes the risk of skin morbidity. The applied model-based approach supports the potential clinical relevance of IMPT for left-side BC and RNI and might be relevant for the setup of cost-effectiveness evaluation strategies based on NTCP predictions, as well as for establishing patient selection criteria.

Direct measurement of the 3-dimensional DNA lesion distribution induced by energetic charged particles in a mouse model tissue.

Charged particles are increasingly used in cancer radiotherapy and contribute significantly to the natural radiation risk. The difference in the biological effects of high-energy charged particles compared with X-rays or γ-rays is determined largely by the spatial distribution of their energy deposition events. Part of the energy is deposited in a densely ionizing manner in the inner part of the track, with the remainder spread out more sparsely over the outer track region. Our knowledge about the dose distribution is derived solely from modeling approaches and physical measurements in inorganic material. Here we exploited the exceptional sensitivity of γH2AX foci technology and quantified the spatial distribution of DNA lesions induced by charged particles in a mouse model tissue. We observed that charged particles damage tissue nonhomogenously, with single cells receiving high doses and many other cells exposed to isolated damage resulting from high-energy secondary electrons. Using calibration experiments, we transformed the 3D lesion distribution into a dose distribution and compared it with predictions from modeling approaches. We obtained a radial dose distribution with sub-micrometer resolution that decreased with increasing distance to the particle path following a 1/r2 dependency. The analysis further revealed the existence of a background dose at larger distances from the particle path arising from overlapping dose deposition events from independent particles. Our study provides, to our knowledge, the first quantification of the spatial dose distribution of charged particles in biologically relevant material, and will serve as a benchmark for biophysical models that predict the biological effects of these particles.

Model-based approach for quantitative estimates of skin, heart, and lung toxicity risk for left-side photon and proton irradiation after breast-conserving surgery.

BACKGROUND: Proton beam therapy represents a promising modality for left-side breast cancer (BC) treatment, but concerns have been raised about skin toxicity and poor cosmesis. The aim of this study is to apply skin normal tissue complication probability (NTCP) model for intensity modulated proton therapy (IMPT) optimization in left-side BC. MATERIAL AND METHODS: Ten left-side BC patients undergoing photon irradiation after breast-conserving surgery were randomly selected from our clinical database. Intensity modulated photon (IMRT) and IMPT plans were calculated with iso-tumor-coverage criteria and according to RTOG 1005 guidelines. Proton plans were computed with and without skin optimization. Published NTCP models were employed to estimate the risk of different toxicity endpoints for skin, lung, heart and its substructures. RESULTS: Acute skin NTCP evaluation suggests a lower toxicity level with IMPT compared to IMRT when the skin is included in proton optimization strategy (0.1% versus 1.7%, p < 0.001). Dosimetric results show that, with the same level of tumor coverage, IMPT attains significant heart and lung dose sparing compared with IMRT. By NTCP model-based analysis, an overall reduction in the cardiopulmonary toxicity risk prediction can be observed for all IMPT compared to IMRT plans: the relative risk reduction from protons varies between 0.1 and 0.7 depending on the considered toxicity endpoint. CONCLUSIONS: Our analysis suggests that IMPT might be safely applied without increasing the risk of severe acute radiation induced skin toxicity. The quantitative risk estimates also support the potential clinical benefits of IMPT for left-side BC irradiation due to lower risk of cardiac and pulmonary morbidity. The applied approach might be relevant on the long term for the setup of cost-effectiveness evaluation strategies based on NTCP predictions.

Proton CT on biological phantoms for x-ray CT calibration in proton treatment planning.

Objective.To present and characterize a novel method for x-ray computed tomography (xCT) calibration in proton treatment planning, based on proton CT (pCT) measurements on biological phantoms.Approach.A pCT apparatus was used to perform direct measurements of 3D stopping power relative to water (SPR) maps on stabilized, biological phantoms. Two single-energy xCT calibration curves-i.e. tissue substitutes and stoichiometric-were compared to pCT data. Moreover, a new calibration method based on these data was proposed, and verified against intra- and inter-species variability, dependence on stabilization, beam-hardening conditions, and analysis procedures.Main results.Biological phantoms were verified to be stable in time, with a dependence on temperature conditions, especially in the fat region: (-2.5 0.5) HU °C-1. The pCT measurements were compared with standard xCT calibrations, revealing an average SPR discrepancy within ±1.60% for both fat and muscle regions. In the bone region the xCT calibrations overestimated the pCT-measured SPR of the phantom, with a maximum discrepancy of about +3%. As a result, a new cross-calibration curve was directly extracted from the pCT data. Overall, the SPR uncertainty margin associated with this curve was below 3%; fluctuations in the uncertainty values were observed across the HU range. Cross-calibration curves obtained with phantoms made of different animal species and anatomical parts were reproducible with SPR discrepancies within 3%. Moreover, the stabilization procedure did not affect the resulting curve within a 2.2% SPR deviation. Finally, the cross-calibration curve was affected by the beam-hardening conditions on xCTs, especially in the bone region, while dependencies below 2% resulted from the image registration procedure.Significance.Our results showed that pCT measurements on biological phantoms may provide an accurate method for the verification of current xCT calibrations and may represent a tool for the implementation of a new calibration method for proton treatment planning.

A direct comparison of multi-energy x-ray and proton CT for imaging and relative stopping power estimation of plastic andex-vivophantoms.

Objective.Proton therapy administers a highly conformal dose to the tumour region, necessitating accurate prediction of the patient's 3D map of proton relative stopping power (RSP) compared to water. This remains challenging due to inaccuracies inherent in single-energy computed tomography (SECT) calibration. Recent advancements in spectral x-ray CT (xCT) and proton CT (pCT) have shown improved RSP estimation compared to traditional SECT methods. This study aims to provide the first comparison of the imaging and RSP estimation performance among dual-energy CT (DECT) and photon-counting CT (PCCT) scanners, and a pCT system prototype.Approach.Two phantoms were scanned with the three systems for their performance characterisation: a plastic phantom, filled with water and containing four plastic inserts and a wood insert, and a heterogeneous biological phantom, containing a formalin-stabilised bovine specimen. RSP maps were generated by converting CT numbers to RSP using a calibration based on low- and high-energy xCT images, while pCT utilised a distance-driven filtered back projection algorithm for RSP reconstruction. Spatial resolution, noise, and RSP accuracy were compared across the resulting images.Main results.All three systems exhibited similar spatial resolution of around 0.54 lp/mm for the plastic phantom. The PCCT images were less noisy than the DECT images at the same dose level. The lowest mean absolute percentage error (MAPE) of RSP,(0.28±0.07)%, was obtained with the pCT system, compared to MAPE values of(0.51±0.08)%and(0.80±0.08)%for the DECT- and PCCT-based methods, respectively. For the biological phantom, the xCT-based methods resulted in higher RSP values in most of the voxels compared to pCT.Significance.The pCT system yielded the most accurate estimation of RSP values for the plastic materials, and was thus used to benchmark the xCT calibration performance on the biological phantom. This study underlined the potential benefits and constraints of utilising such a novelex-vivophantom for inter-centre surveys in future.

Particle Beam Radiobiology Status and Challenges: A PTCOG Radiobiology Subcommittee Report.

Particle therapy (PT) represents a significant advancement in cancer treatment, precisely targeting tumor cells while sparing surrounding healthy tissues thanks to the unique depth-dose profiles of the charged particles. Furthermore, their linear energy transfer and relative biological effectiveness enhance their capability to treat radioresistant tumors, including hypoxic ones. Over the years, extensive research has paved the way for PT's clinical application, and current efforts aim to refine its efficacy and precision, minimizing the toxicities. In this regard, radiobiology research is evolving toward integrating biotechnology to advance drug discovery and radiation therapy optimization. This shift from basic radiobiology to understanding the molecular mechanisms of PT aims to expand the therapeutic window through innovative dose delivery regimens and combined therapy approaches. This review, written by over 30 contributors from various countries, provides a comprehensive look at key research areas and new developments in PT radiobiology, emphasizing the innovations and techniques transforming the field, ranging from the radiobiology of new irradiation modalities to multimodal radiation therapy and modeling efforts. We highlight both advancements and knowledge gaps, with the aim of improving the understanding and application of PT in oncology.

Investigation of In-Field and Out-of-Field Radiation Quality With Microdosimetry and Its Impact on Relative Biological Effectiveness in Proton Therapy.

PURPOSE: Using microdosimetry, this study investigated the relative biological effectiveness (RBE) and quality factor (Q¯) variations in field and out of field as a function of radiation quality for clinical protons. METHODS AND MATERIALS: A water phantom with a spread-out Bragg peak (SOBP) was irradiated to acquire microdosimetric spectra at several distal and lateral depths with a tissue equivalent proportional counter. The measurements were used as inputs to microdosimetric kinetic and Loncol models to determine the RBE spatial distribution and compare it with predictions from the dose-averaged linear energy transfer-based McNamara model. Q¯ values and biological and dose equivalent values were also calculated. RESULTS: The data demonstrated that radiation quality changed more rapidly with depth than lateral distance from the SOBP. In beam, yD ranged from approximately 4 keV/µm at the entrance to 8 keV/µm at the SOBP far end, reaching approximately 15 keV/µm at the penumbra. Out of field, the overall highest value of 23 ± 2 keV/µm was observed at the beam-edge penumbra. Radiation quality changes caused RBE deviations from the clinical value of 1.1, whose extent depends on the approach used for assessing radiation quality as well as on the radiobiological model. For RBE10, microdosimetry-based models appeared to better reproduce the radiobiological data than the dose-averaged linear energy transfer model. Out of field, both the RBE and Q¯ values appeared to have limitations in describing the radiation biological effectiveness. This research also presents a first comprehensive benchmark of TOPAS code against in-field and out-of-field microdosimetric spectra of therapeutic protons. CONCLUSIONS: Further investigation will be necessary to evaluate the quantitative effects of RBE variations on treatment planning and assess the clinical consequences in terms of both tumor control and normal-tissue toxicity. The achievement of this goal calls for accurate radiobiological data to validate the RBE models.

Does variable RBE affect toxicity risks for mediastinal lymphoma patients? NTCP-based evaluation after proton therapy treatment.

INTRODUCTION: Mediastinal lymphoma (ML) is a solid malignancy affecting young patients. Modern combined treatments allow obtaining good survival probability, together with a long life expectancy, and therefore with the need to minimize treatment-related toxicities. We quantified the expected toxicity risk for different organs and endpoints in ML patients treated with intensity-modulated proton therapy (IMPT) at our centre, accounting also for uncertainties related to variable RBE. METHODS: Treatment plans for ten ML patients were recalculated with a TOPAS-based Monte Carlo code, thus retrieving information on LET and allowing the estimation of variable RBE. Published NTCP models were adopted to calculate the toxicity risk for hypothyroidism, heart valve defects, coronary heart disease and lung fibrosis. NTCP was calculated assuming both constant (i.e. 1.1) and variable RBE. The uncertainty associated with individual radiosensitivity was estimated by random sampling α/ß values before RBE evaluation. RESULTS: Variable RBE had a minor impact on hypothyroidism risk for 7 patients, while it led to significant increase for the remaining three (+24% risk maximum increase). Lung fibrosis was slightly affected by variable RBE, with a maximum increase of â‰… 1%. This was similar for heart valve dysfunction, with the exception of one patient showing an about 10% risk increase, which could be explained by means of large heart volume and D1 increase. DISCUSSION: The use of NTCP models allows for identifying those patients associated with a higher toxicity risk. For those patients, it might be worth including variable RBE in plan evaluation.

Characterization of the INFN proton CT scanner for cross-calibration of x-ray CT.

Objective. The goal of this study was to assess the imaging performances of the pCT system developed in the framework of INFN-funded (Italian National Institute of Nuclear Physics) research projects. The spatial resolution, noise power spectrum (NPS) and RSP accuracy has been investigated, as a preliminary step to implement a new cross-calibration method for x-ray CT (xCT).Approach. The INFN pCT apparatus, made of four planes of silicon micro-strip detectors and a YAG:Ce scintillating calorimeter, reconstructs 3D RSP maps by a filtered-back projection algorithm. The imaging performances (i.e. spatial resolution, NPS and RSP accuracy) of the pCT system were assessed on a custom-made phantom, made of plastic materials with different densities ((0.66, 2.18) g cm-3). For comparison, the same phantom was acquired with a clinical xCT system.Main results. The spatial resolution analysis revealed the nonlinearity of the imaging system, showing different imaging responses in air or water phantom background. Applying the Hann filter in the pCT reconstruction, it was possible to investigate the imaging potential of the system. Matching the spatial resolution value of the xCT (0.54 lp mm-1) and acquiring both with the same dose level (11.6 mGy), the pCT appeared to be less noisy than xCT, with an RSP standard deviation of 0.0063. Concerning the RSP accuracy, the measured mean absolute percentage errors were (0.23+-0.09)% in air and (0.21+-0.07)% in water.Significance. The obtained performances confirm that the INFN pCT system provides a very accurate RSP estimation, appearing to be a feasible clinical tool for verification and correction of xCT calibration in proton treatment planning.

The INFN proton computed tomography system for relative stopping power measurements: calibration and verification.

Objective. This paper describes the procedure to calibrate the three-dimensional (3D) proton stopping power relative to water (SPR) maps measured by the proton computed tomography (pCT) apparatus of the Istituto Nazionale di Fisica Nucleare (INFN, Italy). Measurements performed on water phantoms are used to validate the method. The calibration allowed for achieving measurement accuracy and reproducibility to levels below 1%.Approach. The INFN pCT system is made of a silicon tracker for proton trajectory determination followed by a YAG:Ce calorimeter for energy measurement. To perform the calibration, the apparatus has been exposed to protons of energies ranging from 83 to 210 MeV. Using the tracker, a position-dependent calibration has been implemented to keep the energy response uniform across the calorimeter. Moreover, correction algorithms have been developed to reconstruct the proton energy when this is shared in more than one crystal and to consider the energy loss in the non-uniform apparatus material. To verify the calibration and its reproducibility, water phantoms have been imaged with the pCT system during two data-taking sessions.Main results. The energy resolution of the pCT calorimeter resulted to beσEE≅0.9%at 196.5 MeV. The average values of the water SPR in fiducial volumes of the control phantoms have been calculated to be 0.995±0.002. The image non-uniformities were below 1%. No appreciable variation of the SPR and uniformity values between the two data-taking sessions could be identified.Significance. This work demonstrates the accuracy and reproducibility of the calibration of the INFN pCT system at a level below 1%. Moreover, the uniformity of the energy response keeps the image artifacts at a low level even in the presence of calorimeter segmentation and tracker material non-uniformities. The implemented calibration technique allows the INFN-pCT system to face applications where the precision of the SPR 3D maps is of paramount importance.

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.

Performance of LGAD strip detectors for particle counting of therapeutic proton beams.

Objective. The performance of silicon detectors with moderate internal gain, named low-gain avalanche diodes (LGADs), was studied to investigate their capability to discriminate and count single beam particles at high fluxes, in view of future applications for beam characterization and on-line beam monitoring in proton therapy.Approach. Dedicated LGAD detectors with an active thickness of 55µm and segmented in 2 mm2strips were characterized at two Italian proton-therapy facilities, CNAO in Pavia and the Proton Therapy Center of Trento, with proton beams provided by a synchrotron and a cyclotron, respectively. Signals from single beam particles were discriminated against a threshold and counted. The number of proton pulses for fixed energies and different particle fluxes was compared with the charge collected by a compact ionization chamber, to infer the input particle rates.Main results. The counting inefficiency due to the overlap of nearby signals was less than 1% up to particle rates in one strip of 1 MHz, corresponding to a mean fluence rate on the strip of about 5 × 107p/(cm2·s). Count-loss correction algorithms based on the logic combination of signals from two neighboring strips allow to extend the maximum counting rate by one order of magnitude. The same algorithms give additional information on the fine time structure of the beam.Significance. The direct counting of the number of beam protons with segmented silicon detectors allows to overcome some limitations of gas detectors typically employed for beam characterization and beam monitoring in particle therapy, providing faster response times, higher sensitivity, and independence of the counts from the particle energy.

Modelling the HPRT-gene mutation induction of particle beams: systematicin vitrodata collection, analysis and microdosimetric kinetic model implementation.

Objective. Since the early years, particle therapy treatments have been associated with concerns for late toxicities, especially secondary cancer risk (SCR). Nowadays, this concern is related to patients for whom long-term survival is expected (e.g. breast cancer, lymphoma, paediatrics). In the aim to contribute to this research, we present a dedicated statistical and modelling analysis aiming at improving our understanding of the RBE for mutation induction (RBEM˜) for different particle species.Approach. We built a new database based on a systematic collection of RBE data for mutation assays of the gene encoding for the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase from literature (105 entries, distributed among 3 cell lines and 16 particle species). The data were employed to perform statistical and modelling analysis. For the latter, we adapted the microdosimetric kinetic model (MKM) to describe the mutagenesis in analogy to lethal lesion induction.Main results. Correlation analysis between RBE for survival (RBES) andRBEM˜reveals significant correlation between these two quantities (ρ= 0.86,p< 0.05). The correlation gets stronger when looking at subsets of data based on cell line and particle species. We also show that the MKM can be successfully employed to describeRBEM˜,obtaining comparably good agreement with the experimental data. Remarkably, to improve the agreement with experimental data the MKM requires, consistently in all the analysed cases, a reduced domain size for the description of mutation induction compared to that adopted for survival.Significance. We were able to show that RBESandRBEM˜are strongly related quantities. We also showed for the first time that the MKM could be successfully applied to the description of mutation induction, representing an endpoint different from the more traditional cell killing. In analogy to the RBES,RBEM˜can be implemented into treatment planning system evaluations.

Diagnosis of Langerhans cell histiocytosis on cytological examination of cerebrospinal fluid: Report of the first case.

Langerhans cell histiocytosis (LCH) is a disease of unknown etiology characterized by a proliferation of histiocytic cells resembling dendritic Langerhans cells. LCH can be unifocal or multifocal, with one- or many-organ involvement. The serous fluids are rarely involved. Cytological diagnosis of LCH is possible and relies on recognition of the typical cytomorphological features and subsequent immunocytochemical confirmation. Given the possibility of multisystem involvement, after diagnosing LCH it is necessary to carry out staging exams such as a bone survey, abdominal ultrasound, complete blood count, screening for diabetes insipidus and pulmonary function tests. We present the first case of LCH where the diagnosis was reached on cytological material from the cerebrospinal fluid. To the best of our knowledge, this is the first such case reported in the international literature to date. The morphological and immunocytochemical characteristics of our case are described, and the relevant literature is reviewed.

Quantification of biological range uncertainties in patients treated at the Krakow proton therapy centre.

BACKGROUND: Variable relative biological effectiveness (vRBE) in proton therapy might significantly modify the prediction of RBE-weighted dose delivered to a patient during proton therapy. In this study we will present a method to quantify the biological range extension of the proton beam, which results from the application of vRBE approach in RBE-weighted dose calculation. METHODS AND MATERIALS: The treatment plans of 95 patients (brain and skull base patients) were used for RBE-weighted dose calculation with constant and the McNamara RBE model. For this purpose the Monte Carlo tool FRED was used. The RBE-weighted dose distributions were analysed using indices from dose-volume histograms. We used the volumes receiving at least 95% of the prescribed dose (V95) to estimate the biological range extension resulting from vRBE approach. RESULTS: The vRBE model shows higher median value of relative deposited dose and D95 in the planning target volume by around 1% for brain patients and 4% for skull base patients. The maximum doses in organs at risk calculated with vRBE was up to 14 Gy above dose limit. The mean biological range extension was greater than 0.4 cm. DISCUSSION: Our method of estimation of biological range extension is insensitive for dose inhomogeneities and can be easily used for different proton plans with intensity-modulated proton therapy (IMPT) optimization. Using volumes instead of dose profiles, which is the common method, is more universal. However it was tested only for IMPT plans on fields arranged around the tumor area. CONCLUSIONS: Adopting a vRBE model results in an increase in dose and an extension of the beam range, which is especially disadvantageous in cancers close to organs at risk. Our results support the need to re-optimization of proton treatment plans when considering vRBE.

Technical Note: CT calibration for proton treatment planning by cross-calibration with proton CT data.

PURPOSE: This study explores the possibility of a new method for x-ray computed tomography (CT) calibration by means of cross-calibration with proton CT (pCT) data. The proposed method aims at a more accurate conversion of CT Hounsfield Units (HU) into proton stopping power ratio (SPR) relative to water to be used in proton-therapy treatment planning. METHODS: X-ray CT scan was acquired on a synthetic anthropomorphic phantom, composed of different tissue equivalent materials (TEMs). A pCT apparatus was instead adopted to obtain a reference three-dimensional distribution of the phantom's SPR values. After rigid registration, the x-ray CT was artificially blurred to the same resolution of pCT. Then a scatter plot showing voxel-by-voxel SPR values as a function of HU was employed to link the two measurements and thus obtaining a cross-calibrated x-ray CT calibration curve. The cross-calibration was tested at treatment planning system and then compared with a conventional calibration based on exactly the same TEMs constituting the anthropomorphic phantom. RESULTS: Cross-calibration provided an accurate SPR mapping, better than by conventional TEMs calibration. The dose distribution of single beams optimized on the reference SPR map was recomputed on cross-calibrated CT, showing, with respect to conventional calibration, minor deviation at the dose fall-off (lower than 1%). CONCLUSIONS: The presented data demonstrated that, by means of reference pCT data, a heterogeneous phantom can be used for CT calibration, paving the way to the use of biological samples, with their accurate description of patients' tissues. This overcomes the limitations of conventional CT calibration requiring homogenous samples, only available by synthetic TEMs, which fail in accurately mimicking the properties of biological tissues. Once a heterogeneous biological sample is provided with its corresponding reference SPR maps, a cross-calibration procedure could be adopted by other PT centers, even when not equipped with a pCT system.

Biological Impact of Target Fragments on Proton Treatment Plans: An Analysis Based on the Current Cross-Section Data and a Full Mixed Field Approach.

Clinical routine in proton therapy currently neglects the radiobiological impact of nuclear target fragments generated by proton beams. This is partially due to the difficult characterization of the irradiation field. The detection of low energetic fragments, secondary protons and fragments, is in fact challenging due to their very short range. However, considering their low residual energy and therefore high LET, the possible contribution of such heavy particles to the overall biological effect could be not negligible. In this context, we performed a systematic analysis aimed at an explicit assessment of the RBE (relative biological effectiveness, i.e., the ratio of photon to proton physical dose needed to achieve the same biological effect) contribution of target fragments in the biological dose calculations of proton fields. The TOPAS Monte Carlo code has been used to characterize the radiation field, i.e., for the scoring of primary protons and fragments in an exemplary water target. TRiP98, in combination with LEM IV RBE tables, was then employed to evaluate the RBE with a mixed field approach accounting for fragments' contributions. The results were compared with that obtained by considering only primary protons for the pristine beam and spread out Bragg peak (SOBP) irradiations, in order to estimate the relative weight of target fragments to the overall RBE. A sensitivity analysis of the secondary particles production cross-sections to the biological dose has been also carried out in this study. Finally, our modeling approach was applied to the analysis of a selection of cell survival and RBE data extracted from published in vitro studies. Our results indicate that, for high energy proton beams, the main contribution to the biological effect due to the secondary particles can be attributed to secondary protons, while the contribution of heavier fragments is mainly due to helium. The impact of target fragments on the biological dose is maximized in the entrance channels and for small α/ß values. When applied to the description of survival data, model predictions including all fragments allowed better agreement to experimental data at high energies, while a minor effect was observed in the peak region. An improved description was also obtained when including the fragments' contribution to describe RBE data. Overall, this analysis indicates that a minor contribution can be expected to the overall RBE resulting from target fragments. However, considering the fragmentation effects can improve the agreement with experimental data for high energy proton beams.

Study of relationship between dose, LET and the risk of brain necrosis after proton therapy for skull base tumors.

PURPOSE: We investigated the relationship between RBE-weighted dose (DRBE) calculated with constant (cRBE) and variable RBE (vRBE), dose-averaged linear energy transfer (LETd) and the risk of radiographic changes in skull base patients treated with protons. METHODS: Clinical treatment plans of 45 patients were recalculated with Monte Carlo tool FRED. Radiographic changes (i.e. edema and/or necrosis) were identified by MRI. Dosimetric parameters for cRBE and vRBE were computed. Biological margin extension and voxel-based analysis were employed looking for association of DRBE(vRBE) and LETd with brain edema and/or necrosis. RESULTS: When using vRBE, Dmax in the brain was above the highest dose limits for 38% of patients, while such limit was never exceeded assuming cRBE. Similar values of Dmax were observed in necrotic regions, brain and temporal lobes. Most of the brain necrosis was in proximity to the PTV. The voxel-based analysis did not show evidence of an association with high LETd values. CONCLUSIONS: When looking at standard dosimetric parameters, the higher dose associated with vRBE seems to be responsible for an enhanced risk of radiographic changes. However, as revealed by a voxel-based analysis, the large inter-patient variability hinders the identification of a clear effect for high LETd.

Accurate proton treatment planning for pencil beam crossing titanium fixation implants.

PURPOSE: To present a planning strategy for proton pencil-beam scanning when titanium implants need to be crossed by the beam. METHODS: We addressed three issues: the implementation of a CT calibration curve to assign to titanium the correct stopping power; the effect of artefacts on CT images and their reduction by a dedicated algorithm; the differences in dose computation depending on the dose engine, pencil-beam vs Monte-Carlo algorithms. We performed measurement tests on a simple cylinder phantom and on a real implant. These phantoms were irradiated with three geometries (single spots, uniform mono-energetic layer and uniform box), measuring the exit dose either by radio-chromic film or multi-layer ionization chamber. The procedure was then applied on two patients treated for chordoma. RESULTS: We had to set in the calibration curve a mass density equal to 4.37 g/cm3 to saturated Hounsfield Units, in order to have the correct stopping power assigned to titanium in TPS. CT artefact reduction algorithm allowed a better reconstruction of the shape and size of the implant. Monte-Carlo resulted accurate in computing the dose distribution whereas the pencil-beam algorithm failed due to sharp density interfaces between titanium and the surrounding material. Finally, the treatment plans obtained on two patients showed the impact of the dose engine algorithm, with 10-20% differences between pencil-beam and Monte-Carlo in small regions distally to the titanium screws. CONCLUSION: The described combination of CT calibration, artefacts reduction and Monte-Carlo computation provides a reliable methodology to compute dose in patients with titanium implants.