Objective. Treatment planning in proton therapy requires an accurate estimation of stopping power ratio relative to water (SPR) maps. Presently, about 4% of patients submitted to radiotherapy treatments have metallic implants, which are responsible for an incorrect determination of SPRs in prostheses and surrounding regions. This study presents the first application of the proton computed tomography (pCT) technique, able to directly measure SPRs maps, on complex metallic implants. Approach. A homogeneous Ti6Al4V alloy sample, a set of metallic devices used for prostheses and an intra-vertebral titanium alloy implant have been inspected, by means of a prototype pCT system with a 5 × 20 cm 2 field-of-view (FoV) developed by INFN Firenze (Italy), under a proton beam at Trento Proton Therapy Centre (APSS, Trento, Italy). For comparison, a Multi Layer Ionization Chamber (MLIC) has been used to independently determine the SPR mean value of the Ti6Al4V alloy sample. Main Results. Tomographic reconstructions of all devices and materials have been performed and SPR maps have been obtained. All pCT images and profiles, even of metallic components, are characterized by negligible artifacts. The fine spatial resolution of our pCT system, about 0.7 lp mm −1 , allowed us to resolve details within a millimeter scale. The internal grid of the meshed cage as well as details of the screws’ head of the intra-vertebral titanium alloy implant are clearly visible. The SPR of the Ti6Al4V alloy sample measured with pCT, 3.14 ± 0.02, compares well with what was measured by MLIC: 3.17 ± 0.02. Significance. This study presents the first application of the pCT methodology to directly measure SPR maps of complex metal prostheses. The ability of pCT to correctly determine mean SPR values has been experimentally demonstrated. Furthermore, this technique was shown to reconstruct complex metal structures at the millimeter scale with negligible artifacts.

Objective.To measure beam quality correction factors (kQ) in single-layer scanned proton beams using water calorimetry for three ionization chamber types commonly used in clinical proton dosimetry.Approach.Measurements were performed at two proton therapy centers using clinical proton beams with nominal energies of 150, 220 and 226 MeV, at a reference depth of 4 cm. ThekQ-factors were obtained by comparing absorbed dose-to-water determinations from a water calorimeter with ionization chamber readings under identical conditions. Three ionization chamber models were investigated: the IBA FC65-G (cylindrical), PPC05 and PPC40 (plane-parallel). Two independent calorimeter setups were used across three measurement campaigns.Main results.The measuredkQ-factors showed strong agreement with current TRS-398 Rev. 1 (2024) recommendations and literature data. For the FC65-G chamber, excellent alignment was observed with previous water calorimetry-based measurements. For the PPC40 chamber, both chambers yielded consistent results within 0.5% of TRS-398 Rev. 1. For the PPC05 chambers, a maximum deviation of 1.4% was observed relative to TRS-398 Rev. 1, and inter-chamber variability was within 0.5%. The use of two calorimeter setups yielded consistent results within 0.2%, supporting their validity.Significance.This study presents new experimentalkQ-factors for ionization chambers in single-layer scanned proton beams, contributing to the currently scarce experimental database, providing further validation of the TRS-398 Rev. 1 (2024) recommendations, and supplying benchmark data for future Monte Carlo-basedkQcalculations.

Objectives: To investigate how the FLASH effect modulates radiation response on multiple developmental endpoints of zebrafish embryos under normoxic and hypoxic conditions, after irradiation with proton beams at a conventional and an ultra-high dose rate (UHDR). Methods: Embryos were obtained from adult zebrafish and irradiated with a 228 MeV proton beam 24 h post-fertilization (hpf) at a dose rate of 0.6 and 317 Gy/s. For the hypoxic group, samples were kept inside a hypoxic chamber prior to irradiation, while standard incubation was adopted for the normoxic group. After irradiation, images of single embryos were acquired, and radiation effects on larval length, yolk absorption, pericardial edema, head size, eye size, and spinal curvature were assessed at specific time points. Results: Data indicate a general trend of significantly reduced toxicity after exposure to a UHDR compared to conventional regimes, which is maintained under both normoxic and hypoxic conditions. Differences are significant for the levels of pericardial edema induced by a UHDR versus conventional irradiation in normoxic conditions, and for eye and head size in hypoxic conditions. The toxicity scoring analysis shows a tendency toward a protective effect of the UHDR, which appears to be associated with a lower percentage of embryos in the high score categories. Conclusions: A radioprotective effect at a UHDR is observed both for normoxic (pericardial edema) and hypoxic (head and eye size) conditions. These results suggest that while the UHDR may preserve a potential to reduce radiation-induced damage, its protective effects are endpoint-dependent; the role of oxygenation might also be dependent on the tissue involved.

Silicon carbide (SiC) detectors have been widely demonstrated to be suitable alternative detectors for dosimetry in FLASH radiotherapy, showing radiation hardness and dose-rate independence at the FLASH radiotherapy instantaneous dose rates (IDRs). However, the practical use of such devices in the preclinical/clinical environment still requires the development of special handy housing enabling the quality assurance (QA) measurements under the reference dosimetric conditions. A 10μm thick, 4.5 mm2area SiC detector produced by the STLab company was recently embedded at the INFN-Catania Division inside a plastic waterproof 15 mm diameter cylindrical housing. This encapsulated version of SiC (eSiC) allows the measurement of the dose in reference conditions and of the dose profiles in liquid/solid water phantoms for assuring high accuracy dosimetry QA procedures. Dosimetric characterizations were performed with both electron and proton beams at conventional and ultra-high dose rates (UHDR). A first experiment was carried out at the Centro Pisano for Flash Radiotherapy using UHDR 9 MeV electron beams to confirm the linearity of the charge response as a function of the dose per pulse after the encapsulation procedure. A linearity from 1.8 Gy/pulse up to about 12 Gy/pulse, corresponding to an IDR of 3 MGy s-1, was found. The percentage depth dose (PDD) distribution in water of 9 MeV electron beams was also measured and compared with the PDD measured with a Freiburg Physikalisch-Technische Werkstätten Dr. Pychlau GmbH (PTW) flash diamond detector, used as reference dosimeter. The eSiC detector was also tested with proton beams accelerated by the IBA Proteus 235 cyclotron at the Trento Proton Therapy facility. A response independence on the total delivered dose (1-30 Gy) and average dose rate (50-530 Gy s-1) was found using the UHDR 228 MeV proton beam available along the experimental beamline. The depth dose distribution measured with the eSiC within a liquid water phantom was successfully compared with the one simultaneously measured by the IBA PPC05 reference chamber, using 180 MeV clinical proton beams. The excellent results demonstrated that this first realized eSiC prototype can be used to accurately perform reference and relative dosimetry with UHDR electron and proton beams, contributing to support the clinical translation of FLASH radiotherapy.

Purpose: to implement a probabilistic-Robustness-Evaluation (pRE) tool for proton therapy treatments and to correlate these results with the worst-case approach (wRE) implemented in commercial TPS for clinical applications. Materials and Methods: 12 skull base patients were planned with a robust multiple field optimization (MFO) approach. 10 years of machine QA were analysed to derive the uncertainties of our treatment system (beam delivery and patient positioning system). For a large cohort of patients, post-treatment imaging was acquired to determine the intra-fraction uncertainty. The pRE, considered explicitly all these uncertainties, the fractionation and range uncertainty. For each plan a wRE with different combinations of range and setup uncertainties was simulated. wRE results were then compared, in terms of target coverage and OAR dose limits, with pRE results. Results: 43,400 dose distributions were analysed. pRE simulations lasted 18.6 h (+11.5 h). The results showed that the combination of wRE uncertainty parameters that surrogated the best pRE results with a confidence level of 95 % were (1.0 mm/3.5 %). The median OAR's dose indexes difference (D1/D1cc) between pRE and wRE was 1.90 (+1.49) GyRBE, while for target D98 and D95 it was-0.66(+0.95) and-0.67 (+0.52) GyRBE, respectively. Conclusion: A tool able to explicitly simulate the source of treatment uncertainties and the effect of the fractionation was implemented to have a more realistic evaluation of plan robustness. This tool was used to find the best wRE parameters that surrogate the pRE results while maintaining clinically acceptable timing. These results are now used in our clinical workflow.

Purpose To introduce a new model formalism for the assessment of secondary cancer (SC) risk after proton therapy, accounting explicitly for the specific radiation quality of the beam, and to present results of a first application to two patient cohorts. Methods A dedicated adaptation of the microdosimetric kinetic model (MKM) model was combined with the Schneider model for excess absolute risk (EAR) calculation, extending its applicability from reference photon radiation to charged particles with different values of linear energy transfer. Plans for proton treatment of Lymphoma and Breast targets were recalculated with a Monte Carlo tool (TOPAS) to obtain voxel-by-voxel radiation quality distributions. To feed the model for computing an RBE for the specific endpoint of radiation-induced mutations, this information was joined with epidemiology-based parameterization to compute the EAR for the different patients, organs, and for different tentative α/β values of the involved tissues. Results A non-negligible impact of the explicit integration of RBE in the proposed model, as compared to estimates without (i.e. plain Schneider approach) is evident in all evaluated cases, with a strong impact of the α/β value for mutation induction. Lower levels of α/β ratio correlate with larger effects of the LET correction. Conclusions Accounting for the specific radiation quality of proton beams impacts EAR estimation, providing a more comprehensive picture in terms of SC risk prediction. Our analysis confirmed, however, that overall SC risk associated with modern proton treatments is not dramatically larger than that achievable by pure physical dose-based estimates for the most probable α/β values.

BACKGROUND:Proton Arc Treatment (PAT) has shown potential over Multi-Field Optimization (MFO) for out-of-target dose reduction in particular for head and neck (H&N) patients. A feasibility test, including delivery in a clinical environment is still missing in the literature and a necessary requirement before clinical application of PAT. PURPOSE:To perform a comprehensive comparison between clinically delivered MFO plans and static PAT plans for H&N treatments, followed by end-to-end commissioning of the system to prepare for clinical treatments. METHODS:Anonymized datasets of 10 patients treated for H&N cancer (median prescription dose 70 GyRBE) were selected for this study. Both MFO and PAT plans were created in RayStation and robustly optimized for setup and range uncertainties as in our clinical routine. PAT plans were created with 30 angle directions. 1. Comparisons were performed regarding: 2. nominal dose distributions in terms of target coverage, dose to primary and secondary OARs 3. robustness evaluation (D95 of the target and D1 of primary OARs) 4. Normal tissue complication probability (NTCP) values for xerostomia, swallowing dysfunction, tube feeding, and sticky saliva 5. D·LETd distributions 6. the probability of replanning at least once due to anatomical changes 7. delivery time: MFO and PAT plans, for one patient, were delivered in a clinical gantry room. For PAT, two plans with 30 and with 20 discrete beam directions were optimized and delivered. RESULTS:In PAT plans, a significant reduction was observed in the near maximum dose to the brainstem, while no statistically significant differences were found for other primary OARs or target coverage metrics (D95 and D98) in both nominal plans and robustness evaluation scenarios. For secondary OARs, PAT plans achieved an impressive reduction in mean dose. Max D·LETd distributions in brainstem, brain, and temporal lobes showed no statistical differences between MFO and PAT plans while mean D·LETd values were lower with PAT. Median NTCP was significantly reduced for xerostomia as endpoint (ΔNTCP = 8.5%), while reductions in other endpoints were not statistically significant. The number of patients that would need at least one replanning during the treatment for PAT was similar to MFO, showing that the established clinical workflow for monitoring of anatomy changes will remain the same for both delivery methods. Comparison in terms of delivery time from the start of the first beam until the end of the last (comprising all the technically motivated delays due to operation of OIS/Therapy Control System operation, gantry rotations, couch rotations, beam line preparation etc.) resulted in delivery times that were similar for both techniques. CONCLUSION:Static PAT plans demonstrate the capability to increase plan quality with respect to state-of-the-art MFO planning, since dose reduction outside of the target is significant with no reduction of the quality of the target dose distribution. NTCP evaluations, as well as linear energy transfer (LET) distributions, do not indicate risks for unexpected toxicity. Delivery time tests with different beam direction configurations have shown that PAT plans can already be delivered within similar time slots as highly conformal MFO plans. The successful end-to-end commissioning led to the world's first patient treatments using PAT, with eight patients treated to date.

Proton Arc Treatment (PAT) has shown potential over Multi-Field Optimization (MFO) for out-of-target dose reduction in particular for head and neck (H&N) patients. A feasibility test, including delivery in a clinical environment is still missing in the literature and a necessary requirement before clinical application of PAT. To perform a comprehensive comparison between clinically delivered MFO plans and static PAT plans for H&N treatments, followed by end-to-end commissioning of the system to prepare for clinical treatments. Anonymized datasets of 10 patients treated for H&N cancer (median prescription dose 70 GyRBE) were selected for this study. Both MFO and PAT plans were created in RayStation and robustly optimized for setup and range uncertainties as in our clinical routine. PAT plans were created with 30 angle directions. 1. Comparisons were performed regarding: 2. nominal dose distributions in terms of target coverage, dose to primary and secondary OARs 3. robustness evaluation (D 95 of the target and D 1 of primary OARs) 4. Normal tissue complication probability (NTCP) values for xerostomia, swallowing dysfunction, tube feeding, and sticky saliva 5. D·LET d distributions 6. the probability of replanning at least once due to anatomical changes 7. delivery time: MFO and PAT plans, for one patient, were delivered in a clinical gantry room. For PAT, two plans with 30 and with 20 discrete beam directions were optimized and delivered. In PAT plans, a significant reduction was observed in the near maximum dose to the brainstem, while no statistically significant differences were found for other primary OARs or target coverage metrics (D 95 and D 98 ) in both nominal plans and robustness evaluation scenarios. For secondary OARs, PAT plans achieved an impressive reduction in mean dose. Max D·LETd distributions in brainstem, brain, and temporal lobes showed no statistical differences between MFO and PAT plans while mean D·LETd values were lower with PAT. Median NTCP was significantly reduced for xerostomia as endpoint (ΔNTCP = 8.5%), while reductions in other endpoints were not statistically significant. The number of patients that would need at least one replanning during the treatment for PAT was similar to MFO, showing that the established clinical workflow for monitoring of anatomy changes will remain the same for both delivery methods. Comparison in terms of delivery time from the start of the first beam until the end of the last (comprising all the technically motivated delays due to operation of OIS/Therapy Control System operation, gantry rotations, couch rotations, beam line preparation etc.) resulted in delivery times that were similar for both techniques. Static PAT plans demonstrate the capability to increase plan quality with respect to state-of-the-art MFO planning, since dose reduction outside of the target is significant with no reduction of the quality of the target dose distribution. NTCP evaluations, as well as linear energy transfer (LET) distributions, do not indicate risks for unexpected toxicity. Delivery time tests with different beam direction configurations have shown that PAT plans can already be delivered within similar time slots as highly conformal MFO plans. The successful end-to-end commissioning led to the world's first patient treatments using PAT, with eight patients treated to date.