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This work aimed to characterize a dedicated phantom for assessing the dose near metal implants for radiotherapy with photons and protons. A dosimetry audit phantom was redesigned to position a Gafchromic EBT-3 film within a bisected titanium pedicle screw (6.5 mm diameter). The mass density and the water equivalent thickness (WET) of the phantom material were determined. The phantom was irradiated using a photon arc and a horizontal proton beam in combination with a couch rotation of 20°, with three repeated measurements each. Treatment plans utilizing a single field covering the screw and the EBT-3 film were optimized to deliver a physical dose of 2 Gy using a collapsed cone and Monte Carlo dose engine for photons and protons, respectively. The mass density and the WET of the phantom were determined as (1.033 ± 0.010) gcm-3 and (1.022 ± 0.013), respectively. Ionisation chamber measurements agreed within 1% (photons) and 0.5% (protons) with the calculated dose values. Relative photon dosimetry measurements using EBT-3 films revealed an agreement between measured and calculated horizontal profiles within the confidence interval for areas beyond 5 mm from the center. For photon plans, significant deviations of more than 10% were found at the interfaces between phantom material and screw. The proton measurements showed a gradual decrease of 3% across both profiles. In contrast to photon plans, no dose increase was measured within the screw, but significant dose fluctuations (>5%) in the beam's exit region. This study showed that the behavior of dose engine is affected by metal implants and thus dosimetric measurements are highly recommended. The presented phantom can serve as foundation for dedicated end-2-end phantoms. [ABSTRACT FROM AUTHOR]

In order to overcome the resistance to radiotherapy in human chondrosarcoma cells, the prevention from efficient DNA repair with a combined treatment with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitor AZD7648 was explored for carbon ion (C-ion) as well as reference photon (X-ray) irradiation (IR) using gene expression analysis, flow cytometry, protein phosphorylation, and telomere length shortening. Proliferation markers and cell cycle distribution changed significantly after combined treatment, revealing a prominent G2/M arrest. The expression of the G2/M checkpoint genes cyclin B, CDK1, and WEE1 was significantly reduced by IR alone and the combined treatment. While IR alone showed no effects, additional AZD7648 treatment resulted in a dose-dependent reduction in AKT phosphorylation and an increase in Chk2 phosphorylation. Twenty-four hours after IR, the key genes of DNA repair mechanisms were reduced by the combined treatment, which led to impaired DNA repair and increased radiosensitivity. A time-dependent shortening of telomere length was observed in both cell lines after combined treatment with AZD7648 and 8 Gy X-ray/C-ion IR. Our data suggest that the inhibition of DNA-PKcs may increase sensitivity to X-rays and C-ion IR by impairing its functional role in DNA repair mechanisms and telomere end protection. [ABSTRACT FROM AUTHOR]

Recent advancements in large language models (LMM; e.g., ChatGPT (OpenAI, San Francisco, California, USA)) have seen widespread use in various fields, including healthcare. This case study reports on the first use of LMM in a pretreatment discussion and in obtaining informed consent for a radiation oncology treatment. Further, the reproducibility of the replies by ChatGPT 3.5 was analyzed. A breast cancer patient, following legal consultation, engaged in a conversation with ChatGPT 3.5 regarding her radiotherapy treatment. The patient posed questions about side effects, prevention, activities, medications, and late effects. While some answers contained inaccuracies, responses closely resembled doctors' replies. In a final evaluation discussion, the patient, however, stated that she preferred the presence of a physician and expressed concerns about the source of the provided information. The reproducibility was tested in ten iterations. Future guidelines for using such models in radiation oncology should be driven by medical professionals. While artificial intelligence (AI) supports essential tasks, human interaction remains crucial. [ABSTRACT FROM AUTHOR]

Background: Carbon ion beams are well accepted as densely ionizing radiation with a high linear energy transfer (LET). However, the current clinical practice does not fully exploit the highest possible dose‐averaged LET (LETd) and, consequently, the biological potential in the target. This aspect becomes worse in larger tumors for which inferior clinical outcomes and corresponding lower LETd was reported. Purpose: The vicinity to critical organs in general and the inferior overall survival reported for larger sacral chordomas treated with carbon ion radiotherapy (CIRT), makes the treatment of such tumors challenging. In this work it was aimed to increase the LETd in large volume tumors while maintaining the relative biological effectiveness (RBE)‐weighted dose, utilizing the LETd optimization functions of a commercial treatment planning system (TPS). Methods: Ten reference sequential boost carbon ion treatment plans, designed to mimic clinical plans for large sacral chordoma tumors, were generated. High dose clinical target volumes (CTV‐HD) larger than 250cm3$250 \,{\rm cm}^{3}$ were considered as large targets. The total RBE‐weighted median dose prescription with the local effect model (LEM) was DRBE,50%=73.6Gy$\textrm {D}_{\rm RBE, 50\%}=73.6 \,{\rm Gy}$ in 16 fractions (nine to low dose and seven to high dose planning target volume). No LETd optimization was performed in the reference plans, while LETd optimized plans used the minimum LETd (Lmin) optimization function in RayStation 2023B. Three different Lmin values were investigated and specified for the seven boost fractions: Lmin=60keV/μm$\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$, Lmin=80keV/μm$\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ and Lmin=100keV/μm$\textrm {L}_{\rm min}=100 \,{\rm keV}/{\umu }{\rm m}$. To compare the LETd optimized against reference plans, LETd and RBE‐weighted dose based goals similar to and less strict than clinical ones were specified for the target. The goals for the organs at risk (OAR) remained unchanged. Robustness evaluation was studied for eight scenarios (±3.5%$\pm 3.5\%$ range uncertainty and ±3mm$\pm 3 \,{\rm mm}$ setup uncertainty along the main three axes). Results: The optimization method with Lmin=60keV/μm$\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ resulted in an optimal LETd distribution with an average increase of LETd,98%${\rm {LET}}_{{\rm {d,}}98\%}$ (and LETd,50%${\rm {LET}}_{{\rm {d,}}50\%}$) in the CTV‐HD by 8.9±1.5keV/μm$8.9\pm 1.5 \,{\rm keV}/{\umu }{\rm m}$ (27%$27\%$) (and 6.9±1.3keV/μm$6.9\pm 1.3 \,{\rm keV}/{\umu }{\rm m}$ (17%$17\%$)), without significant difference in the RBE‐weighted dose. By allowing ±5%$\pm 5\%$ over‐ and under‐dosage in the target, the LETd,98%${\rm {LET}}_{{\rm {d,}}98\%}$ (and LETd,50%${\rm {LET}}_{{\rm {d,}}50\%}$) can be increased by 11.3±1.2keV/μm$11.3\pm 1.2 \,{\rm keV}/{\umu }{\rm m}$ (34%$34\%$) (and 11.7±3.4keV/μm$11.7\pm 3.4 \,{\rm keV}/{\umu }{\rm m}$ (29%$29\%$)), using the optimization parameters Lmin=80keV/μm$\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$. The pass rate for the OAR goals in the LETd optimized plans was in the same level as the reference plans. LETd optimization lead to less robust plans compared to reference plans. Conclusions: Compared to conventionally optimized treatment plans, the LETd in the target was increased while maintaining the RBE‐weighted dose using TPS LETd optimization functionalities. Regularly assessing RBE‐weighted dose robustness and acquiring more in‐room images remain crucial and inevitable aspects during treatment. [ABSTRACT FROM AUTHOR]

Objective: 3D printing has seen use in many fields of imaging and radiation oncology, but applications in (anthropomorphic) phantoms, especially for particle therapy, are still lacking. The aim of this work was to characterize various available 3D printing methods and epoxy-based materials with the specific goal of identifying suitable tissue surrogates for dosimetry applications in particle therapy. Methods: 3D-printed and epoxy-based mixtures of varying ratios combining epoxy resin, bone meal, and polyethylene powder were scanned in a single-energy computed tomography (CT), a dual-energy CT, and a μCT scanner. Their CT-predicted attenuation was compared to measurements in a 148.2 MeV proton and 284.7 MeV/u carbon ion beam. The sample homogeneity was evaluated in the respective CT images and in the carbon beam, additionally via widening of the Bragg peak. To assess long-term stability attenuation, size and weight measurements were repeated after 6-12 months. Results: Four 3D-printed materials, acrylonitrile butadiene styrene polylactic acid, fused deposition modeling printed nylon, and selective laser sintering printed nylon, and various ratios of epoxy-based mixtures were found to be suitable tissue surrogates. The materials' predicted stopping power ratio matched the measured stopping power ratio within 3% for all investigated CT machines and protocols, except for μCT scans employing cone beam CT technology. The heterogeneity of the suitable surrogate samples was adequate, with a maximum Bragg peak width increase of 11.5 ± 2.5%. The repeat measurements showed no signs of degradation after 6-12 months. Conclusion: We identified surrogates for soft tissue and low- to medium-density bone among the investigated materials. This allows low-cost, adaptable phantoms to be built for quality assurance and end-to-end tests for particle therapy. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the feasibility of a thermo-optical surface imaging (SGRT) system combined with room-based stereoscopic X‑ray image guidance (IGRT) in a dedicated breast deep inspiration breath-hold (DIBH) irradiation workflow. In this context, benchmarking of portal imaging (EPID) and cone-beam CT (CBCT) against stereoscopic X‑rays was performed. Methods: SGRT + IGRT data of 30 left-sided DIBH breast patients (1 patient with bilateral cancer) treated in 351 fractions using thermo-optical surface imaging and X-ray IGRT were retrospectively analysed. Patients were prepositioned based on a free-breathing surface reference derived from a CT scan. Once the DIBH was reached using visual feedback, two stereoscopic X‑ray images were acquired and registered to the digitally reconstructed radiographs derived from the DIBH CT. Based on this registration, a couch correction was performed. Positioning and monitoring by surface and X-ray imaging were verified by protocol-based EPID or CBCT imaging at selected fractions and the calculation of residual geometric deviations. Results: The median X‑ray-derived couch correction vector was 4.9 (interquartile range [IQR] 3.3–7.1) mm long. Verification imaging was performed for 134 fractions (216 RT field verifications) with EPID and for 37 fractions with CBCT, respectively. The median 2D/3D deviation vector length over all verification images was 2.5 (IQR 1.6–3.9) mm/3.4 (IQR 2.2–4.8) mm for EPID/CBCT, both being well within the planning target volume (PTV) margins (7 mm). A moderate correlation (0.49–0.65) was observed between the surface signal and X-ray position in DIBH. Conclusion: DIBH treatments using thermo-optical SGRT and X-ray IGRT were feasible for breast cancer patients. Stereoscopic X‑ray positioning was successfully verified by standard IGRT techniques. [ABSTRACT FROM AUTHOR]

Background: The combination of magnetic resonance imaging and proton therapy offers the potential to improve cancer treatment. The magnetic field (MF)‐dependent change in the dosage of ionization chambers in magnetic resonance imaging‐integrated proton therapy (MRiPT) is considered by the correction factor kB⃗,M,Q$k_{\vec{B},M,Q}$, which needs to be determined experimentally or computed via Monte Carlo (MC) simulations. Purpose: In this study, kB⃗,M,Q$k_{\vec{B},M,Q}$ was both measured and simulated with high accuracy for a plane‐parallel ionization chamber at different clinical relevant proton energies and MF strengths. Material and methods: The dose‐response of the Advanced Markus chamber (TM34045, PTW, Freiburg, Germany) irradiated with homogeneous 10 ×$\times$ 10 cm 2$^2$ quasi mono‐energetic fields, using 103.3, 128.4, 153.1, 223.1, and 252.7 MeV proton beams was measured in a water phantom placed in the MF of an electromagnet with MF strengths of 0.32, 0.5, and 1 T. The detector was positioned at a depth of 2 g/cm 2$^2$ in water, with chamber electrodes parallel to the MF lines and perpendicular to the proton beam incidence direction. The measurements were compared with TOPAS MC simulations utilizing COMSOL‐calculated 0.32, 0.5, and 1 T MF maps of the electromagnet. kB⃗,M,Q$k_{\vec{B},M,Q}$ was calculated for the measurements for all energies and MF strengths based on the equation: kB⃗,M,Q=MQMQB⃗$k_{\vec{B},M,Q}=\frac{M_\mathrm{Q}}{M_\mathrm{Q}^{\vec{B}}}$, where MQB⃗$M_\mathrm{Q}^{\vec{B}}$ and MQ$M_\mathrm{Q}$ were the temperature and air‐pressure corrected detector readings with and without the MF, respectively. MC‐based correction factors were determined as kB⃗,M,Q=DdetDdetB⃗$k_{\vec{B},M,Q}=\frac{D_\mathrm{det}}{D_\mathrm{det}^{\vec{B}}}$, where DdetB⃗$D_\mathrm{det}^{\vec{B}}$ and Ddet$D_\mathrm{det}$ were the doses deposited in the air cavity of the ionization chamber model with and without the MF, respectively. Furthermore, MF effects on the chamber dosimetry are studied using MC simulations, examining the impact on the absorbed dose‐to‐water (DW$D_{W}$) and the shift in depth of the Bragg peak. Results: The detector showed a reduced dose‐response for all measured energies and MF strengths, resulting in experimentally determined kB⃗,M,Q$k_{\vec{B},M,Q}$ values larger than unity. For all energies and MF strengths examined, kB⃗,M,Q$k_{\vec{B},M,Q}$ ranged between 1.0065 and 1.0205. The dependence on the energy and the MF strength was found to be non‐linear with a maximum at 1 T and 252.7 MeV. The MC simulated kB⃗,M,Q$k_{\vec{B},M,Q}$ values agreed with the experimentally determined correction factors within their standard deviations with a maximum difference of 0.6%. The MC calculated impact on DW$D_{W}$ was smaller 0.2 %. Conclusion: For the first time, measurements and simulations were compared for proton dosimetry within MFs using an Advanced Markus chamber. Good agreement of kB⃗,M,Q$k_{\vec{B},M,Q}$ was found between experimentally determined and MC calculated values. The performed benchmarking of the MC code allows for calculating kB⃗,M,Q$k_{\vec{B},M,Q}$ for various ionization chamber models, MF strengths and proton energies to generate the data needed for a proton dosimetry protocol within MFs and is, therefore, a step towards MRiPT. [ABSTRACT FROM AUTHOR]

Background: Large tumor size has been reported as a predicting factor for inferior clinical outcome in carbon ion radiotherapy (CIRT). Besides the clinical factors accompanied with such tumors, larger tumors receive typically more low linear energy transfer (LET) contributions than small ones which may be the underlying physical cause. Although dose averaged LET is often used as a single parameter descriptor to quantify the beam quality, there is no evidence that this parameter is the optimal clinical predictor for the complex mixed radiation fields in CIRT. Purpose: Purpose of this study was to investigate on a novel dosimetric quantity, namely high‐LET‐dose (D>Lthr$\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$, the physical dose filtered based on an LET threshold) as a single parameter estimator to differentiate between carbon ion treatment plans (cTP) with a small and large tumor volume. Methods: Ten cTPs with a planning target volume, PTV≥500cm3$\mathrm{PTV}\ge {500}\,{{\rm cm}^{3}}$ (large) and nine with a PTV<500cm3$\mathrm{PTV}<{500}\,{{\rm cm}^{3}}$ (small) were selected for this study. To find a reasonable LET threshold (Lthr$\textrm {L}_{\textrm {thr}}$) that results in a significant difference in terms of D>Lthr$\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$, the voxel based normalized high‐LET‐dose (D̂>Lthr$\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$) distribution in the clinical target volume (CTV) was studied on a subset (12 out of 19 cTPs) for 18 LET thresholds, using standard distribution descriptors (mean, variance and skewness). The classical dose volume histogram concept was used to evaluate the D>Lthr$\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ and D̂>Lthr$\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ distributions within the target of all 19 cTPs at the before determined Lthr$\textrm {L}_{\textrm {thr}}$. Statistical significance of the difference between the two groups in terms of mean D>Lthr$\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ and D̂>Lthr$\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ volume histogram parameters was evaluated by means of (two‐sided) t‐test or Mann‐Whitney‐U‐test. In addition, the minimum target coverage at the above determined Lthr$\textrm {L}_{\textrm {thr}}$ was compared and validated against three other thresholds to verify its potential in differentiation between small and large volume tumors. Results: An Lthr$\textrm {L}_{\textrm {thr}}$ of approximately 30keV/μm${30}\,{\rm keV/}\umu {\rm m}$ was found to be a reasonable threshold to classify the two groups. At this threshold, the D>Lthr$\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ and D̂>Lthr$\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ were significantly larger (p<0.05$p<0.05$) in small CTVs. For the small tumor group, the near‐minimum and median D>Lthr$\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ (and D̂>Lthr$\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$) in the CTV were in average 9.3±1.5Gy$9.3\pm {1.5}\,{\rm Gy}$ (0.31 ± 0.08) and 13.6±1.6Gy$13.6\pm {1.6}\,{\rm Gy}$ (0.46 ± 0.06), respectively. For the large tumors, these parameters were 6.6±0.2Gy$6.6\pm {0.2}\,{\rm Gy}$ (0.20 ± 0.01) and 8.6±0.4Gy$8.6\pm {0.4}\,{\rm Gy}$ (0.28 ± 0.02). The difference between the two groups in terms of mean near‐minimum and median D>Lthr$\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ (D̂>Lthr$\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$) was 2.7 Gy (11%) and 5.0 Gy (18%), respectively. Conclusions: The feasibility of high‐LET‐dose based evaluation was shown in this study where a lower D>Lthr$\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ was found in cTPs with a large tumor size. Further investigation is needed to draw clinical conclusions. The proposed methodology in this work can be utilized for future high‐LET‐dose based studies. [ABSTRACT FROM AUTHOR]

Background: Ion beam therapy allows for a substantial sparing of normal tissues and higher biological efficacy. Synthetic single crystal diamond is a very good material to produce high‐spatial‐resolution and highly radiation hard detectors for both dosimetry and microdosimetry in ion beam therapy. Purpose: The aim of this work is the design, fabrication and test of an integrated waterproof detector based on synthetic single crystal diamond able to simultaneously perform dosimetric and microdosimetric characterization of clinical ion beams. Methods: The active elements of the integrated diamond device, that is, dosimeter and microdosimeter, were both realized in a Schottky diode configuration featured by different area, thickness, and shape by means of photolithography technologies for the selective growth of intrinsic and boron‐doped CVD diamond. The cross‐section of the sensitive volume of the dosimetric element is 4 mm2 and 1 μm‐thick, while the microdosimetric one has an active cross‐sectional area of 100 × 100 μm2 and a thickness of about 6.2 μm. The dosimetric and microdosimetric performance of the developed device was assessed at different depths in a water phantom at the MedAustron ion beam therapy facility using a monoenergetic uniformly scanned carbon ion beam of 284.7 MeV/u and proton beam of 148.7 MeV. The particle flux in the region of the microdosimeter was 6·107 cm2/s for both irradiation fields. At each depth, dose and dose distributions in lineal energy were measured simultaneously and the dose mean lineal energy values were then calculated. Monte Carlo simulations were also carried out by using the GATE‐Geant4 code to evaluate the relative dose, dose averaged linear energy transfer (LETd), and microdosimetric spectra at various depths in water for the radiation fields used, by considering the contribution from the secondary particles generated in the ion interaction processes as well. Results: Dosimetric and microdosimetric quantities were measured by the developed prototype with relatively low noise (∼2 keV/μm). A good agreement between the measured and simulated dose profiles was found, with discrepancies in the peak to plateau ratio of about 3% and 4% for proton and carbon ion beams respectively, showing a negligible LET dependence of the dosimetric element of the device. The microdosimetric spectra were validated with Monte Carlo simulations and a good agreement between the spectra shapes and positions was found. Dose mean lineal energy values were found to be in close agreement with those reported in the literature for clinical ion beams, showing a sharp increase along the Bragg curve, being also consistent with the calculated LETd for all depths within the experimental error of 10%. Conclusions: The experimental indicate that the proposed device can allow enhanced dosimetry in particle therapy centers, where the absorbed dose measurement is implemented by the microdosimetric characterization of the radiation field, thus providing complementary results. In addition, the proposed device allows for the reduction of the experimental uncertainties associated with detector positioning and could facilitate the partial overcoming of some drawbacks related to the low sensitivity of diamond microdosimeters to low LET radiation. [ABSTRACT FROM AUTHOR]

In vitro therapeutic efficacy studies are commonly conducted in cell monolayers. However, three-dimensional (3D) tumor spheroids are known to better represent in vivo tumors. This study used [177Lu]Lu-PSMA-I&T, an already clinically applied radiopharmaceutical for targeted radionuclide therapy against metastatic castrate-resistant prostate cancer, to demonstrate the differences in the radiobiological response between 2D and 3D cell culture models of the prostate cancer cell lines PC-3 (PSMA negative) and LNCaP (PSMA positive). After assessing the target expression in both models via Western Blot, cell viability, reproductive ability, and growth inhibition were assessed. To investigate the geometric effects on dosimetry for the 2D vs. 3D models, Monte Carlo simulations were performed. Our results showed that PSMA expression in LNCaP spheroids was highly preserved, and target specificity was shown in both models. In monolayers of LNCaP, no short-term (48 h after treatment), but only long-term (14 days after treatment) radiobiological effects were evident, showing decreased viability and reproductive ability with the increasing activity. Further, LNCaP spheroid growth was inhibited with the increasing activity. Overall, treatment efficacy was higher in LNCaP spheroids compared to monolayers, which can be explained by the difference in the resulting dose, among others. [ABSTRACT FROM AUTHOR]

Background: To evaluate a novel CBCT conversion algorithm for dose calculation implemented in a research version of a treatment planning system (TPS). Methods: The algorithm was implemented in a research version of RayStation (v. 11B-DTK, RaySearch, Stockholm, Sweden). CBCTs acquired for each ten head and neck (HN), gynecology (GYN) and lung cancer (LNG) patients were collected and converted using the new algorithm (CBCTc). A bulk density overriding technique implemented in the same version of the TPS was used for comparison (CBCTb). A deformed CT (dCT) was created by using deformable image registration of the planning CT (pCT) to the CBCT to reduce anatomical changes. All treatment plans were recalculated on the pCT, dCT, CBCTc and the CBCTb. The resulting dose distributions were analyzed using the MICE toolkit (NONPIMedical AB Sweden, Umeå) with local gamma analysis, with 1% dose difference and 1 mm distance to agreement criteria. A Wilcoxon paired rank sum test was applied to test the differences in gamma pass rates (GPRs). A p value smaller than 0.05 considered statistically significant. Results: The GPRs for the CBCTb method were systematically lower compared to the CBCTc method. Using the 10% dose threshold and the dCT as reference the median GPRs were for the CBCTc method were 100% and 99.8% for the HN and GYN cases, respectively. Compared to that the GPRs of the CBCTb method were lower with values of 99.8% and 98.0%, for the HN and GYN cases, respectively. The GPRs of the LNG cases were 99.9% and 97.5% for the CBCTc and CBCTb method, respectively. These differences were statistically significant. The main differences between the dose calculated on the CBCTs and the pCTs were found in regions near air/tissue interfaces, which are also subject to anatomical variations. Conclusion: The dose distribution calculated using the new CBCTc method showed excellent agreement with the dose calculated using dCT and pCT and was superior to the CBCTb method. The main reasons for deviations of the calculated dose distribution were caused by anatomical variations between the pCT and the corrected CBCT. [ABSTRACT FROM AUTHOR]

Background: Combining carbon ion therapy with on‐bed MR imaging has the potential to bring particle therapy to a new level of precision. However, the introduction of magnetic fields brings challenges for dosimetry and quality assurance. For protons, a small, but significant change in detector response was shown in the presence of magnetic fields previously. For carbon ion beams, so far no such experiments have been performed. Purpose: To investigate the influence of external magnetic fields on the response of air‐filled ionization chambers. Methods: Four commercially available ionization chambers, three thimble type (Farmer, Semiflex, and PinPoint), and a plane parallel (Bragg peak) detector were investigated. Detectors were aligned in water such that their effective point of measurement was located at 2 cm depth. Irradiations were performed using 10×10cm2$10\times 10\nobreakspace \mathrm{cm}^2$ square fields for carbon ions of 186.1, 272.5, and 402.8 MeV/u employing magnetic field strengths of 0, 0.25, 0.5, and 1 T. In addition, the detector response for protons and carbon ions was compared taking into account the secondary electron spectra and employing protons of 252.7 MeV for comparison. Results: For all four detectors, a statistically significant change in detector response, dependent on the magnetic field strength, was found. The effect was more pronounced for higher energies. The highest effects were found at 0.5 T for the PinPoint detector with a change in detector response of 1.1%. The response of different detector types appeared to be related to the cavity diameter. For proton and carbon ion irradiation with similar secondary electron spectra, the change in detector response was larger for carbon ions compared to protons. Conclusion: A small, but significant dependence of the detector response was found for carbon ion irradiation in a magnetic field. The effect was found to be larger for smaller cavity diameters and at medium magnetic field strengths. Changes in detector response were more pronounced for carbon ions compared to protons. [ABSTRACT FROM AUTHOR]

The aim of this work is to present the first microdosimetric spectra measured with a miniaturised tissue-equivalent proportional counter in the clinical environment of the MedAustron ion-beam therapy facility. These spectra were gathered with a 62.4-MeV proton beam and have been compared with microdosimetric spectra measured in the 62-MeV clinical proton beam of the CATANA beam line. Monte Carlo simulations were performed using the Geant4 toolkit GATE and a fully commissioned clinical beam line model. Finally, similarities and discrepancies of the measured data to simulations based on a simple and complex detector geometry are discussed. [ABSTRACT FROM AUTHOR]

Particle therapy (PT) that utilizes protons and carbon ions offers a promising way to reduce the side effects of radiation oncology, especially in pediatric patients. To investigate the influence of PT on growing bone, we exposed an organotypic rat ex vivo femur culture model to PT. After irradiation, histological staining, immunohistochemical staining, and gene expression analysis were conducted following 1 or 14 days of in vitro culture (DIV). Our data indicated a significant loss of proliferating chondrocytes at 1 DIV, which was followed by regeneration attempts through chondrocytic cluster formation at 14 DIV. Accelerated levels of mineralization were observed, which correlated with increased proteoglycan production and secretion into the pericellular matrix. Col2α1 expression, which increased during the cultivation period, was significantly inhibited by PT. Additionally, the decrease in ColX expression over time was more pronounced compared to the non-IR control. The chondrogenic markers BMP2, RUNX2, OPG, and the osteogenic marker ALPL, showed a significant reduction in the increase in expression after 14 DIV due to PT treatment. It was noted that carbon ions had a stronger influence than protons. Our bone model demonstrated the occurrence of pathological and regenerative processes induced by PT, thus building on the current understanding of the biological mechanisms of bone. [ABSTRACT FROM AUTHOR]

PURPOSE: To demonstrate how the efficiency of the treatment planning processes of a university radiation oncology department (2,500 new patients/year) could be improved by constructing and implementing a workflow-monitoring application. METHODS: A web-based application was developed in house, which enhanced the process management tools of the clinic's oncology information system. The application calculates the days left for the next task in the treatment planning process and visualizes the information on a browser-based whiteboard. Workflow monitoring considers tumor types (breast, prostate, lung, etc) and treatment techniques and is backward planned from the planned start of treatment. The effect of introducing this application was analyzed over four phases: (1) baseline data without the workflow-monitoring application, (2) after introducing workflow visualization via a browser-based whiteboard, (3) after upgrading the whiteboard and introducing backend rules, and (4) after updating these rules on the basis of data from the previous phase. RESULTS: Implementing the workflow-monitoring application and the introduced measures significantly reduced delays and, consequently, stress and a negative working atmosphere in the treatment planning process. Most notably, the amount of last-minute physics checks (on the day of the treatment start) could be reduced by 50%. CONCLUSION: The study showed what measures can help organize and prioritize the treatment planning workflow. The increased efficiency is believed to improve the quality and reduce the risk of human error. Deep learning predicts response to chemotherapy in GEJ patients using HE-stained tissue samples. [ABSTRACT FROM AUTHOR]

Background: Deep learning‐based auto‐planning is an active research field; however, for some tasks a treatment planning system (TPS) is still required. Purpose: To introduce a deep learning‐based model generating deliverable DICOM RT treatment plans that can be directly irradiated by a linear accelerator (LINAC). The model was based on an encoder‐decoder network and can predict multileaf collimator (MLC) motion sequences for prostate VMAT radiotherapy. Methods: A total of 619 treatment plans from 460 patients treated for prostate cancer with single‐arc VMAT were included in this study. An encoder‐decoder network was trained using 465 clinical treatment plans and validated on 77 plans. The performance was analyzed on a separate test set of 77 treatment plans. Separate L1 losses were computed for the leaf and jaw positions as well as the monitor units, with the leaf loss being weighted by a factor of 100 before being added to the other losses. The generated treatment plans were recalculated in a treatment planning system and the dose‐volume metrics and gamma passing rates were compared to the original dose. Results: All generated treatment plans showed good agreement with the original data, with an average gamma passing rate (3%/3 mm) of 91.9 ± 7.1%. However, the coverage of the PTVs. was slightly lower for the generated plans (D98% = 92.9 ± 2.6%) in comparison to the original plans (D98% = 95.7 ± 2.2%). There was no significant difference in mean dose to the bladder between the predicted and original plan (Dmean of 28.0 ± 13.5 vs. 28.1 ± 13.3% of prescribed dose) or rectum (Dmean of 42.3 ± 7.4 vs. 42.6 ± 7.5%). The maximum dose to bladder was only slightly higher in the predicted plans (D2% of 100.7 ± 5.3 vs. 99.8 ± 4.0%) and for the rectum it was even lower (D2% of 100.5 ± 3.7 vs. 100.1 ± 4.3). Conclusions: The deep learning‐based model could predict MLC motion sequences in prostate VMAT plans, eliminating the need for sequencing inside a TPS, thus revolutionizing autonomous treatment planning workflows. This research completes the loop in deep learning‐based treatment planning processes, enabling more efficient workflows for real‐time or online adaptive radiotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The study retrospectively analysed the clinical proton treatment strategy for pancreas patients with small moving tumours. Seventeen hypofractionated proton treatment plans were analysed based on 4D dose calculations, which gives insight into the interplay of beam and organ motion. The results showed that the synchrotron-based dose delivery employing horizontal and vertical beams and robust optimisation was robust against intra-fractional movements up to 3.7 mm. However, outliers were observed in some patients, indicating the need for continuous monitoring during clinical practice to identify patient cases with more significant deviations. The research serves as a basis for future treatment strategies for patients with larger motion amplitudes and the transition towards carbon ion treatments. Motion compensation strategies in particle therapy depend on the anatomy, motion amplitude and underlying beam delivery technology. This retrospective study on pancreas patients with small moving tumours analysed existing treatment concepts and serves as a basis for future treatment strategies for patients with larger motion amplitudes as well as the transition towards carbon ion treatments. The dose distributions of 17 hypofractionated proton treatment plans were analysed using 4D dose tracking (4DDT). The recalculation of clinical treatment plans employing robust optimisation for mitigating different organ fillings was performed on phased-based 4D computed tomography (4DCT) data considering the accelerator (pulsed scanned pencil beams delivered by a synchrotron) and the breathing-time structure. The analysis confirmed the robustness of the included treatment plans concerning the interplay of beam and organ motion. The median deterioration of D50% (ΔD50%) for the clinical target volume (CTV) and the planning target volume (PTV) was below 2%, while the only outlier was observed for ΔD98% with −35.1%. The average gamma pass rate over all treatment plans (2%/ 2 mm) was 88.8% ± 8.3, while treatment plans for motion amplitudes larger than 1 mm performed worse. For organs at risk (OARs), the median ΔD2% was below 3%, but for single patients, essential changes, e.g., up to 160% for the stomach were observed. The hypofractionated proton treatment for pancreas patients based on robust treatment plan optimisation and 2 to 4 horizontal and vertical beams showed to be robust against intra-fractional movements up to 3.7 mm. It could be demonstrated that the patient's orientation did not influence the motion sensitivity. The identified outliers showed the need for continuous 4DDT calculations in clinical practice to identify patient cases with more significant deviations. [ABSTRACT FROM AUTHOR]

Background: The increasing number of studies dealing with linear energy transfer (LET)-based evaluation and optimization in the field of carbon ion radiotherapy (CIRT) indicates the rising demand for LET implementation in commercial treatment planning systems (TPS). Benchmarking studies could play a key role in detecting (and thus preventing) computation errors prior implementing such functionalities in a TPS. Purpose: This in silico study was conducted to benchmark the following two LET-related functionalities in a commercial TPS against Monte Carlo simulations: (1) dose averaged LET (LETd) scoring and (2) physical dose filtration based on LET for future LET-based treatment plan evaluation and optimization studies. Methods: The LETd scoring and LET-based dose filtering (in which the deposited dose can be separated into the dose below and above the user specified LET threshold) functionalities for carbon ions in the research version RayStation (RS) 9A-IonPG TPS (RaySearch Laboratories, Sweden) were benchmarked against GATE/Geant4 simulations. Pristine Bragg peaks (BPs) and cuboid targets, positioned at different depths in a homogeneous water phantom and a setup with heterogeneity were used for this study. Results: For all setups (homogeneous and heterogeneous), the mean absolute (and relative) LETd difference was less than 1 keV/μm (3.5%) in the plateau and target and less than 2 keV/μm (8.3%) in the fragmentation tail. The maximum local differences were 4 and 6 keV/μm, respectively. The mean absolute (and relative) physical dose differences for both low- and high-LET doses were less than 1 cGy (1.5%) in the plateau, target and tail with a maximum absolute difference of 2 cGy. Conclusions: No computation error was found in the tested functionalities except for LETd in lateral direction outside the target, showing the limitation of the implemented monochrome model in the tested TPS version. [ABSTRACT FROM AUTHOR]

To overcome the resistance to radiotherapy in chondrosarcomas, the prevention of efficient DNA repair with an additional treatment was explored for particle beams as well as reference X-ray irradiation. The combined treatment with DNA repair inhibitors—with a focus on ATRi VE-821—and proton or carbon ions irradiation was investigated regarding cell viability, proliferation, cell cycle distribution, MAPK phosphorylation, and the expression of key DNA repair genes in two human chondrosarcoma cell lines. Pre-treatment with the PARPis Olaparib or Veliparib, the ATMi Ku-55933, and the ATRi VE-821 resulted in a dose-dependent reduction in viability, whereas VE-821 has the most efficient response. Quantification of γH2AX phosphorylation and protein expression of the DNA repair pathways showed a reduced regenerative capacity after irradiation. Furthermore, combined treatment with VE-821 and particle irradiation increased MAPK phosphorylation and the expression of apoptosis markers. At the gene expression and at the protein expression/phosphorylation level, we were able to demonstrate the preservation of DNA damage after combined treatment. The present data showed that the combined treatment with ATMi VE-821 increases the radiosensitivity of human chondrosarcoma cells in vitro and significantly suppresses efficient DNA repair mechanisms, thus improving the efficiency of radiotherapy. [ABSTRACT FROM AUTHOR]

Radiation therapy is one of the most effective tools in cancer therapy. However, success varies individually, necessitating improved understanding of radiobiology. Three-dimensional (3D) tumor spheroids are increasingly gaining attention, being a superior in vitro cancer model compared to 2D cell cultures. This in vitro study aimed at comparing radiation responses in 2D and 3D cell culture models of different human cancer cell lines (PC-3, LNCaP and T-47D) irradiated with varying doses (1, 2, 4, 6, 8 or 20 Gy) of X-ray beams. Radiation response was analyzed by growth analysis, various cell viability assays (e.g., clonogenic assay, resazurin assay) and amount of DNA damage (γH2AX Western Blot). Results showed decreasing cell proliferation with the increase of radiation doses for all cell lines in monolayers and spheroids of LNCaP and T-47D. However, significantly lower radiosensitivity was detected in spheroids, most pronounced in PC-3, evincing radiation resistance of PC-3 spheroids up to 8 Gy and significant growth inhibition only by a dose escalation of 20 Gy. Cell line comparison showed highest radiosensitivity in LNCaP, followed by T-47D and PC-3 in 2D, whereas, in 3D, T-47D showed highest sensitivity. The results substantiate the significant differences in radiobiological response to X-rays between 2D and 3D cell culture models. [ABSTRACT FROM AUTHOR]

Background: Radiation therapy is continuously moving towards more precise dose delivery. The combination of online MR imaging and particle therapy, for example, radiation therapy using protons or carbon ions, could enable the next level of precision in radiotherapy. In particle therapy, research towards a combination of MR and particle therapy is well underway, but still far from clinical systems. The combination of high magnetic fields with particle therapy delivery poses several challenges for treatment planning, treatment workflow, dose delivery, and dosimetry. Purpose: To present a workflow for commissioning of a light ion beam line with an integrated dipole magnet to perform MR-guided particle therapy (MRgPT) research, producing not only basic beam data but also magnetic field maps for accurate dose calculation. Accurate dose calculation in magnetic field environments requires high-quality magnetic field maps to compensate for magnetic-field-dependent trajectory changes and dose perturbations. Methods: The research beam line at MedAustron was coupled with a resistive dipole magnet positioned at the isocenter. Beam data were measured for proton and carbon ions with and without an applied magnetic field of 1 T. Laterally integrated depth-dose curves (IDC) as well as beam profiles were measured in water while beam trajectories were measured in air. Based on manufacturer data, an in silico model of the magnet was created, allowing to extract highquality 3D magnetic field data. An existing GATE/Geant4 Monte Carlo (MC) model of the beam line was extended with the generated magnetic field data and benchmarked against experimental data. Results: A 3D magnetic field volume covering fringe fields until 50 mT was found to be sufficient for an accurate beam trajectory modeling. The effect on particle range retraction was found to be 2.3 and 0.3 mm for protons and carbon ions, respectively. Measured lateral beam offsets in water agreed within 0.4 and -0.5 mm with MC simulations for protons and carbon ions, respectively. Experimentally determined in-air beam trajectories agreed within 0.4 mm in the homogeneous magnetic field area. Conclusion: The presented approach based on in silico modeling and measurements allows to commission a beam line for MRgPT while providing benchmarking data for the magnetic field modeling, required for state-of -the art dose calculation methods. [ABSTRACT FROM AUTHOR]

Chondrosarcomas are particularly difficult to treat due to their resistance to chemotherapy and radiotherapy. However, particle therapy can enhance local control and patient survival rates. To improve our understanding of the basic cellular radiation response, as a function of dose and linear energy transfer (LET), we developed a novel water phantom-based setup for cell culture experiments and characterized it dosimetrically. In a direct comparison, human chondrosarcoma cell lines were analyzed with regard to their viability, cell proliferation, cell cycle, and DNA repair behavior after irradiation with X-ray, proton, and carbon ions. Our results clearly showed that cell viability and proliferation were inhibited according to the increasing ionization density, i.e., LET, of the irradiation modes. Furthermore, a prominent G2/M arrest was shown. Gene expression profiling proved the upregulation of the senescence genes CDKN1A (p21), CDKN2A (p16NK4a), BMI1, and FOXO4 after particle irradiation. Both proton or C-ion irradiation caused a positive regulation of the repair genes ATM, NBN, ATXR, and XPC, and a highly significant increase in XRCC1/2/3, ERCC1, XPC, and PCNA expression, with C-ions appearing to activate DNA repair mechanisms more effectively. The link between the physical data and the cellular responses is an important contribution to the improvement of the treatment system. [ABSTRACT FROM AUTHOR]

Purpose: Radiochromic films are versatile 2D dosimeters with high‐resolution and near tissue equivalence. To assure high precision and accuracy, a time‐consuming calibration process is required. To improve the time efficiency, a novel calibration method utilizing the ratio of the same dose profile measured at different monitor units (MUs) is introduced and tested in a proton and photon beam. Methods: The calibration procedure employs the dose ratio of film measurements of the same relative profile for different absolute dose values. Hence, the ratio of the dose is constant at any point of the profile, but the ratio of the net optical densities is not constant. The key idea of the method is to optimize the calibration function until the ratio of the calculated doses is constant. The proposed method was tested in the dose range between 0.25–12 and 1–6 Gy in a proton and photon beam, respectively. A radial symmetric profile and a rectangular profile were created, both having a central plateau region of about 3 cm diameter and a dose falloff of about 1.5 cm at larger distances. The dose falloff region was used as input for the optimization method and the central plateau region served as dose reference points. Only the plateau region of the highest dose entered the optimization as an additional objective. The measured data were randomly split into differently sized training and test sets. The optimization was repeated 1000 times with random start value initialization using the same start values for the standard and the gradient method. Finally, a proton plan with four dose levels was created, which were separated spatially, to test the possibility of a full calibration within a single measurement. Results: Parameter estimation was possible with as low as one dose ratio used for optimization in both the photon and the proton case, yet exhibiting a high sensitivity on the dose level. The root mean squared deviation (RMSD) of the dose was less than 1% when the dose ratio was in the order of 20, whereas the median RMSD of all optimizations was 1.7%. Using four dose levels for optimization resulted in a median RMSD of 1% when randomly selecting the dose levels. Having at least one dose ratio of about 20 included in the optimization considerably improved the RMSD of the calibration function. Using six or eight dose levels reduced the sensitivity on the dose level selection and the median RMSD was 0.8%. A full calibration was possible in a single measurement having four dose levels in one plan but spatially separated. Conclusions: The number of measurements required to obtain an EBT3 film calibration function could be reduced using the proposed dose ratio method while maintaining the same accuracy as with the standard method. [ABSTRACT FROM AUTHOR]

Background: Real‐time tumor motion monitoring (TMM) is a crucial process for intra‐fractional respiration management in lung cancer radiotherapy. Since the tumor can be partly or fully located behind the ribs, the TMM is challenging. Purpose: The aim of this work was to develop a bone suppression (BS) algorithm designed for real‐time 2D/3D marker‐less TMM to increase the visibility of the tumor when overlapping with bony structures and consequently to improve the accuracy of TMM. Method: A BS method was implemented in the in‐house developed software for ultrafast intensity‐based 2D/3D tumor registration (Fast Image‐based Registration [FIRE]). The method operates on both, digitally reconstructed radiograph (DRR) and intra‐fractional X‐ray images. The bony structures are derived from computed tomography data by thresholding during ray‐casting, and the resulting bone DRR is subtracted from intra‐fractional X‐ray images to obtain a soft‐tissue‐only image for subsequent tumor registration. The accuracy of TMM utilizing BS was evaluated within a retrospective phantom study with nine different 3D‐printed tumor phantoms placed in the in‐house developed Advanced Radiation DOSimetry (ARDOS) breathing phantom. A 24 mm craniocaudal tumor motion, including rib eclipses, was simulated, and X‐ray images were acquired on the Elekta Versa HD Linac in the lateral and posterior–anterior directions. An error assessment for BS images was evaluated with respect to the ground truth tumor position. Results: A total error (root mean square error) of 0.87 ± 0.23 mm and 1.03 ± 0.26 mm was found for posterior–anterior and lateral imaging; the mean time for BS was 8.03 ± 1.54 ms. Without utilizing BS, TMM failed in all X‐ray images since the registration algorithm focused on the rib position due to the predominant intensity of this tissue within DRR and X‐ray images. Conclusion: The BS algorithm developed and implemented improved the accuracy, robustness, and stability of real‐time TMM in lung cancer in a phantom study, even in the case of rib interlude where normal tumor registration fails. [ABSTRACT FROM AUTHOR]

Purpose: The Local Effect Model version one (LEM I) is applied clinically across Europe to quantify the relative biological effectiveness (RBE) of carbon ion beams. It requires the full particle fluence spectrum differential in energy in each voxel as input parameter. Treatment planning systems (TPSs) use beamline‐specific look‐up tables generated with Monte Carlo (MC) codes. In this study, the changes in RBE weighted dose were quantified using different levels of details in the simulation or different MC codes. Methods: The particle fluence differential in energy was simulated with FLUKA and Geant4 at 500 depths in water in 1‐mm steps for 58 initial carbon ion energies (between 120.0 and 402.8 MeV/u). A dedicated beam model was applied, including the full description of the Nozzle using GATE‐RTionV1.0 (Geant4.10.03p03). In addition, two tables generated with FLUKA were compared. The starting points of the FLUKA simulations were phase space (PhS) files from, firstly, the Geant4 nozzle simulations, and secondly, a clinical beam model where an analytic approach was used to mimic the beamline. Treatment plans (TPs) were generated with RayStation 8B (RaySearch Laboratories AB, Sweden) for cubic targets in water and 10 clinical patient cases using the clinical beam model. Subsequently, the RBE weighted dose was re‐computed using the two other fluence tables (FLUKA PhS or Geant4). Results: The fluence spectra of the primary and secondary particles simulated with Geant4 and FLUKA generally agreed well for the primary particles. Differences were mainly observed for the secondary particles. Interchanging the two energy spectra (FLUKA vs. GEANT4) to calculate the RBE weighted dose distributions resulted in average deviations of less than 1% in the entrance up to the end of the target region, with a maximum local deviation at the distal edge of the target. In the fragment tail, larger discrepancies of up to 5% on average were found for deep‐seated targets. The patient and water phantom cases demonstrated similar results. Conclusion: RBE weighted doses agreed well within all tested setups, confirming the clinical beam model provided by the TPS vendor. Furthermore, the results showed that the open source and generally available MC code Geant4 (in particular using GATE or GATE‐RTion) can also be used to generate basic beam data required for RBE calculation in carbon ion therapy. [ABSTRACT FROM AUTHOR]

Objective: Hypersensitivity towards proton versus photon irradiation was demonstrated in homologous recombination repair (HRR)-deficient cell lines. Hence, combined treatment concepts targeting HRR provide a rational for potential pharmaceutical exploitation. The HSP90 inhibitor ganetespib (STA-9090) downregulates a multitude of HRR-associated proteins and sensitizes for certain chemotherapeutics. Thus, the radiosensitizing effect of HSP90-inhibiting ganetespib was investigated for reference photon irradiation and proton irradiation at a proximal and distal position in a spread-out Bragg peak (SOBP).Methods: A549 and FaDu cells were treated with low-dose (2 nM resp. 1 nM) ganetespib and irradiated with 200 kV photons. Proton irradiation was performed at a proximal and a distal position within a SOBP, with corresponding dose-averaged linear-energy transfer (LETD) values of 2.1 and 4.5 keV/µm, respectively. Cellular survival data was fitted to the linear-quadratic model to calculate relative biological effectiveness (RBE) and the dose-modifying factor (DMF). Additionally, A549 cells were treated with increasing doses of ganetespib and investigated by flow cytometry, immunoblotting, and immunofluorescence microscopy to investigate cell cycle distribution, Rad51 protein levels, and γH2AX foci, respectively.Results: Low-dosed ganetespib significantly sensitized both cancer cell lines exclusively for proton irradiation at both investigated LETD, resulting in increased RBE values of 10-40%. In comparison to photon irradiation, the fraction of cells in S/G2/M phase was elevated in response to proton irradiation with 10 nM ganetespib consistently reducing this population. No changes in cell cycle distribution were detected in unirradiated cells by ganetespib alone. Protein levels of Rad51 are downregulated in irradiated A549 cells by 10 nM and also 2 nM ganetespib within 24 h. Immunofluorescence staining demonstrated similar induction and removal of γH2AX foci, irrespective of irradiation type or ganetespib administration.Conclusion: Our findings illustrate a proton-specific sensitizing effect of low-dosed ganetespib in both employed cell lines and at both investigated SOBP positions. We provide additional experimental data on cellular response and a rational for future combinatorial approaches with proton radiotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The interplay of breathing and beam motion reduces the efficacy of particle irradiation in moving tumours. The effect of motion on protons and carbon ion treatments was investigated dosimetrically and the results were benchmarked against each other by employing an anthropomorphic thorax phantom that was able to simulate tumour, rib, and lung motion. The critical question was whether target coverage and organ-at-risk sparing could be maintained when the application of simple motion mitigation was addressed. Special focus was put on unique synchrotron characteristics, such as pulsed beam delivery and beam intensity variations. It could be demonstrated that the effect of motion was greater for carbon ions than for protons. These findings demonstrated the need for applying motion mitigation techniques depending on the motion amplitude, particle type, and treatment prescription considering complex time correlations. Motion amplitudes, in need of mitigation for moving targets irradiated with pulsed carbon ions and protons, were identified to guide the decision on treatment and motion mitigation strategy. Measurements with PinPoint ionisation chambers positioned in an anthropomorphic breathing phantom were acquired to investigate different tumour motion scenarios, including rib and lung movements. The effect of beam delivery dynamics and spot characteristics was considered. The dose in the tumour centre was deteriorated up to 10% for carbon ions but only up to 5% for protons. Dose deviations in the penumbra increased by a factor of two when comparing carbon ions to protons, ranging from 2 to 30% for an increasing motion amplitude that was strongly dependent on the beam intensity. Layer rescanning was able to diminish the dose distortion caused by tumour motion, but an increase in spot size could reduce it even further to 5% within the target and 10% at the penumbra. An increased need for motion mitigation of carbon ions compared to protons was identified to assure target coverage and sparing of adjacent organs at risk in the penumbra region and outside the target. For the clinical implementation of moving target treatments at a synchrotron-based particle facility complex, time dependencies needed to be considered. [ABSTRACT FROM AUTHOR]

Purpose: The accurate knowledge of the effective point of measurement (Peff) is particularly important for measurements in proximity to high dose gradients such as in the distal fall‐off of particle beams. For plane‐parallel ionization chambers (ICs), Peff is well known and located at the center of the inner surface of the entrance window. For cylindrical ICs, Peff is shifted from the chamber's center toward the beam source. According to IAEA TRS‐398, this shift can be calculated as 0.75·rcyl for light ions with rcyl being the radius of the cavity. For proton beams and in absence of a dose gradient, no shift is recommended. We have experimentally determined Peff for the 0.125 cc Semiflex IC in both proton and carbon ion beams. Methods: The first method consisted of simultaneous irradiation of a plane‐parallel IC and the Semiflex in a 4‐cm wide spread‐out Bragg peak. In the second method, a single‐energy beam was used, and both ICs were positioned successively at the same measurement depths. For both approaches, the shift of the distal edge of the depth ionization distributions recorded by the two chambers at different reference points was used to calculate Peff of the Semiflex. Both methods were applied in carbon ion beams, and only the latter was applied in proton beams. Results: Both methods yielded a similar Peff for carbon ions, 0.88·rcyl, and 0.84·rcyl, which results in a difference of only 0.1 mm. The difference to the recommended value of 0.75·rcyl is 0.4 and 0.3 mm, respectively, which is larger than the positioning uncertainty. In the proton beam, a Peff of 0.92·rcyl was obtained. Conclusions: The Peff for the 0.125 cc Semiflex IC is shifted further from the cavity center as recommended by IAEA TRS‐398 for light ions, with the shift for proton beams being even larger than for carbon ion beams. [ABSTRACT FROM AUTHOR]

Although particle therapy with protons has proven to be beneficial in the treatment of chondrosarcoma compared to photon-based (X-ray) radiation therapy, the cellular and molecular mechanisms have not yet been sufficiently investigated. Cell viability and colony forming ability were analyzed after X-ray and proton irradiation (IR). Cell cycle was analyzed using flow cytometry and corresponding regulator genes and key players of the DNA repair mechanisms were measured using next generation sequencing, protein expression and immunofluorescence staining. Changes in metabolic phenotypes were determined with nuclear magnetic resonance spectroscopy. Both X-ray and proton IR resulted in reduced cell survival and a G2/M phase arrest of the cell cycle. Especially 1 h after IR, a significant dose-dependent increase of phosphorylated γH2AX foci was observed. This was accompanied with a reprogramming in cellular metabolism. Interestingly, within 24 h the majority of clearly visible DNA damages were repaired and the metabolic phenotype restored. Involved DNA repair mechanisms are, besides the homology directed repair (HDR) and the non-homologous end-joining (NHEJ), especially the mismatch mediated repair (MMR) pathway with the key players EXO1, MSH3, and PCNA. Chondrosarcoma cells regenerates the majority of DNA damages within 24 h. These molecular mechanisms represent an important basis for an improved therapy. [ABSTRACT FROM AUTHOR]

Purpose: This work presents the validation of an analytical pencil beam dose calculation algorithm in a commercial treatment planning system (TPS) for carbon ions by measurements of dose distributions in heterogeneous phantom geometries. Additionally, a comparison study of carbon ions versus protons is performed considering current best solutions in commercial TPS. Methods: All treatment plans were optimized and calculated using the RayStation TPS (RaySearch, Sweden). The dose distributions calculated with the TPS were compared with measurements using a 24‐pinpoint ionization chamber array (T31015, PTW, Germany). Tissue‐like inhomogeneities (bone, lung, and soft tissue) were embedded in water, while a target volume of 4 x 4 x 4 cm3 was defined at two different depths behind the heterogeneities. In total, 10 different test cases, with and without range shifter as well as different air gaps, were investigated. Dose distributions inside as well as behind the target volume were evaluated. Results: Inside the target volume, the mean dose difference between calculations and measurements, averaged over all test cases, was 1.6% for carbon ions. This compares well to the final agreement of 1.5% obtained in water at the commissioning stage of the TPS for carbon ions and is also within the clinically acceptable interval of 3%. The mean dose difference and maximal dose difference obtained outside the target area were 1.8% and 13.4%, respectively. The agreement of dose distributions for carbon ions in the target volumes was comparable or better to that between Monte Carlo (MC) dose calculations and measurements for protons. Percentage dose differences of more than 10% were present outside the target area behind bone–lung structures, where the carbon ion calculations systematically over predicted the dose. MC dose calculations for protons were superior to carbon ion beams outside the target volumes. Conclusion: The pencil beam dose calculations for carbon ions in RayStation were found to be in good agreement with dosimetric measurements in heterogeneous geometries for points of interest located within the target. Large local discrepancies behind the target may contribute to incorrect dose predictions for organs at risk. [ABSTRACT FROM AUTHOR]

Independent verification of the dose per monitor unit (MU) to deliver the prescribed dose to a patient has been a mainstay of radiation oncology quality assurance (QA). We discuss the role of secondary dose/MU calculation programs as part of a comprehensive QA program. This report provides guidelines on calculation‐based dose/MU verification for intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) provided by various modalities. We provide a review of various algorithms for "independent/second check" of monitor unit calculations for IMRT/VMAT. The report makes recommendations on the clinical implementation of secondary dose/MU calculation programs; on commissioning and acceptance of various commercially available secondary dose/MU calculation programs; on benchmark QA and periodic QA; and on clinically reasonable action levels for agreement of secondary dose/MU calculation programs. [ABSTRACT FROM AUTHOR]

Purpose: To present the technical details of the runner‐up model in the open knowledge‐based planning (OpenKBP) challenge for the dose–volume histogram (DVH) stream. The model was designed to ensure simple and reproducible training, without the necessity of costly advanced generative adversarial network (GAN) techniques. Methods: The model was developed based on the OpenKBP challenge dataset, consisting of 200 and 40 head‐and‐neck patients for training and validation, respectively. The final model is a U‐Net with additional ResNet blocks between up‐ and down convolutions. The results were obtained by training the model with AdamW with the One Cycle scheduler. The loss function is a combination of the L1 loss with a feature loss, which uses a pretrained video classifier as a feature extractor. The performance was evaluated on another 100 patients in the OpenKBP test dataset. The DVH metrics of the test data were evaluated, where D0.1cc, and Dmean were calculated for the organs at risk (OARs) and D1%, D95%, and D99% were computed for the target structures. DVH metric differences between predicted and true dose are reported in percentage. Results: The model achieved 2nd and 4th place in the DVH and dose stream of the OpenKBP challenge, respectively. The dose and DVH score were 2.62 ± 1.10 and 1.52 ± 1.06, respectively. Mean dose differences for the different structures and DVH parameters were within ±1%. Conclusion: This straightforward approach produced excellent results. It incorporated One Cycle Learning, ResNet, and feature‐based losses, which are common computer vision techniques. [ABSTRACT FROM AUTHOR]

Purpose: In the past years, many different neural network‐based conversion techniques for synthesizing computed tomographys (sCTs) from MR images have been published. While the model's performance can be checked during the training against the test set, test datasets can never represent the whole population. Conversion errors can still occur for special cases, for example, for unusual anatomical situations. Therefore, the performance of sCT conversion needs to be verified on a patient specific level, especially in the absence of a planning CT (pCT). In this study, the capability of cone‐beam CTs (CBCTs) for the validation of sCTs generated by a neural network was investigated. Methods: 41 patients with tumors in the head region were selected. 20 of them were used for model training and 10 for validation. Different implementations of CycleGAN (with/without identity and feature loss) were used to generate sCTs. The pixel (MAE, RMSE, PSNR) and geometric error (DICE, Sensitivity, Specificity) values were reported to identify the best model. VMAT plans were created for the remaining 11 patients on the pCTs. These plans were re‐calculated on sCTs and CBCTs. An automatic density overriding method (CBCTRS) and a population‐based dose calculation method (CBCTPop) were employed for CBCT‐based dose calculation. The dose distributions were analysed using 3D global gamma analysis, applying a threshold of 10% with respect to the prescribed dose. Differences in DVH metrics for the PTV and the organs‐at‐risk were compared among the dose distributions based on pCTs, sCTs, and CBCTs. Results: The best model was the CycleGAN without identity and feature matching loss. Including the identity loss led to a metric decrease of 10% for DICE and a metric increase of 20–60 HU for MAE. Using the 2%/2 mm gamma criterion and pCT as reference, the mean gamma pass rates were 99.0 ± 0.4% for sCTs. Mean gamma pass rate values comparing pCT and CBCT were 99.0 ± 0.8% and 99.1 ± 0.8% for the CBCTRS and CBCTPop, respectively. The mean gamma pass rates comparing sCT and CBCT resulted in 98.4 ± 1.6% and 99.2 ± 0.6% for CBCTRS and CBCTPop, respectively. The differences between the gamma‐pass‐rates of the sCT and two CBCT‐based methods were not significant. The majority of deviations of the investigated DVH metrices between sCTs and CBCTs were within 2%. Conclusion: The dosimetric results demonstrate good agreement between sCT, CBCT, and pCT based calculations. A properly applied CBCT conversion method can serve as a tool for quality assurance procedures in an MR only radiotherapy workflow for head patients. Dosimetric deviations of DVH metrics between sCT and CBCTs of larger than 2% should be followed up. A systematic shift of approximately 1% should be taken into account when using the CBCTRS approach in an MR only workflow. [ABSTRACT FROM AUTHOR]

Purpose: Predicting morbidity for patients with locally advanced cervix cancer after external beam radiotherapy (EBRT) based on dose-volume parameters remains an unresolved issue in definitive radiochemotherapy. The aim of this prospective study was to correlate patient characteristics and dose-volume parameters to various early morbidity endpoints for different EBRT techniques, including volumetric modulated arc therapy (VMAT) and adaptive radiotherapy (ART).Methods and Materials: The study population consisted of 48 patients diagnosed with locally advanced cervix cancer, treated with definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT). Multiple questionnaires (CTCAE 4.03, QLQ-C30 and EORTC QLQ-CX24) were assessed prospectively for patients treated with different EBRT techniques, including online adaptive VMAT. Contouring and treatment planning was based on the EMBRACE protocols. Acute toxicity, classified as general, gastrointestinal (GI) or genitourinary (GU) and their corresponding dose-volume histograms (DVHs) were first correlated by applying least absolute shrinkage and selection operator (LASSO) and subsequently evaluated by multiple logistic binomial regression.Results: The treated EBRT volumes varied for the different techniques with ~2500 cm3 for 3D conformal radiotherapy (3D-CRT), ~2000 cm3 for EMBRACE‑I VMAT, and ~1800 cm3 for EMBRACE-II VMAT and ART. In general, a worsening of symptoms during the first 5 treatment weeks and recovery afterwards was observed. Dose-volume parameters significantly correlating with stool urgency, rectal and urinary incontinence were as follows: bowel V40Gy < 250 cm3, rectum V40Gy < 80% and bladder V40Gy < 80-90%.Conclusion: This prospective study demonstrated the impact of EBRT treatment techniques in combination with chemotherapy on early morbidity. Dose-volume effects for dysuria, urinary incontinence, stool urgency, diarrhea, rectal bleeding, rectal incontinence and weight loss were found. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the response of detectors for proton dosimetry in the presence of magnetic fields. Material and Methods: Four ionization chambers (ICs), two thimble‐type and two plane‐parallel‐type, and a diamond detector were investigated. All detectors were irradiated with homogeneous single‐energy‐layer fields, using 252.7 MeV proton beams. A Farmer IC was additionally irradiated in the same geometrical configuration, but with a lower nominal energy of 97.4 MeV. The beams were subjected to magnetic field strengths of 0, 0.25, 0.5, 0.75, and 1 T produced by a research dipole magnet placed at the room's isocenter. Detectors were positioned at 2 cm water equivalent depth, with their stem perpendicular to both the magnetic field lines and the proton beam's central axis, in the direction of the Lorentz force. Normality and two sample statistical Student's t tests were performed to assess the influence of the magnetic field on the detectors' responses. Results: For all detectors, a small but significant magnetic field‐dependent change of their response was found. Observed differences compared to the no magnetic field case ranged from +0.5% to −0.7%. The magnetic field dependence was found to be nonlinear and highest between 0.25 and 0.5 T for 252.7 MeV proton beams. A different variation of the Farmer chamber response with magnetic field strength was observed for irradiations using lower energy (97.4 MeV) protons. The largest magnetic field effects were observed for plane‐parallel ionization chambers. Conclusion: Small magnetic field‐dependent changes in the detector response were identified, which should be corrected for dosimetric applications. [ABSTRACT FROM AUTHOR]

To evaluate the long-term results after hypofractionated stereotactic photon radiotherapy (SRT) in patients with choroidal melanoma treated between 1997 and 2016. A total of 335 patients (183 male and 152 female) with choroidal melanoma unsuitable for ruthenium-106 brachytherapy or local resection were treated with linear accelerator-based SRT at the Medical University of Vienna. All patients received five fractions with either 10, 12 or 14 Gy per fraction. A complete ophthalmic examination including visual acuity and measurement of the tumor base and height using standardized A- and B-scan ultrasonography was performed every 3 months in the first 2 years, every 6 months until 5 years and yearly thereafter. Early and late adverse side effects were assessed at every follow-up visit. The median overall follow-up was 78.6 months (39.1 to 113.7 months). Local tumor control was 95.4% after 10 and 12 years, respectively. Fifty-four patients developed metastatic disease, and 31 died during the follow-up. Mean visual acuity decreased from 0.55 Snellen at baseline to 0.05 Snellen at the last individual follow-up. Ischemic retinopathy (192/335cases) and optic neuropathy (174/335cases) were the most common radiogenic side effects, followed by radiogenic cataract (n = 127), neovascular glaucoma (n = 71) and corneal epithelium defects (n = 49). Enucleation was performed in 54 patients mostly due to neovascular glaucoma (n = 41) or tumor recurrence (n = 10) during the study period. The eye retention rate was 79.7% after 10 and 12 years. Hypofractionated stereotactic photon radiotherapy showed a high rate of local tumor control for choroidal melanoma and an acceptable rate of radiogenic side effects. [ABSTRACT FROM AUTHOR]

Purpose: To develop a computer‐driven and thus less user‐dependent method, allowing for a simple and straightforward generation of a Monte Carlo (MC) beam model of a scanned proton and carbon ion beam delivery system. Methods: In a first step, experimental measurements were performed for proton and carbon ion energies in the available energy ranges. Data included depth dose profiles measured in water and spot sizes in air at various isocenter distances. Using an automated regularization‐based optimization process (AUTO‐BEAM), GATE/Geant4 beam models of the respective beam lines were generated. These were obtained sequentially by using least square weighting functions with and without regularization, to iteratively tune the beam parameters energy, energy spread, beam sigma, divergence, and emittance until a user‐defined agreement was reached. Based on the parameter tuning for a set of energies, a beam model was semi‐automatically generated. The resulting beam models were validated for all centers comparing to independent measurements of laterally integrated depth dose curves and spot sizes in air. For one representative center, three‐dimensional dose cubes were measured and compared to simulations. The method was applied on one research as well as four different clinical beam lines for proton and carbon ions of three different particle therapy centers using synchrotron or cyclotron accelerator systems: (a) MedAustron ion therapy center, (b) University Proton Therapy Dresden, and (c) Center Antoine Lacassagne Nice. Results: Particle beam ranges in the MC beam models agreed on average within 0.2 mm compared to measurements for all energies and beam lines. Spot sizes in air (full‐width at half maximum) at all positions differed by less than 0.4% from the measurements. Dose calculation with the beam model for the clinical beam line at MedAustron agreed better than 1.7% in absolute dose for a representative clinical case treated with protons. For protons, beam model generation, including geometry creation, data conversion, and validation, was possible within three working days. The number of iterations required for the optimization process to converge, was found to be similar for all beam line geometries and particle types. Conclusion: The presented method was demonstrated to work independently of the beam optics behavior of the different beam lines, particle types, and geometries. Furthermore, it is suitable for non‐expert users and requires only limited user interaction. Beam model validation for different beam lines based on different beam delivery systems, showed good agreement. [ABSTRACT FROM AUTHOR]

Purpose: To design and commission a water phantom suitable for constrained environments and magnetic fields for magnetic resonance (MR)‐guided proton therapy. Methods: A phantom was designed, to enable precise, remote controlled detector positioning in water within the constrained environment of a magnet for MR‐guided proton therapy. The phantom consists of a PMMA enclosure whose outer dimensions of 81×40×12.5cm3 were chosen to optimize space usage inside the 13.5‐cm bore gap of the magnet. The moving mechanism is based on a low‐height H‐shaped non‐ferromagnetic belt drive, driven by stepper motors located outside of the magnetic field. The control system and the associated electronics were designed in house, with similar features as available in commercial water phantoms. Reproducibility as well as accuracy of the phantom positioning were tested using a high‐precision Leica AT 402 laser tracker. Laterally integrated depth dose curves and lateral beam profiles at three depths were acquired repeatedly for a 148.2 MeV proton beam in water. Results: The phantom was successfully operated with and without applied magnetic fields. For complex movements, a positioning uncertainty within 0.16 mm was found with an absolute accuracy typically below 0.3 mm. Laterally integrated depth dose curves agreed within 0.1 mm with data taken using a commercial water phantom. The lateral beam offset determined from beam profile measurements agreed well with data from Monte Carlo simulations. Conclusion: The phantom is optimally suited for detector positioning and dosimetric experiments within constrained environments in high magnetic fields. [ABSTRACT FROM AUTHOR]

Purpose: We developed a target‐based cone beam computed tomography (CBCT) imaging framework for optimizing an unconstrained three dimensional (3D) source‐detector trajectory by incorporating prior image information. Our main aim is to enable a CBCT system to provide topical information about the target using a limited angle noncircular scan orbit with a minimal number of projections. Such a customized trajectory should include enough information to sufficiently reconstruct a particular volume of interest (VOI) under kinematic constraints, which may result from the patient size or additional surgical or radiation therapy‐related equipment. Methods: A patient‐specific model from a prior diagnostic computed tomography (CT) volume is used as a digital phantom for CBCT trajectory simulations. Selection of the best projection views is accomplished through maximizing an objective function fed by the imaging quality provided by different x‐ray positions on the digital phantom data. The final optimized trajectory includes a limited angular range and a minimal number of projections which can be applied to a C‐arm device capable of general source‐detector positioning. The performance of the proposed framework is investigated in experiments involving an in‐house‐built box phantom including spherical targets as well as an Alderson‐Rando head phantom. In order to quantify the image quality of the reconstructed image, we use the average full‐width‐half‐maximum (FWHMavg) for the spherical target and feature similarity index (FSIM), universal quality index (UQI), and contrast‐to‐noise ratio (CNR) for an anatomical target. Results: Our experiments based on both the box and head phantom showed that optimized trajectories could achieve a comparable image quality in the VOI with respect to the standard C‐arm circular CBCT while using approximately one quarter of projections. We achieved a relative deviation <7% for FWHMavg between the reconstructed images from the optimized trajectories and the standard C‐arm CBCT for all spherical targets. Furthermore, for the anatomical target, the relative deviation of FSIM, UQI, and CNR between the reconstructed image related to the proposed trajectory and the standard C‐arm circular CBCT was found to be 5.06%, 6.89%, and 8.64%, respectively. We also compared our proposed trajectories to circular trajectories with equivalent angular sampling as the optimized trajectories. Our results show that optimized trajectories can outperform simple partial circular trajectories in the VOI in term of image quality. Typically, an angular range between 116° and 152° was used for the optimized trajectories. Conclusion: We demonstrated that applying limited angle noncircular trajectories with optimized orientations in 3D space can provide a suitable image quality for particular image targets and has a potential for limited angle and low‐dose CBCT‐based interventions under strong spatial constraints. [ABSTRACT FROM AUTHOR]

A newly-designed large-area plane-parallel ionization chamber (of type PTW 34089), denoted BPC150, with a nominal active volume diameter of 147 mm is characterized in this study. Such chambers exhibit benefits compared to smaller chambers in the field of scanned light-ion beam dosimetry because they capture a larger fraction of the laterally-spread beam fragments and ease positioning with respect to small fields. The chamber was characterized in 60Co, 200 kV x-ray, proton and carbon ion beams. The chamber-specific beam-quality correction factor kQ,Q0 was determined. To investigate the homogeneity of the chamber's response, a radial response map was acquired. An edge correction was applied when the proton beam only partly impinged on the chamber's active surface. The measured response map showed that the response in the chamber's center is 3% lower than the average response over the total active area. Furthermore, percentage depth dose (PDD) curves in carbon ions were acquired and compared to those obtained with smaller-diameter chambers (i.e. 81.6 mm and 39.6 mm) as well as with results from Monte Carlo simulations. The measured absorbed dose to water cross calibration coefficients resulted in a kQ,Q0 of 0.981 ± 0.020. Regarding carbon ion PDD curves, relative differences between the BPC150 and smaller chambers were observed, especially for higher energies and in the fragmentation tail. These differences reached 10%–22% in the fragmentation tail (compared to the 81.6 mm diameter chamber). Differences increased when comparing to a chamber with 39.6 mm diameter. The provided results characterize the BPC150 thoroughly for usage in scanned light-ion beam dosimetry and demonstrate its advantage of capturing a larger fraction of the laterally-integrated dose in the fragmentation tail. [ABSTRACT FROM AUTHOR]

Purpose: A relative biological effectiveness (RBE) of 1.1 is commonly used in clinical proton therapy, irrespective of tissue type and depth. This in vitro study was conducted to quantify the RBE of scanned protons as a function of the dose‐averaged linear energy transfer (LETd) and the sensitivity factor (α/ß)X. Additionally, three phenomenological models (McNamara, Rørvik, and Jones) and one mechanistic model (repair‐misrepair‐fixation, RMF) were applied to the experimentally derived data. Methods: Four human cell lines (FaDu, HaCat, Du145, SKMel) with differential (α/ß)X ratios were irradiated in a custom‐designed irradiation setup with doses between 0 and 6 Gy at proximal, central, and distal positions of a 80 mm spread‐out Bragg peak (SOBP) centered at 80 mm (setup A: proton energies 66.5–135.6 MeV) and 155 mm (setup B: proton energies 127.2–185.9 MeV) depth, respectively. LETd values at the respective cell positions were derived from Monte Carlo simulations performed with the treatment planning system (TPS, RayStation). Dosimetric measurements were conducted to verify dose homogeneity and dose delivery accuracy. RBE values were derived for doses that resulted in 90 % (RBE90) and 10 % (RBE10) of cell survival, and survival after a 0.5 Gy dose (RBE0.5Gy), 2 Gy dose (RBE2Gy), and 6 Gy dose (RBE6Gy). Results: LETd values at sample positions were 1.9, 2.1, 2.5, 2.8, 4.1, and 4.5 keV/µm. For the cell lines with high (α/ß)X ratios (FaDu, HaCat), the LETd did not impact on the RBE. For low (α/ß)X cell lines (Du145, SKMel), LQ‐derived survival curves indicated a clear correlation of LETd and RBE. RBE90 values up to 2.9 and RBE10 values between 1.4 and 1.8 were obtained. Model‐derived RBE predictions slightly overestimated the RBE for the high (α/ß)X cell lines, although all models except the Jones model provided RBE values within the experimental uncertainty. For low (α/ß)X cell lines, no agreement was found between experiments and model predictions, that is, all models underestimated the measured RBE. Conclusions: The sensitivity parameter (α/ß)X was observed to be a major influencing factor for the RBE of protons and its sensitivity toward LETd changes. RBE prediction models are applicable for high (α/ß)X cell lines but do not estimate RBE values with sufficient accuracy in low (α/ß)X cell lines. [ABSTRACT FROM AUTHOR]

Purpose: The dose response of Gafchromic EBT3 films exposed to proton beams depends on the dose, and additionally on the beam quality, which is often quantified with the linear energy transfer (LET) and, hence, also referred to as LET quenching. Fundamentally different methods to determine correction factors for this LET quenching effect have been reported in literature and a new method using the local proton fluence distribution differential in LET is presented. This method was exploited to investigate whether a more practical correction based on the dose‐ or fluence‐averaged LET is feasible in a variety of clinically possible beam arrangements. Methods: The relative effectiveness (RE) was characterized within a high LET spread‐out Bragg peak (SOBP) in water made up by the six lowest available energies (62.4–67.5 MeV, configuration "b1") resulting in one of the highest clinically feasible dose‐averaged LET distributions. Additionally, two beams were measured where a low LET proton beam (252.7 MeV) was superimposed on "b1", which contributed either 50% of the initial particle fluence or 50% of the dose in the SOBP, referred to as configuration "b2" and "b3," respectively. The proton LET spectrum was simulated with GATE/Geant4 at all measurement positions. The net optical density change differential in LET was integrated over the local proton spectrum to calculate the net optical density and therefrom the beam quality correction factor. The LET dependence of the film response was accounted for by an LET dependence of one of the three parameters in the calibration function and was determined from inverse optimization using measurement "b1." This method was then validated on the measurements of "b2" and "b3" and subsequently used to calculate the RE at 900 positions in nine clinically relevant beams. The extrapolated RE set was used to derive a simple linear correction function based on dose‐averaged LET (Ld) and verify the validity in all points of the comprehensive RE set. Results: The uncorrected film dose deviated up to 26% from the reference dose, whereas the corrected film dose agreed within 3% in all three beams in water ("b1", "b2" and "b3"). The LET dependence of the calibration function started to strongly increase around 5 keV/μm and flatten out around 30 keV/μm. All REs calculated from the proton fluence in the nine simulated beams could be approximated with a linear function of dose‐averaged LET (RE = 1.0258−0.0211 μm/keV Ld). However, no functional relationship of RE‐ and fluence‐averaged LET could be found encompassing all beam energies and modulations. Conclusions: The film quenching was found to be nonlinear as a function of proton LET as well as of the dose‐averaged LET. However, the linear relation of RE on dose‐averaged LET was a good approximation in all cases. In contrast to dose‐averaged LET, fluence‐averaged LET could not describe the RE when multiple beams were applied. [ABSTRACT FROM AUTHOR]

Background: The targeting accuracy of proton therapy (PT) for moving soft-tissue tumours is expected to greatly improve by real-time magnetic resonance imaging (MRI) guidance. The integration of MRI and PT at the treatment isocenter would offer the opportunity of combining the unparalleled soft-tissue contrast and real-time imaging capabilities of MRI with the most conformal dose distribution and best dose steering capability provided by modern PT. However, hybrid systems for MR-integrated PT (MRiPT) have not been realized so far due to a number of hitherto open technological challenges. In recent years, various research groups have started addressing these challenges and exploring the technical feasibility and clinical potential of MRiPT. The aim of this contribution is to review the different aspects of MRiPT, to report on the status quo and to identify important future research topics.Methods: Four aspects currently under study and their future directions are discussed: modelling and experimental investigations of electromagnetic interactions between the MRI and PT systems, integration of MRiPT workflows in clinical facilities, proton dose calculation algorithms in magnetic fields, and MRI-only based proton treatment planning approaches.Conclusions: Although MRiPT is still in its infancy, significant progress on all four aspects has been made, showing promising results that justify further efforts for research and development to be undertaken. First non-clinical research solutions have recently been realized and are being thoroughly characterized. The prospect that first prototype MRiPT systems for clinical use will likely exist within the next 5 to 10 years seems realistic, but requires significant work to be performed by collaborative efforts of research groups and industrial partners. [ABSTRACT FROM AUTHOR]

Recent developments in magnetic resonance (MR) to synthetic computed tomography (sCT) conversion have shown that treatment planning is possible without an initial planning CT. Promising conversion results have been demonstrated recently using conditional generative adversarial networks (cGANs). However, the performance is generally only tested on images from one MR scanner, which neglects the potential of neural networks to find general high-level abstract features. In this study, we explored the generalizability of the generator models, trained on a single field strength scanner, to data acquired with higher field strengths. T2-weighted 0.35T MRIs and CTs from 51 patients treated for prostate (40) and cervical cancer (11) were included. 25 of them were used to train four different generators (SE-ResNet, DenseNet, U-Net, and Embedded Net). Further, an ensemble model was created from the four network outputs. The models were validated on 16 patients from a 0.35T MR scanner. Further, the trained models were tested on the Gold Atlas dataset, containing T2-weighted MR scans of different field strengths; 1.5T(7) and 3T(12), and 10 patients from the 0.35T scanner. The sCTs were dosimetrically compared using clinical VMAT plans for all test patients. For the same scanner (0.35T), the results from the different models were comparable on the test set, with only minor differences in the mean absolute error (MAE) (35-51HU body). Similar results were obtained for conversions of 3T GE Signa and the 3T GE Discovery images (40-62HU MAE) for three of the models. However, larger differences were observed for the 1.5T images (48-65HU MAE). The overall best model was found to be the ensemble model. All dose differences were below 1%. This study shows that it is possible to generalize models trained on images of one scanner to other scanners and different field strengths. The best metric results were achieved by the combination of all networks. [ABSTRACT FROM AUTHOR]

Background: Dosimetric effects of inaccuracies of output factors (OFs) implemented in treatment planning systems (TPSs) were investigated. Materials and methods: Modified beam models (MBM) for which the OFs of small fields (down to 1 × 1 cm2) were increased by up to 12% compared to the original beam models (OBM) were created for two TPSs. These beam models were used to recalculate treatment plans of different complexity. Treatment plans using stereotactic 3D-conformal (s3D-CRT) for brain metastasis as well as VMAT plans for head and neck and prostate cancer patients were generated. Dose distributions calculated with the MBM and the OBM were compared to measured dose distributions acquired using film dosimetry and a 2D-detector-array. For the s3D-CRT plans the calculated and measured dose at the isocenter was evaluated. For VMAT, gamma pass rates (GPRs) were calculated using global gamma index with 3%/3 mm, 2%/3 mm, 1%/3 mm and 2%/2 mm with a 20% threshold. Contribution of small fields to the total fluence was expressed as the ratio (F) of fluence trough leaf openings smaller than 2 cm to the total fluence. Results: Using film dosimetry for the s3D-CRT plans, the average of the ratio of calculated dose to measured dose at the isocenter was 1.01 and 1.06 for the OBM and MBM model, respectively. A significantly lower GPR of the MBM compared to the OBM was only found for the localized prostate cases (F = 12.4%) measured with the 2D-detector-array and an acceptance criterion of 1%/3 mm. Conclusion: The effects of uncertainties in small field OFs implemented in TPSs are most pronounced for s3D-CRT cases and can be clearly identified using patient specific quality assurance. For VMAT these effects mainly remain undetected using standard patient specific quality assurance. Using tighter acceptance criteria combined with an analysis of the fluence generated by small fields can help identifying inaccuracies of OFs implemented in TPSs. [ABSTRACT FROM AUTHOR]

Purpose: The dose response of Gafchromic EBT3 films exposed to proton beams depends on the dose, and additionally on the beam quality, which is often quantified with the linear energy transfer (LET) and, hence, also referred to as LET quenching. Fundamentally different methods to determine correction factors for this LET quenching effect have been reported in literature and a new method using the local proton fluence distribution differential in LET is presented. This method was exploited to investigate whether a more practical correction based on the dose‐ or fluence‐averaged LET is feasible in a variety of clinically possible beam arrangements. Methods: The relative effectiveness (RE) was characterized within a high LET spread‐out Bragg peak (SOBP) in water made up by the six lowest available energies (62.4–67.5 MeV, configuration "b1") resulting in one of the highest clinically feasible dose‐averaged LET distributions. Additionally, two beams were measured where a low LET proton beam (252.7 MeV) was superimposed on "b1", which contributed either 50% of the initial particle fluence or 50% of the dose in the SOBP, referred to as configuration "b2" and "b3," respectively. The proton LET spectrum was simulated with GATE/Geant4 at all measurement positions. The net optical density change differential in LET was integrated over the local proton spectrum to calculate the net optical density and therefrom the beam quality correction factor. The LET dependence of the film response was accounted for by an LET dependence of one of the three parameters in the calibration function and was determined from inverse optimization using measurement "b1." This method was then validated on the measurements of "b2" and "b3" and subsequently used to calculate the RE at 900 positions in nine clinically relevant beams. The extrapolated RE set was used to derive a simple linear correction function based on dose‐averaged LET (Ld) and verify the validity in all points of the comprehensive RE set. Results: The uncorrected film dose deviated up to 26% from the reference dose, whereas the corrected film dose agreed within 3% in all three beams in water ("b1", "b2" and "b3"). The LET dependence of the calibration function started to strongly increase around 5 keV/μm and flatten out around 30 keV/μm. All REs calculated from the proton fluence in the nine simulated beams could be approximated with a linear function of dose‐averaged LET (RE = 1.0258−0.0211 μm/keV Ld). However, no functional relationship of RE‐ and fluence‐averaged LET could be found encompassing all beam energies and modulations. Conclusions: The film quenching was found to be nonlinear as a function of proton LET as well as of the dose‐averaged LET. However, the linear relation of RE on dose‐averaged LET was a good approximation in all cases. In contrast to dose‐averaged LET, fluence‐averaged LET could not describe the RE when multiple beams were applied. [ABSTRACT FROM AUTHOR]

Purpose: To present an analytical formalism for the in depth assessment of uncertainties of field output factors in small fields related to detector positioning based on dose profile measurements. Additionally, a procedure for the propagation of these uncertainties was developed. Methods: Based on the assumption that one dimensional and two dimensional second‐order polynomial functions can be fitted to dose profiles of small photon beams, equations for the calculation of the expectation value, the variance, and the standard deviation were developed. The following fitting procedures of the dose profiles were considered: A one‐dimensional case (1D), a quasi two‐dimensional case (2Dq) based on independently measured line profiles and a full 2D case (2Df) which also considers cross‐correlations in a two‐dimensional dose distribution. A rectangular and a Gaussian probability density function (PDF) characterizing the probability of possible positions of the detector relative to the maximum dose were used. Uncertainty components such as the finite resolution of the scanning water phantom, the reproducibility of the determination of the position of the maximum dose, and the reproducibility of the collimator system were investigated. This formalism was tested in a 0.5 x 0.5 cm2 photon field where dose profiles were measured using a radiochromic film, a synthetic diamond detector, and an unshielded diode detector. Additionally, the dose distribution measured with the radiochromic film was convoluted with a convolution kernel mimicking the active volume of the unshielded diode. Results: Analytic expressions for the calculation of uncertainties on field output factors were found for the 1D, the 2Dq, and the 2Df case. The uncertainty of the field output factor related to the relative position of the detector to the maximum dose increased quadratically with increasing limits of possible detector positions. Analysis of the radiochromic film showed that the 2Dq case gave a more conservative assessment of the uncertainty compared to the 2Df case with a difference of < 0.1%. The 2Dq case applied to the film measurements agreed well with the same approach as was applied to the unshielded diode. The investigated uncertainty components propagated to an uncertainty of the field output factors of 0.5% and 0.4% for the synthetic diamond and the unshielded diode, respectively. Additionally, the expectation value was lower than the maximum dose. The difference was 0.4% and 0.3% for the synthetic diamond and the unshielded diode, respectively. Conclusions: The assessment of uncertainties of field output factors related to detector positioning is feasible using the proposed formalism. The 2Dq case is applicable when using online detectors. Accurate positioning in small fields is essential for accurate dosimetry as its related uncertainty increases quadratically. The observed drop of the expectation value needs to be considered in small field dosimetry. [ABSTRACT FROM AUTHOR]

Purpose: Magnetic resonance guidance in proton therapy (MRPT) is expected to improve its current performance. The combination of magnetic fields with clinical proton beam lines poses several challenges for dosimetry, treatment planning and dose delivery. Proton beams are deflected by magnetic fields causing considerable changes in beam trajectories and also a retraction of the Bragg peak positions. A proper prediction and compensation of these effects is essential to ensure accurate dose calculations. This work aims to develop and benchmark a Monte Carlo (MC) beam model for dose calculation of MRPT for static magnetic fields up to 1 T. Methods: Proton beam interactions with magnetic fields were simulated using the GATE/Geant4 toolkit. The transport of charged particle in custom 3D magnetic field maps was implemented for the first time in GATE. Validation experiments were done using a horizontal proton pencil beam scanning system with energies between 62.4 and 252.7 MeV and a large gap dipole magnet (B = 0–1 T), positioned at the isocenter and creating magnetic fields transverse to the beam direction. Dose was measured with Gafchromic EBT3 films within a homogeneous PMMA phantom without and with bone and tissue equivalent material slab inserts. Linear energy transfer (LET) quenching of EBT3 films was corrected using a linear model on dose‐averaged LET method to ensure a realistic dosimetric comparison between simulations and experiments. Planar dose distributions were measured with the films in two different configurations: parallel and transverse to the beam direction using single energy fields and spread‐out Bragg peaks. The MC model was benchmarked against lateral deflections and spot sizes in air of single beams measured with a Lynx PT detector, as well as dose distributions using EBT3 films. Experimental and calculated dose distributions were compared to test the accuracy of the model. Results: Measured proton beam deflections in air at distances of 465, 665, and 1155 mm behind the isocenter after passing the magnetic field region agreed with MC‐predicted values within 4 mm. Differences between calculated and measured beam full width at half maximum (FWHM) were lower than 2 mm. For the homogeneous phantom, measured and simulated in‐depth dose profiles showed range and average dose differences below 0.2 mm and 1.2%, respectively. Simulated central beam positions and widths differed <1 mm to the measurements with films. For both heterogenous phantoms, differences within 1 mm between measured and simulated central beam positions and widths were obtained, confirming a good agreement of the MC model. Conclusions: A GATE/Geant4 beam model for protons interacting with magnetic fields up to 1 T was developed and benchmarked to experimental data. For the first time, the GATE/Geant4 model was successfully validated not only for single energy beams, but for SOBP, in homogeneous and heterogeneous phantoms. EBT3 film dosimetry demonstrated to be a powerful dosimetric tool, once the film response function is LET corrected, for measurements in‐line and transverse to the beam direction in magnetic fields. The proposed MC beam model is foreseen to support treatment planning and quality assurance (QA) activities toward MRPT. [ABSTRACT FROM AUTHOR]