Background and purpose:Sphenoid wing meningiomas (SWMs) are located adjacent to critical organs of interest (OOIs) and present challenges for surgery and radiotherapy. Given the favorable overall survival in meningioma patients, preserving quality of life is important. Dose reductions within OOIs may lower adverse events. This study aimed to evaluate potential advantages of particle therapy regarding dose distribution and side effects for SWMs. Materials and methods:Nine patients (eight females, one male; median age at radiotherapy: 55 years) with SWM received proton radiotherapy (PRT, 54 Gy (RBE), 1.8 Gy (RBE) per fraction). Comparative treatment plans were generated for volumetric modulated arc therapy (VMAT, 54 Gy, 1.8 Gy per fraction) and carbon ion radiotherapy (CIRT, 42 Gy (RBE), 3 Gy (RBE) per fraction). Target volumes and OOI dose guidance were maintained. OOI dose-volume parameters, normal tissue complication probabilities (NTCP), and risk ratios of radiation-induced secondary central nervous system (CNS) malignancies were assessed. Results:Compared to VMAT, mean relative brain doses were reduced by -41.5% with PRT, and - 63.8% with CIRT. Particle therapy achieved significant dose sparing of bilateral hippocampi and lenses, and the ipsilateral inner ear. NTCPs indicated lower risks of ipsilateral hearing loss and cataract with particle therapy. The mean estimated risk of radiation-induced secondary malignancies was 1.7 for photons over protons, and 2.7 for photons over carbon ions. Conclusions:For SWMs, particle therapy demonstrated reduced dose exposure to several OOIs, and may lower the risk of side effects compared with VMAT.

Ultrahigh dose rate radiotherapy (RT) with electrons and protons has shown potential for cancer treatment by effectively targeting tumors while sparing healthy tissues (FLASH effect). This study aimed to investigate the potential FLASH sparing effect of ultrahigh dose rate helium ion irradiation, focusing on acute brain injury and subcutaneous tumor response in a preclinical in vivo setting. Raster-scanned helium ion beams were used to compare the effects of standard dose rate (SDR; at 0.2 Gy/second) and FLASH (at 141 Gy/second) RT on healthy brain tissue. Irradiation-induced brain injury was studied in C57BL/6 mice via DNA damage response, using nuclear gamma H2AX as a marker for double-strand breaks. The integrity of neurovascular and immune compartments was assessed through CD31+ microvascular density and activation of microglia/macrophages. IBA1+ ramified and CD68+ phagocytic microglia/macrophages were quantified, along with the expression of inducible nitric oxide synthetase. Tumor response to SDR (0.2 Gy/second) and FLASH (250 Gy/second) RT was evaluated in an A549 carcinoma model, using tumor volume and Kaplan-Meier survival as endpoints. The results showed that helium FLASH RT significantly reduced acute brain tissue injury compared with SDR, evidenced by lower levels of double-strand breaks and preserved the neurovascular endothelium. Additionally, FLASH RT reduced neuroinflammatory signals compared with SDR, as indicated by fewer CD68+ inducible nitric oxide synthetase-positive microglia/macrophages. FLASH RT achieved tumor control comparable with that of SDR RT. To the best of our knowledge, this is the first study to report the FLASH sparing effect of raster scanning helium ion RT in vivo, highlighting its potential for neuroprotection and effective tumor control.

BACKGROUND:The emerging FLASH radiotherapy technique employs "Ultra-High Dose Rate" (UHDR) irradiations and offers the potential to spare normal tissue while maintaining iso-effective tumor treatment. Given the physical and biological advantages inherent to high "Linear Energy Transfer" (LET) particles, the combination of UHDR and high LET has the capability to enhance the normal tissues sparing, as indicated by initial in vivo trials. However, to ensure a safe implementation of this combined modality, it is essential to establish robust dosimetric protocols utilizing dose-, dose rate-, and LET-independent detectors. PURPOSE:The objective of this study is to characterize the dose, dose rate, and LET dependency of two diamond detectors with high LET carbon and oxygen ion irradiation under "Standard Dose Rate" (SDR) and UHDR conditions. METHODS:The "microDiamond" (mD) and a "flashDiamond" (fD) prototype were benchmarked against measurements with a monitoring ionization chamber, Advanced Markus chamber (AMC), and simulations for carbon and oxygen irradiation, with energies of 274.98 MeV/u and 325.98 MeV/u under SDR and UHDR conditions. First, the entire depth-dose profiles obtained during SDR irradiations and the partial in-depth profiles of the Bragg peak region in UHDR were compared to the corresponding simulation values. Secondly, the linearity of the diamond detector response during dose escalation measurements was investigated for both dose rates. RESULTS:The two detectors exhibited alignment with the simulated depth-dose distributions for oxygen and carbon irradiations across both dose rate conditions. The mD overestimated the dose values for carbon and oxygen measurements. This overestimation increased with "dose-averaged LET" (LETd) during SDR irradiation and maintained a stable value of 5% for UHDR. Meanwhile, the fD demonstrated a high degree of agreement with the simulation, with a maximum discrepancy of 5% across all irradiation modalities in the plateau and "Bragg Peak" (BP). Deviations were observed in the BP fall-off region, while both diamond detectors exhibited a strong alignment with the AMC measurements. Furthermore, both detectors exhibited dose linearity under SDR and UHDR irradiation for both carbon and oxygen irradiation, with a coefficient of determination (R2) above 0.99. CONCLUSION:In the context of heavy ion carbon and oxygen irradiation in UHDR and SDR, the two diamond detectors demonstrated dose-rate independence. While the mD exhibited a tendency to overestimate dose values with increasing LETd, the fD was found to be LET-independent. The fD appears to offer accurate and reliable dose assessments for UHDR heavy ion experiments.

Within this study, we demonstrated the feasibility of ultra-high dose rate (UHDR) oxygen ion irradiation at three different levels of biological complexity. The difference in oxygen consumption between UHDR and standard dose rates (SDR) was negligible in a protein-enriched saline solution. For the studied conditions of dose, dose rate and linear energy transfer (LET), UHDR irradiation showed comparable efficacy to SDR in pancreatic cancer cell killing in vitro, along with inducing a similar tumor growth delay in vivo. These findings emphasize the potential of high-LET UHDR irradiation and support further investigation of oxygen ions at UHDR.

Background: The current study aims to evaluate the occurrence of temporal lobe reactions and identify possible risk factors for patients who underwent particle therapy of the skull base. Methods: 244 patients treated for skull base chordoma (n = 144) or chondrosarcoma (n = 100) at the Heidelberg Ion Beam Therapy Center (HIT) using a raster scan technique, were analyzed. Follow-up MRI-scans were matched with the initial planning images. Radiogenic reactions were contoured and analyzed based on volume and dose of treatment. Results: 51 patients with chordoma (35.4%) and 30 patients (30%) with chondrosarcoma experienced at least one temporal lobe reaction within the follow-up period (median 49 months for chondrosarcoma, 62 months for chordoma). Age, irradiated volume, and dose values were significant risk factors for the development of temporal lobe reactions with the highest significance for the value of DMax-7 being defined as the dose maximum in the temporal lobe minus the 7cc with the highest dose (p = 0.000000000019; OR 1.087). Conclusion: Temporal lobe reactions are a common side effect after particle therapy of the skull base. We were able to develop a multivariate model, which predicted radiation reactions with a specificity of 99% and a sensitivity of 52.2%.

BackgroundMonte Carlo (MC) simulations are considered the gold-standard for accuracy in radiotherapy dose calculation; so far however, no commercial treatment planning system (TPS) provides a fast MC for supporting clinical practice in carbon ion therapy.PurposeTo extend and validate the in-house developed fast MC dose engine MonteRay for carbon ion therapy, including physical and biological dose calculation.MethodsMonteRay is a CPU MC dose calculation engine written in C++ that is capable of simulating therapeutic proton, helium and carbon ion beams. In this work, development steps taken to include carbon ions in MonteRay are presented. Dose distributions computed with MonteRay are evaluated using a comprehensive validation dataset, including various measurements (pristine Bragg peaks, spread out Bragg peaks in water and behind an anthropomorphic phantom) and simulations of a patient plan. The latter includes both physical and biological dose comparisons. Runtimes of MonteRay were evaluated against those of FLUKA MC on a standard benchmark problem.ResultsDosimetric comparisons between MonteRay and measurements demonstrated good agreement. In terms of pristine Bragg peaks, mean errors between simulated and measured integral depth dose distributions were between -2.3% and +2.7%. Comparing SOBPs at 5, 12.5 and 20 cm depth, mean absolute relative dose differences were 0.9%, 0.7% and 1.6% respectively. Comparison against measurements behind an anthropomorphic head phantom revealed mean absolute dose differences of 1.2%& PLUSMN;1.1%$1.2\% \pm 1.1\;\% \;$with global 3%/3 mm 3D-& gamma; passing rates of 99.3%, comparable to those previously reached with FLUKA (98.9%). Comparisons against dose predictions computed with the clinical treatment planning tool RayStation 11B for a meningioma patient plan revealed excellent local 1%/1 mm 3D-& gamma; passing rates of 98% for physical and 94% for biological dose. In terms of runtime, MonteRay achieved speedups against reference FLUKA simulations ranging from 14x to 72x, depending on the beam's energy and the step size chosen.ConclusionsValidations against clinical dosimetric measurements in homogeneous and heterogeneous scenarios and clinical TPS calculations have proven the validity of the physical models implemented in MonteRay. To conclude, MonteRay is viable as a fast secondary MC engine for supporting clinical practice in proton, helium and carbon ion radiotherapy.

Objective. Magnetic resonance (MR) images free of artefacts are of pivotal importance for MR-guided ion radiotherapy. This study investigates MR image quality for simultaneous irradiation in an experimental setup using phantom imaging as well as in-vivo imaging. Observed artefacts are described within the study and their cause is investigated with the goal to find conclusions and solutions for potential future hybrid devices. Approach. An open MR scanner with a field strength of 0.25 T has been installed in front of an ion beamline. Simultaneous magnetic resonance imaging and irradiation using raster scanning were performed to analyze image quality in dedicated phantoms. Magnetic field measurements were performed to assist the explanation of observed artifacts. In addition, in-vivo images were acquired by operating the magnets for beam scanning without transporting a beam. Main Results. The additional frequency component within the isocenter caused by the fringe field of the horizontal beam scanning magnet correlates with the amplitude and frequency of the scanning magnet steering and can cause ghosting artifacts in the images. These are amplified with high currents and fast operating of the scanning magnet. Applying a real-time capable pulse sequence in-vivo revealed no ghosting artifacts despite a continuously changing current pattern and a clinical treatment plan activation scheme, suggesting that the use of fast imaging is beneficial for the aim of creating high quality in-beam MR images. This result suggests, that the influence of the scanning magnets on the MR acquisition might be of negligible importance and does not need further measures like extensive magnetic shielding of the scanning magnets. Significance. Our study delimited artefacts observed in MR images acquired during simultaneous raster scanning ion beam irradiation. The application of a fast pulse sequence showed no image artefacts and holds the potential that online MR imaging in future hybrid devices might be feasible.

This study showcases the feasibility of oxygen ion ultra-high dose rate irradiation for in vitro and in vivo experiments at the Heidelberg Ion-Beam Therapy Center. The results indicate comparable effectiveness to standard dose rate in pancreatic cancer cell killing and tumor control, highlighting its potential to address challenges in treating radio-resistant tumors. ### Competing Interest Statement Conflicts of Interest: J. Debus reports grants from CRI The Clinical Research Institue GmbH grants from View Ray Inc., grants from Accuray International Sarl, grants from Accuray Incorposrated, grants from RaySearch Laboratories AB, grants from Vision RT limited, grants from Merck Serono GmbH, grants from Astellas Pharma GmbH, grants from Astra Zeneca GmbH, grants from Siemens Healthcare GmbH, grants from Merck KGaA Accounts Payable, grants from Solution Akademie GmbH, grants from Ergomed PLC Surrey Research Park, grants from Siemens Healthcare GmbH, grants from Quintiles GmbH, grants from Pharmaceutecal Research Associates GmbH, grants from Boehringer Ingelheim Pharma GmbH Co, grants from PTW-Freiburg Dr. Pychlau GmbH. A. Abdollahi reports grants and other support from Merck KGaA, FibroGen Inc., Bayer, Roche, and Merck Serono and other support from BMS and BioMedX outside the submitted work. Other authors: none. Source of Funding: This work was supported by intramural funds from the National Center for Tumor Diseases (NCTPRO: 1030000042 and Biodose: 1030000043 programs). This work was supported in part by the National Institutes of Health (NIH1P01CA25790401A1). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

BackgroundThe role of radiolytic oxygen consumption for the in-vitro "Ultra-High Dose Rate" (UHDR) sparing and in-vivo FLASH effect is subject to active debate, but data on key dependencies such as the radiation quality are lacking.PurposeThe influence of "dose-averaged Linear Energy Transfer" (LETd) and dose rate on radiolytic oxygen consumption was investigated by monitoring the oxygen concentration during irradiation with electrons, protons, helium, carbon, and oxygen ions at UHDR and "Standard Dose Rates" (SDR).MethodsSealed "Bovine Serum Albumin" (BSA) 5% samples were exposed to 15 Gy of electrons and protons, and for the first time helium, carbon, and oxygen ions with LETd values of 1, 5.4, 14.4, 65, and 100.3 keV/mu m, respectively, delivered at mean dose rates of either 0.3-0.4 Gy/s for SDR or approximately 100 Gy/s for UHDR. The Oxylite (Oxford Optronics) system allowed measurements of the oxygen concentration before and after irradiation to calculate the oxygen consumption rate.ResultsThe oxygen consumption rate was found to decrease with increasing LETd from 0.351 mmHg/Gy for low LET electrons to 0.1796 mmHg/Gy for high LET oxygen ions at SDR and for UHDR from 0.317 to 0.1556 mmHg/Gy, respectively. A higher consumption rate for SDR irradiation compared to the corresponding UHDR irradiation persisted for all particle types.ConclusionThe measured consumption rates demonstrate a distinct LETd dependence. The obtained dataset, encompassing a wide range of LETd values, could serve as a benchmark for Monte Carlo simulations, which may aid in enhancing our comprehension of oxygen-related mechanisms after irradiations. Ultimately, they could help assess the viability of different hypotheses regarding UHDR sparing mechanisms and the FLASH effect. The found LETd dependence underscores the potential of heavy ion therapy, wherein elevated consumption rates in adjacent normal tissue offer protective benefits, while leaving tumor regions with generally higher "Linear Energy Transfer" (LET) vulnerable.

Background: Interpatient variation of tumor radiosensitivity is rarely considered during the treatment planning process despite its known significance for the therapeutic outcome. PurposeTo apply our mechanistic biophysical model to investigate the biological robustness of carbon ion radiotherapy (CIRT) against DNA damage repair interference (DDRi) associated patient-to-patient variability in radiosensitivity and its potential clinical advantages against conventional radiotherapy approaches. Methods and Materials: The "UNIfied and VERSatile bio response Engine" (UNIVERSE) was extended by carbon ions and its predictions were compared to a panel of in vitro and in vivo data including various endpoints and DDRi settings within clinically relevant dose and linear energy transfer (LET) ranges. The implications of UNIVERSE predictions were then assessed in a clinical patient scenario considering DDRi variance. Results: UNIVERSE tests well against the applied benchmarks. While in vitro survival curves were predicted with an R-2 > 0.92, deviations from in vivo RBE data were less than 5.6% The conducted paradigmatic patient plan study implies a markedly reduced significance of DDRi based radiosensitivity variability in CIRT (13% change of D-50 in target) compared to conventional radiotherapy (62%) and that boosting the LET within the target further amplifies this robustness of CIRT (8%). In the case of heightened tumor radiosensitivity, a dose de-escalation strategy for photons allows a reduction of the maximum effective dose within the normal tissue (NT) from a D-2 of 2.65 to 1.64 Gy, which lies below the level found for CIRT (D-2 = 2.41 Gy) for the analyzed plan and parameters. However, even after de-escalation, the integral effective dose in the NT is found to be substantially higher for conventional radiotherapy in comparison to CIRT (D(mean )of 0.75, 0.46, and 0.24 Gy for the conventional plan, its de-escalation and CIRT, respectively). Conclusions: The framework offers adequate predictions of in vitro and in vivo radiation effects of CIRT while allowing the consideration of DRRi based solely on parameters derived from photon data. The results of the patient planning study underline the potential of CIRT to minimize important sources of interpatient divergence in therapy outcome, especially when combined with techniques that allow to maximize the LET within the tumor. Despite the potential of de-escalation strategies for conventional radiotherapy to reduce the maximum effective dose in the NT, CIRT appears to remain a more favorable option due to its ability to reduce the integral effective dose within the NT.

Purpose: Recent experimental studies and clinical trial results might indicate that - at least for some indications - continued use of the mechanistic model for relative biological effectiveness (RBE) applied at carbon ion therapy facilities in Europe for several decades (LEM-I) may be unwarranted. We present a novel clinical framework for prostate cancer treatment planning and tumor control probability (TCP) prediction based on the modified microdosimetric kinetic model (mMKM) for particle therapy.Methods: Treatment plans of 91 prostate tumor patients (proton: 46, carbon ions: 45) applying 66GyRBE [RBE=1.1 for protons and LEM-I, (α/β)x=2.0Gy, for carbon ions] in 20 fractions were recalculated using mMKM ((α/β)x=3.1Gy). Based solely on the response data of photon-irradiated patient groups stratified according to risk and usage of ADT, we derived parameters for an mMKM-based Poisson-TCP model. Subsequently, new carbon and helium ion plans, adhering to prescribed biological dose criteria, were generated. These were systematically compared to the clinical experience of Japanese centers employing an analogous fractionation scheme and existing proton plans.Results: mMKM predictions suggested significant biological dose deviation between proton and carbon ion arms. Patients irradiated with protons received 3.25±0.08GyRBEmMKM/Fx, while patients treated with carbon ions received 2.51±0.05GyRBEmMKM/Fx. TCP predictions were 86±3% for protons and 52±4% for carbon ions, matching the clinical outcome of 85% and 50%. Newly optimized carbon ion plans, guided by the mMKM/TCP model, effectively replicated clinical data from Japanese centers. Using mMKM, helium ions exhibited similar target coverage as proton and carbon ions and an improved rectum and bladder sparing compared to proton.Conclusions: Our mMKM-based model for prostate cancer treatment planning and TCP prediction was validated against clinical data for proton and carbon ion therapy and its application was extended to helium ion therapy. Based on the data presented in this work, mMKM seems to be a good candidate for clinical biological calculations in carbon ion therapy for prostate cancer.