Ion Beam Therapy Research Articles

Development and Benchmarking of a Monte Carlo Dose Engine for Proton Radiation Therapy

Dose calculation algorithms based on Monte Carlo (MC) simulations play a crucial role in radiotherapy. Here, the development and benchmarking of a novel MC dose engine, MonteRay, is presented for proton therapy aiming to support clinical activity at the Heidelberg Ion Beam Therapy center (HIT) and the development of MRI (magnetic resonance imaging)-guided particle therapy. Comparisons against dosimetric data and gold standard MC FLUKA calculations at different levels of complexity, ranging from single pencil beams in water to patient plans, showed high levels of agreement, validating the physical approach implemented in the dose engine. Additionally, MonteRay has been found to match satisfactorily to FLUKA dose predictions in magnetic fields both in homogeneous and heterogeneous scenarios advocating its use for future MRI-guided proton therapy applications. Benchmarked on 150 MeV protons transported on a 2 × 2 × 2 mm3 grid, MonteRay achieved a high computational throughput and was able to simulate the histories of more than 30,000 primary protons per second on a single CPU core.

Dual-layer spectral CT for proton, helium, and carbon ion beam therapy planning of brain tumors.

Pretreatment computed tomography (CT) imaging is an essential component of the particle therapy treatment planning chain. Treatment planning and optimization with charged particles require accurate and precise estimations of ion beam range in tissues, characterized by the stopping power ratio (SPR). Reduction of range uncertainties arising from conventional CT‐number‐to‐SPR conversion based on single‐energy CT (SECT) imaging is of importance for improving clinical practice. Here, the application of a novel imaging and computational methodology using dual‐layer spectral CT (DLCT) was performed toward refining patient‐specific SPR estimates.A workflow for DLCT‐based treatment planning was devised to evaluate SPR prediction for proton, helium, and carbon ion beam therapy planning in the brain. DLCT‐ and SECT‐based SPR predictions were compared in homogeneous and heterogeneous anatomical regions. This study included eight patients scanned for diagnostic purposes with a DLCT scanner. For each patient, four different treatment plans were created, simulating tumors in different parts of the brain.For homogeneous anatomical regions, mean SPR differences of about 1% between the DLCT‐ and SECT‐based approaches were found. In plans of heterogeneous anatomies, relative (absolute) proton range shifts of 0.6% (0.4 mm) in the mean and up to 4.4% (2.1 mm) at the distal fall‐off were observed. In the investigated cohort, 12% of the evaluated organs‐at‐risk (OARs) presented differences in mean or maximum dose of more than 0.5 Gy (RBE) and up to 6.8 Gy (RBE) over the entire treatment. Range shifts and dose differences in OARs between DLCT and SECT in helium and carbon ion treatment plans were similar to protons.In the majority of investigated cases (75th percentile), SECT‐ and DLCT‐based range estimations were within 0.6 mm. Nonetheless, the magnitude of patient‐specific range deviations between SECT and DLCT was clinically relevant in heterogeneous anatomical sites, suggesting further study in larger, more diverse cohorts. Results indicate that patients with brain tumors may benefit from DLCT‐based treatment planning.

Combined DNA Damage Repair Interference and Ion Beam Therapy: Development, Benchmark, and Clinical Implications of a Mechanistic Biological Model

Our purpose was to develop a mechanistic model that describes and predicts radiation response after combined DNA damage repair interference (DDRi) and particle radiation therapy. The heterogeneous dose distributions of protons and 4He ions were implemented into the "UNIfied and VERSatile bio-response Engine" (UNIVERSE). Predictions for monoenergetic and mixed fields over clinically relevant dose and linear energy transfer range were compared with experimental in vitro survival data measured in this work as well as data available in the literature, including different cell lines and DDR interferences. Ultimately, UNIVERSE predictions were investigated in a patient plan. UNIVERSE accurately predicts survival of cell lines with and without DDRi in clinical settings of ion beam therapy based only on 3 parameters derived from photon data. With increasing dose or linear energy transfer, the radiosensitizing effect of DDRi decreases, resulting in diminished relative biological effect of ion beam radiation for cells subjected to DDRi in comparison to cells that are not. Similar trends were observed in patient plan recalculations; however, this analysis also suggests that DDRi+particle radiation therapy may better preserve the therapeutic window in comparison to DDRi+photon radiation therapy. The presented framework represents the first mechanistic model of combined DDRi and particle radiation therapy comprehensively benchmarked in clinically relevant scenarios and a step toward more personalized treatment. It reveals potential differences between DDRi+photon radiation therapy versus DDRi+particle radiation therapy, which have not been described so far. UNIVERSE could aid in appraising the clinical viability of combined administration of radiosensitizing drugs and charged particle therapy, as well as the identification of patients with known DDR deficiencies in the tumor who might benefit from therapy with light ions, freeing limited space at heavy ion therapy centers.

Combined DNA Damage Repair Inhibition and Ion Beam Therapy: Development, Benchmark and Clinical Implications of a Mechanistic Biological Model

Cellular radiosensitivity is tightly linked to DNA damage repair (DDR) capability. In a clinical context, inhibition of key DDR enzymes within tumor results in improved tumor control after radiotherapy and many preclinical and clinical trials of radiosensitizing drugs targeting DDR enzymes have been recently conducted or launched. Concurrently, interest in ion beam therapy continues to grow globally and its high precision may provide ideal treatment attributes in combination with tumor radiosensitizers. However, most studies of tumor radiosensitization based on DDR inhibition have been or are conducted using prevalent photon beams. Here, a mechanistic model of biological radiation response is presented to accurately translate findings in DDR inhibition studies to the case of charged particle radiation.The mechanistic "UNIfied and VErsatile bio-response Engine" (UNIVERSE) and its model of radiosensitization by DDR inhibition is extended to charged particles by implementing the heterogeneous dose distributions of protons and helium ions utilizing GPU computation. Predictions for monoenergetic and mixed fields over clinically relevant dose and LET range are compared to cell survival data from the literature and own dedicated experiments, including different cell lines and DDR inhibited variants. Our own experimental data represents the first comprehensive measurement of cell survival of repair competent and deficient cell lines in a helium spread-out bragg peak. Ultimately, the predictions of UNIVERSE are considered in a concrete clinical situation based on patient plan recalculations.UNIVERSE is able to precisely predict cell survival of DDR competent and deficient cell lines in clinically relevant settings of ion beam therapy based only on up to 3 parameters derived solely from conventional photon data. With increasing LET the effect of DDR deficiency reduces. This results in a diminished RBE of ion beam radiation for DDR deficient cells in comparison to DDR proficient cells.The capabilities of UNIVERSE could lead towards more personalized and "biological" planning in charged particle therapy, that could be guided by bio-marker based imaging in the future. By increasing the coverage of a tumor with high-LET using modifications of the treatment planning optimizer or advanced irradiation techniques, one could exploit the reduced impact of DDR inhibition at high LET to reduce the adverse effects of heterogeneous tumor radiosensitivity. UNIVERSE could also aid the appraisal of clinical viability of combined administration of radiosensitizing drugs and charged particle therapy and the identification of patients with known DDR inhibition which might not benefit from ion beam therapy, facilitating the management of limited capacities at therapy centers.

Next Evolutions in Particle Therapy: Helium Ion Treatment Planning, Delivery and Clinical Implications of Biological Modeling

This work aims to investigate the implication of relevant biological parameters in clinical treatment planning for the first helium ion beam therapy with active beam delivery.Patient plan optimization was performed using the first clinical TPS commissioned for Helium ion therapy with active beam delivery. Biological calculations are coupled to the modified microdosimetric kinetic model (mMKM) for considering bio-effect specific to each tumor and mixed radiation field spectra. Several plans for patients previously treated with proton beams were re-optimized with helium ions. Comparisons of the resulting biological dose distributions between the ions for the same fractionation scheme were conducted. Sensitivity studies were performed with these plans with respect to the chosen (α/β)x for changes in β (high or low in its clinical range) or on the fractionation scheme. Physical and biological quantities such as physical dose, LET and BED were also compared after computation with the secondary dose engine FRoG.During treatment plan optimization, all clinical constraints were reached with the helium ions. Overall, results indicate better CTV conformity and sparing of surrounding healthy tissue. Robustness analysis on 2mm/3% do not show any disadvantages in setup/SPR inaccuracies of helium ions compared to protons. Investigation on the sensitivity studies suggest clinically relevant levels of RBE-related uncertainties with selected (α/β)x, thus calling for compromise between fractionation scheme and RBE sensitivity in treatment design. All plans were dosimetrically verified in water and found to be within clinical tolerances.Prior to the first patient treatment using helium ions with active beam scanning delivery, assessment of clinical parameters and feasibility of patient planning using the mMKM was successfully performed.

Biological effectiveness of He-3 and He-4 ion beams for cancer hadrontherapy: a study based on the BIANCA biophysical model

While cancer therapy with protons and C-ions is continuously spreading, in the near future patients will be also treated with He-ions which, in comparison to photons, combine the higher precision of protons with the higher relative biological effectiveness (RBE) of C-ions. Similarly to C-ions, also for He-ions the RBE variation along the beam must be known as precisely as possible, especially for active beam delivery systems. In this framework the BIANCA biophysical model, which has already been applied to calculate the RBE along proton and C-ion beams, was extended to 4He-ions and, following interface with the FLUKA code, was benchmarked against cell survival data on CHO normal cells and Renca tumour cells irradiated at different positions along therapeutic-like 4He-ion beams at the Heidelberg Ion-beam Therapy centre, where the first He-ion patient will be treated soon. Very good agreement between simulations and data was obtained, showing that BIANCA can now be used to predict RBE following irradiation with all ion types that are currently used, or will be used soon, for hadrontherapy. Thanks to the development of a reference simulation database describing V79 cell survival for ion and photon irradiation, these predictions can be cell-type specific because analogous databases can be produced, in principle, for any cell line. Furthermore, survival data on CHO cells irradiated by a He-3 beam were reproduced to compare the biophysical properties of He-4 and He-3 beams, which is currently an open question. This comparison showed that, at the same depth, He-4 beams tend to have a higher RBE with respect to He-3 beams, and that this difference is also modulated by the considered physical dose, as well as the cell radiosensitivity. However, at least for the considered cases, no significant difference was found for the ratio between the RBE-weighted dose in the SOBP and that in the entrance plateau.

The GATE-RTion/IDEAL Independent Dose Calculation System for Light Ion Beam Therapy

Patient specific quality assurance can be improved using an independent dose calculation system. In addition, the implementation of such a system may support light ion beam therapy facilities in reducing the needs for beam time, by substituting some of the experimental patient-specific quality assurance procedures by independent dose calculation. The GATE-RTion-based IDEAL system for light ion beam therapy was developed for this purpose. It was built in a DICOM-in, DICOM-out fashion, for easy integration into a state-of-the-art technology-based workflow for scanned ion beam therapy. This article describes the IDEAL system, followed by its clinical implementation at MedAustron for proton and carbon ion beams. Medical physics acceptance and commissioning steps are presented together with key results: for 3D proton and carbon ion reference boxes, 97% of the points agreed within 5% from the measurements. Experimental validation of stopping powers using real pig samples were between 1.8% and 3.8% for soft tissues. Finally, five clinical cases are described, i.e. two proton and three carbon ion treatments. Dosimetric benchmarking against TPS calculations are presented and discussed in details. As expected, the IDEAL software evidenced limitations arising from the pencil beam algorithm available in the TPS for carbon ions, especially in the presence of air cavities. The IDEAL system was found to satisfy the clinical requirements for independent dose calculation of scanned ion beam delivery systems and is being clinically implemented at MedAustron. The open-source code as well as the documentation was released on the OpenGATE collaboration website, thus allowing for long term maintenance and future upgrades based on a more widespread utilization.

Carbon ion radiotherapy as definitive treatment in locally recurrent pancreatic cancer

PurposeData on management of locally recurrent pancreatic cancer (LRPC) after primary resection are limited. Recently, surprisingly high overall survival rates were reported after irradiation with carbon ions. Here, we report on our clinical experience using carbon ion radiotherapy as definitive treatment in LRPC at the Heidelberg Ion-Beam Therapy Center (HIT).MethodsBetween 2015 and 2019, we treated 13 patients with LRPC with carbon ions with a median total dose of 48 Gy (RBE) in 12 fractions using an active raster-scanning technique at a rotating gantry. No concomitant chemotherapy was administered. Overall survival, local control, and toxicity rates were evaluated 18 months after the last patient finished radiotherapy.ResultsWith a median follow-up time of 9.5 months, one patient is still alive (8%). Median OS was 12.7 months. Ten patients (77%) developed distant metastases. Additionally, one local recurrence (8%) and two regional tumor recurrences (15%) were observed. The estimated 1‑year local control and locoregional control rates were 87.5% and 75%, respectively. During radiotherapy, we registered one gastrointestinal bleeding CTCAE grade III (8%) due to gastritis. The bleeding was sufficiently managed with conservative therapy. No further higher-grade acute or late toxicities were observed.ConclusionWe demonstrate high local control rates in a rare cohort of LRPC patients treated with carbon ion radiotherapy. The observed median overall survival rate was not improved compared to historical in-house data using photon radiotherapy. This is likely due to a high rate of distant tumor progression, highlighting the necessity of additional chemotherapy.

Effectiveness of Carbon Ion Radiation in Locally Advanced Pancreatic Cancer.

PurposeEffective treatment strategies for unresectable locally advanced pancreatic cancer (LAPC) patients are eagerly warranted. Recently, convincing oncological outcomes were demonstrated by carbon ion radiotherapy. Nevertheless, there is a lack of evidence for this modern radiation technique due to the limited number of carbon ion facilities worldwide. Here, we analyze feasibility and efficacy of carbon ion radiotherapy in the management of LAPC at Heidelberg Ion Beam Therapy Center (HIT).MethodsBetween 2015 and 2020, 21 LAPC patients were irradiated with carbon ions with a total dose of 48 Gy (RBE) in single doses of 4 Gy (RBE). Three patients (14%) were treated with concomitant chemotherapy with gemcitabine 300 mg/m2 body surface weekly. Toxicity rates were extracted from the charts. Overall survival, progression free survival, local control, and locoregional control were evaluated using Kaplan–Meier estimates.ResultsOne patient developed ascites CTCAE grade III during radiotherapy, which was related to a later histologically confirmed metachronous peritoneal carcinomatosis. No further higher-graded toxicity could be observed. The most common symptoms were nausea and abdominal pain. After a median estimated follow-up time of 19.1 months, the median progression free survival was 3.7 months, and the median overall survival was 11.9 months. The estimated 1-year local control and locoregional control rates were 89 and 84%, respectively.ConclusionCarbon ion radiotherapy of LAPC patients is safely feasible. Local tumor control rates were high. Nevertheless, compared to historical data, an overall survival improvement could not be observed. This could be explained by the poor prognosis of the selected underlying patients that mostly did not respond to prior chemotherapy as well as the early and frequent emergence of distant metastases that demonstrate the necessity of additional chemotherapy in further studies.

Stochastic radiotherapy appointment scheduling

When scheduling the starting times for treatment appointments of patients in hospitals or outpatient clinics such as radiotherapy centers, minimizing patient waiting time and simultaneously maximizing resource usage is crucial. Significant uncertainty in the treatment durations makes scheduling those activities particularly challenging. In addition to the treatments themselves, also preparation times and exiting times have to be considered, which are uncertain as well. To address and analyze this type of problems, the current study develops a model for planning appointment times under uncertain activity durations for a medical unit with a single “core resource” (in our application case a radiotherapy beam device), several treatment rooms, and required preparation and exiting phases for each patient. We employ a novel buffer concept based on quantiles of duration distributions and introduce a reactive procedure that adapts a pre-determined baseline schedule to the actual patient flow. For heuristically solving the resulting stochastic optimization model, a combination of a Genetic Algorithm and Monte Carlo simulation is proposed. A case study uses real-world data on activity durations gathered from an ion beam therapy facility in Austria. Experimental results comparing different variants of the method are carried out. In particular, comparisons of the stochastic optimization approach to a simpler deterministic approach are given.

Quality assurance method for monitoring of lateral pencil beam positions in scanned carbon-ion radiotherapy using tracking of secondary ions.

Ion beam radiotherapy offers enhances dose conformity to the tumor volume while better sparing healthy tissue compared to conventional photon radiotherapy. However, the increased dose gradient also makes it more sensitive to uncertainties. While the most important uncertainty source is the patient itself, the beam delivery is also subject to uncertainties. Most of the proton therapy centers used cyclotrons, which deliver typically a stable beam over time, allowing a continuous extraction of the beam. Carbon-ion beam radiotherapy (CIRT) in contrast uses synchrotrons and requires a larger and energy-dependent extrapolation of the nozzle-measured positions to obtain the lateral beam positions in the isocenter, since the nozzle-to-isocenter distance is larger than for cyclotrons. Hence, the control of lateral pencil beam positions at isocenter in CIRT is more sensitive to uncertainties than in proton radiotherapy. Therefore, an independent monitoring of the actual lateral positions close to the isocenter would be very valuable and provide additional information. However, techniques capable to do so are scarce, and they are limited in precision, accuracy and effectivity. The detection of secondary ions (charged nuclear fragments) has previously been exploited for the Bragg peak position of C-ion beams. In our previous work, we investigated for the first time the feasibility of lateral position monitoring of pencil beams in CIRT. However, the reported precision and accuracy were not sufficient for a potential implementation into clinical practice. In this work, it is shown how the performance of the method is improved to the point of clinical relevance. To minimize the observed uncertainties, a mini-tracker based on hybrid silicon pixel detectors was repositioned downstream of an anthropomorphic head phantom. However, the secondary-ion fluence rate in the mini-tracker rises up to 1.5×105 ions/s/cm2 , causing strong pile-up of secondary-ion signals. To solve this problem, we performed hardware changes, optimized the detector settings, adjusted the setup geometry and developed new algorithms to resolve ambiguities in the track reconstruction. The performance of the method was studied on two treatment plans delivered with a realistic dose of 3Gy (RBE) and averaged dose rate of 0.27Gy/s at the Heidelberg Ion-Beam Therapy Center (HIT) in Germany. The measured lateral positions were compared to reference beam positions obtained either from the beam nozzle or from a multi-wire proportional chamber positioned at the room isocenter. The presented method is capable to simultaneously monitor both lateral pencil beam coordinates over the entire tumor volume during the treatment delivery, using only a 2-cm2 mini-tracker. The effectivity (defined as the fraction of analyzed pencil beams) was 100%. The reached precision of (0.6 to 1.5) mm and accuracy of (0.5 to 1.2) mm are in line with the clinically accepted uncertainty for QA measurements of the lateral pencil beam positions. It was demonstrated that the performance of the method for a non-invasive lateral position monitoring of pencil beams is sufficient for a potential clinical implementation. The next step is to evaluate the method clinically in a group of patients in a future observational clinical study.

The impact of path estimates in iterative ion CT reconstructions for clinical-like cases

Ion computed tomography (CT) promises to mitigate range uncertainties inherent in the conversion of x-ray Hounsfield units into ion relative stopping power (RSP) for ion beam therapy treatment planning. To improve accuracy and spatial resolution of ion CT by accounting for statistical multiple Coulomb scattering deflection of the ion trajectories from a straight line path (SLP), the most likely path (MLP) and the cubic spline path (CSP) have been proposed. In this work, we use FLUKA Monte Carlo simulations to investigate the impact of these path estimates in iterative tomographic reconstruction algorithms for proton, helium and carbon ions. To this end the ordered subset simultaneous algebraic reconstruction technique was used and coupled with a total variation superiorization (TVS). We evaluate the image quality and dose calculation accuracy in proton therapy treatment planning of cranial patient anatomies. CSP and MLP generally yielded nearly equal image quality with an average RSP relative error improvement over the SLP of 0.6%, 0.3% and 0.3% for proton, helium and carbon ion CT, respectively. Bone and low density materials have been identified as regions of largest enhancement in RSP accuracy. Nevertheless, only minor differences in dose calculation results were observed between the different models and relative range errors of better than 0.5% were obtained in all cases. Largest improvements were found for proton CT in complex scenarios with strong heterogeneities along the beam path. The additional TVS provided substantially reduced image noise, resulting in improved image quality in particular for soft tissue regions. Employing the CSP and MLP for iterative ion CT reconstructions enabled improved image quality over the SLP even in realistic and heterogeneous patient anatomy. However, only limited benefit in dose calculation accuracy was obtained even though an ideal detector system was simulated.

Monte Carlo computation of 3D distributions of stopping power ratios in light ion beam therapy using GATE-RTion.

This paper presents a novel method for the calculation of three-dimensional (3D) Bragg-Gray water-to-detector stopping power ratio (sw,det ) distributions for proton and carbon ion beams. Contrary to previously published fluence-based calculations of the stopping power ratio, the sw,det calculation method used in this work is based on the specific way GATE/Geant4 scores the energy deposition. It only requires the use of the so-called DoseActor, as available in GATE, for the calculation of the sw,det at any point of a 3D dose distribution. The simulations are performed using GATE-RTion v1.0, a dedicated GATE release that was validated for the clinical use in light ion beam therapy. The Bragg-Gray water-to-air stopping power ratio (sw,air ) was calculated for monoenergetic proton and carbon ion beams with the default stopping power data in GATE-RTion v1.0 and the new ICRU90 recommendation. The sw,air differences between the use of the default and the ICRU90 configuration were 0.6% and 5.4% at the physical range (R80 - 80% dose level in the distal dose fall-off) for a 70MeV proton beam and a 120MeV/u carbon ion beam, respectively. For protons, the sw,det results for lithium fluoride, silicon, gadolinium oxysulfide, and the active layer material of EBT2 (radiochromic film) were compared with the literature and a reasonable agreement was found. For a real patient treatment plan, the 3D distributions of sw,det in proton beams were calculated. Our method was validated by comparison with available literature data. Its equivalence with Bragg-Gray cavity theory was demonstrated mathematically. The capability of GATE-RTion v1.0 for the sw,det calculation at any point of a 3D dose distribution for simple and complex proton and carbon ion plans was presented.

Results of an independent dosimetry audit for scanned proton beam therapy facilities

PurposeAn independent dosimetry audit based on end-to-end testing of the entire chain of radiation therapy delivery is highly recommended to ensure consistent treatments among proton therapy centers. This study presents an auditing methodology developed by the MedAustron Ion Beam Therapy Center (Austria) in collaboration with the National Physical Laboratory (UK) and audit results for five scanned proton beam therapy facilities in Europe. MethodsThe audit procedure used a homogeneous and an anthropomorphic head phantom. The phantoms were loaded either with an ionization chamber or with alanine pellets and radiochromic films. Homogeneously planned doses of 10Gy were delivered to a box-like target volume in the homogeneous phantom and to two clinical scenarios with increasing complexity in the head phantom. ResultsFor all tests the mean of the local differences of the absolute dose to water determined with the alanine pellets compared to the predicted dose from the treatment planning system installed at the audited institution was determined. The mean value taken over all tests performed was −0.1±1.0%. The measurements carried out with the ionization chamber were consistent with the dose determined by the alanine pellets with a mean deviation of −0.5±0.6%. ConclusionThe developed dosimetry audit method was successfully applied at five proton centers including various “turn-key” Cyclotron solutions by IBA, Varian and Mevion. This independent audit with extension to other tumour sites and use of the correspondent anthropomorphic phantoms may be proposed as part of a credentialing procedure for future clinical trials in proton beam therapy.

On possible role of hydrogen peroxide molecules in ion beam therapy of cancer cells

The possible role of molecular products of cell radiolysis, in particular, hydrogen peroxide molecules, in blocking DNA activity in cancer cells during irradiation with heavy ions is investigated. It is supposed that hydrogen peroxide molecules can form long-lived molecular complexes with DNA atomic groups and, thus, prevent the realization of genetic information in the biological cells. Using the quantum-mechanical approach based on density functional method and implicitly taking into account the aqueous medium, the competitive interactions of water and hydrogen peroxide molecules with DNA nucleic bases have been analyzed. Estimates of the characteristic lifetimes of complexes of water molecules and hydrogen peroxide with atomic groups of DNA allow showing the possibility to block the genetic activity of DNA by hydrogen peroxide in biological cells after their irradiation with ion beams. The effect of DNA blocking in cancer cells could be enhanced by a decrease in the cell temperature.

Linking Microdosimetric Measurements to Biological Effectiveness in Ion Beam Therapy: A Review of Theoretical Aspects of MKM and Other Models

Different qualities of radiation are known to cause different biological effects at the same absorbed dose. Enhancements of the biological effectiveness are a direct consequence of the energy deposition clustering at the scales of DNA molecule and cell nucleus whilst absorbed dose is a macroscopic averaged quantity which does not take into account heterogeneities at the nanometer and micrometer scales. Microdosimetry aims to measure radiation quality at cellular or sub-cellular levels trying to increase the understanding of radiation damage mechanisms and effects. Existing microdosimeters rely on the well-established gas-based detectors or the more recent solid-state devices. They provide specific energy z spectra and other derived quantities as lineal energy (y) spectra assessed at the micrometer level. The interpretation of the radio-biological experimental data in the framework of different models has raised interest and various investigations have been performed to link in vitro and in vivo radiobiological outcomes with the observed microdosimetric data. A review of the major models based on experimental microdosimetry, with a particular focus on ion beam therapy applications and an emphasis on the microdosimetric kinetic model (MKM), will be presented in this work, enlightening the advantages of each one in terms of accuracy, initial assumptions, and agreement with experimental data. The MKM has been used to predict different kinds of radiobiological quantities such as the relative biological effects for cell inactivation or the oxygen enhancement ratio. Recent developments of the MKM will be also presented, including new non-Poissonian correction approaches for high linear energy transfer radiation, the inclusion of partial repair effects for fractionation studies, and the extension of the model to account for non-targeted effects. We will also explore developments for improving the models by including track structure and the spatial damage correlation information, by using the full fluence spectrum and by better accounting for the energy-deposition fluctuations at the intra- and inter-cellular level.

EVALUATION OF NEUTRON AMBIENT DOSE EQUIVALENT IN INTENSITY-MODULATED COMPOSITE PARTICLE THERAPY.

Several studies have reported benefits derived from cancer treatment using various heavy-ion beams. Based on these reports, the National Institutes for Quantum and Radiological Science and Technology started developing intensity-modulated composite particle therapy (IMPACT) using He-, C-, O-, and Ne-ions. In ion beam therapy, nuclear interactions in the beamline devices or patient produce secondary neutrons. This study evaluated the characteristics of secondary neutrons in IMPACT. Neutron ambient dose equivalents were measured using WENDI-II. Measurements were performed under realistic case scenarios using He-, C-, O- and Ne-ion beams. Moreover, neutron ambient dose equivalents generated by He-, C-, O- and Ne-ion beams were compared with neutron ambient dose equivalents in proton therapy. No differences exist in the distance-dependence even when the primary ions are different. Neutrons generated by primary ion beams of high atomic numbers tend to emit forward. Moreover, in contrast with proton therapy, IMPACT can reduce neutron doses.

Intensity Modulated Radiotherapy with Carbon Ion Radiotherapy Boost for Acinic Cell Carcinoma of the Salivary Glands.

Simple SummaryAcinic cell carcinoma is a rare disease treated usually by surgery. The role of radiotherapy is controversially discussed. In this retrospective analysis based on 15 patients undergoing postoperative or definitive radiotherapy (intensity-modulated radiotherapy, IMRT) with carbon ion radiotherapy boost leads to excellent results after R1-resection, and is a promising treatment modality in inoperable patients. G1-2 xerostomia, dysgeusia, and trismus were the main reported morbidity symptoms after radiotherapy. Confirmation of the results with larger patient cohorts is needed.Aim: to report clinical outcome in patients with acinic cell carcinoma of the salivary glands treated with intensity-modulated radiotherapy (IMRT) and carbon ion radiotherapy (CIRT) boost. Materials and Methods: all patients with acinic cell carcinoma of the salivary glands treated at the Heidelberg Ion-Beam Therapy Center were considered for this retrospective analysis. All patients received a CIRT boost with 18–24 Gy radiobiologic effectiveness (RBE)-weighted dose in 3 Gy RBE-weighted dose per fraction followed by IMRT, with 50–54 Gy in 2 Gy per fraction. Disease outcome was evaluated for local (LR), nodal (NR), distant recurrence (DR), and disease-free (DFS) and overall survival (OS). Morbidity was scored based on Common Terminology Criteria for Adverse Events (CTCAE) version 5. Descriptive statistics and the Kaplan-Meier method were used for analysis. Results: fifteen patients were available for analysis. Median follow-up after radiotherapy was 43 months. Six patients were treated for primary disease and nine for recurrent disease. Eight patients were treated with radiotherapy for macroscopic disease. Disease recurrence was observed in four patients: 1 LR, 2 NR, and 2 DR; 5-year local control, DFS, and OS were 80%, 52%, and 80%, respectively. No radiotherapy-related G3-5 morbidity was observed. Conclusion: In acinic cell carcinoma, IMRT with carbon ion radiotherapy boost leads to excellent results after R1-resection and is a promising treatment modality for definitive treatment in inoperable patients.

Interaction of hydrogen peroxide molecules with non-specific DNA recognition sites

Ion beam therapy is one of the most progressive methods in cancer treatment. Studies of the water radiolysis process show that the most long-living species that occur in the medium of a biological cell under the action of ionizing irradiation are hydrogen peroxide (H$_2$O$_2$) molecules. But the role of H$_2$O$_2$ molecules in the DNA deactivation of cancer cells in ion beam therapy has not been determined yet. In the present paper, the competitive interaction of hydrogen peroxide and water molecules with atomic groups of non-specific DNA recognition sites (phosphate groups PO$_4$) is investigated. The interaction energies and optimized spatial configurations of the considered molecular complexes are calculated with the help of molecular mechanics method and quantum chemistry approach. The results show that the H$_2$O$_2$ molecule can form a complex with the PO$_4$ group (with and without a sodium counterion) that is more energetically stable than the same complex with the water molecule. Formation of such complexes can block genetic information transfer processes in cancer cells and can be an important factor during ion beam therapy treatment.

Rapid effective dose calculation for raster-scanning 4He ion therapy with the modified microdosimetric kinetic model (mMKM).

To develop and verify effective dose (DRBE) calculation in 4He ion beam therapy based on the modified microdosimetric kinetic model (mMKM) and evaluate the bio-sensitivity of mMKM-based plans to clinical parameters using a fast analytical dose engine. Mixed radiation field particle spectra (MRFS) databases have been generated with Monte-Carlo (MC) simulations for 4He-ion beams. Relative biological effectiveness (RBE) and DRBE calculation using MRFS were established within a fast analytical engine. Spread-out Bragg-Peaks (SOBPs) in water were optimized for two dose levels and two tissue types with photon linear-quadratic model parameters αph, βph, and (α/β)ph to verify MRFS-derived database implementation against computations with MC-generated mixed-field α and β databases. Bio-sensitivity of the SOBPs was investigated by varying absolute values of βph, while keeping (α/β)ph constant. Additionally, dose, dose-averaged linear energy transfer, and bio-sensitivity were investigated for two patient cases. Using MRFS-derived databases, dose differences ≲2% in the plateau and SOBP are observed compared to computations with MC-generated databases. Bio-sensitivity studies show larger deviations when altering the absolute βph value, with maximum D50% changes of ~5%, with similar results for patient cases. Bio-sensitivity analysis indicates a greater impact on DRBE varying (α/β)ph than βph in mMKM. The MRSF approach yielded negligible differences in the target and small differences in the plateau compared to MC-generated databases. The presented analyses provide guidance for proper implementation of RBE-weighted 4He ion dose prescription and planning with mMKM. The MRFS-DRBE calculation approach using mMKM will be implemented in a clinical treatment planning system.