An in-vivo treatment monitoring system for ion-beam radiotherapy based on 28 Timepix3 detectors.

Ion-beam radiotherapy is an advanced cancer treatment modality offering steep dose gradients and a high biological effectiveness. These gradients make the therapy vulnerable to patient-setup and anatomical changes between treatment fractions, which may go unnoticed. Charged fragments from nuclear interactions of the ion beam with the patient tissue may carry information about the treatment quality. Currently, the fragments escape the patient undetected. Inter-fractional in-vivo treatment monitoring based on these charged nuclear fragments could make ion-beam therapy safer and more efficient. We developed an ion-beam monitoring system based on 28 hybrid silicon pixel detectors (Timepix3) to measure the distribution of fragment origins in three dimensions. The system design choices as well as the ion-beam monitoring performance measurements are presented in this manuscript. A spatial resolution of 4 mm along the beam axis was achieved for the measurement of individual fragment origins. Beam-range shifts of 1.5 mm were identified in a clinically realistic treatment scenario with an anthropomorphic head phantom. The monitoring system is currently being used in a prospective clinical trial at the Heidelberg Ion Beam Therapy Centre for head-and-neck as well as central nervous system cancer patients.

A quantitative assessment of Geant4 for predicting the yield and distribution of positron-emitting fragments in ion beam therapy.

Objective.To compare the accuracy with which different hadronic inelastic physics models across ten Geant4 Monte Carlo simulation toolkit versions can predict positron-emitting fragments produced along the beam path during carbon and oxygen ion therapy.Approach.Phantoms of polyethylene, gelatin, or poly(methyl methacrylate) were irradiated with monoenergetic carbon and oxygen ion beams. Post-irradiation, 4D PET images were acquired and parent11C,10C and15O radionuclides contributions in each voxel were determined from the extracted time activity curves. Next, the experimental configurations were simulated in Geant4 Monte Carlo versions 10.0 to 11.1, with three different fragmentation models-binary ion cascade (BIC), quantum molecular dynamics (QMD) and the Liege intranuclear cascade (INCL++) - 30 model-version combinations. Total positron annihilation and parent isotope production yields predicted by each simulation were compared between simulations and experiments using normalised mean squared error and Pearson cross-correlation coefficient. Finally, we compared the depth of the maximum positron annihilation yield and the distal point at which the positron yield decreases to 50% of peak between each model and the experimental results.Main results.Performance varied considerably across versions and models, with no one version/model combination providing the best prediction of all positron-emitting fragments in all evaluated target materials and irradiation conditions. BIC in Geant4 10.2 provided the best overall agreement with experimental results in the largest number of test cases. QMD consistently provided the best estimates of both the depth of peak positron yield (10.4 and 10.6) and the distal 50%-of-peak point (10.2), while BIC also performed well and INCL generally performed the worst across most Geant4 versions.Significance.The best predictions of the spatial distribution of positron annihilations and positron-emitting fragment production along the beam path during carbon and oxygen ion therapy was obtained using Geant4 10.2.p03 with BIC or QMD. These version/model combinations are recommended for future heavy ion therapy research.

Diamond based integrated detection system for dosimetric and microdosimetric characterization of radiotherapy ion beams.

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.

Characteristics of breathing-adapted gating using surface guidance for use in particle therapy: A phantom-based end-to-end test from CT simulation to dose delivery.

To account for intra-fractional tumor motion during dose delivery in radiotherapy, various treatment strategies are clinically implemented such as breathing-adapted gating and irradiating the tumor during specific breathing phases. In this work, we present a comprehensive phantom-based end-to-end test of breathing-adapted gating utilizing surface guidance for use in particle therapy. A commercial dynamic thorax phantom was used to reproduce regular and irregular breathing patterns recorded by the GateRT respiratory monitoring system. The amplitudes and periods of recorded breathing patterns were analysed and compared to planned patterns (ground-truth). In addition, the mean absolute deviations (MAD) and Pearson correlation coefficients (PCC) between the measurements and ground-truth were assessed. Measurements of gated and non-gated irradiations were also analysed with respect to dosimetry and geometry, and compared to treatment planning system (TPS). Further, the latency time of beam on/off was evaluated. Compared to the ground-truth, measurements performed with GateRT showed amplitude differences between 0.03 ± 0.02 mm and 0.26 ± 0.03 mm for regular and irregular breathing patterns, whilst periods of both breathing patterns ranged with a standard deviation between 10 and 190 ms. Furthermore, the GateRT software precisely acquired breathing patterns with a maximum MAD of 0.30 ± 0.23 mm. The PCC constantly ranged between 0.998 and 1.000. Comparisons between TPS and measured dose profiles indicated absolute mean dose deviations within institutional tolerances of ±5%. Geometrical beam characteristics also varied within our institutional tolerances of 1.5 mm. The overall time delays were <60 ms and thus within both recommended tolerances published by ESTRO and AAPM of 200 and 100 ms, respectively. In this study, a non-invasive optical surface-guided workflow including image acquisition, treatment planning, patient positioning and gated irradiation at an ion-beam gantry was investigated, and shown to be clinically viable. Based on phantom measurements, our results show a clinically-appropriate spatial, temporal, and dosimetric accuracy when using surface guidance in the clinical setting, and the results comply with international and institutional guidelines and tolerances.

Creation, evolution, and future challenges of ion beam therapy from a medical physicist's viewpoint (Part 3): Chapter 3. Clinical research, Chapter 4. Future challenges, Chapter 5. Discussion, and Conclusion.

Clinical studies of ion beam therapy have been performed at the Lawrence Berkeley Laboratory (LBL), National Institute of Radiological Sciences (NIRS), Gesellschaft für Schwerionenforschung (GSI), and Deutsches Krebsforschungszentrum (DKFZ), in addition to the development of equipment, biophysical models, and treatment planning systems. Although cancers, including brain tumors and pancreatic cancer, have been treated with the Bevalac's neon-ion beam at the LBL (where the first clinical research was conducted), insufficient results were obtained owing to the limited availability of neon-ion beams and immaturity of related technologies. However, the 184-Inch Cyclotron's helium-ion beam yielded promising results for chordomas and chondrosarcomas at the base of the skull. Using carbon-ion beams, NIRS has conducted clinical trials for the treatment of common cancers for which radiotherapy is indicated. Because better results than X-ray therapy results have been obtained for lung, liver, pancreas, and prostate cancers, as well as pelvic recurrences of rectal cancer, the Japanese government recently approved the use of public medical insurance for carbon-ion radiotherapy, except for lung cancer. GSI obtained better results than LBL for bone and soft tissue tumors, owing to dose enhancement enabled by scanning irradiation. In addition, DKFZ compared treatment results of proton and carbon-ion radiotherapy for these tumors. This article summarizes a series of articles (Parts 1-3) and describes future issues of immune ion beam therapy and linear energy transfer optimization.

In Vitro Carbon Ion Beam and Gemcitabine Chemoradiation in a Mucoepidermoid Carcinoma Cell Line.

BACKGROUND/AIM: To determine the interaction of gemcitabine in chemoradiotherapy with heavy carbon ions in vitro in a mucoepidermoid carcinoma (MEC) cell line. MATERIALS AND METHODS: The human lymphatic MEC metastasis cell line NCI-H292 was used. The cells were treated with photons, carbon ions, and gemcitabine. Survival fractions (SF), apoptosis, and cell cycle progression were analyzed. A paired two-sided t-test was used. Significance was defined as p<0.05. RESULTS: Cell proliferation assays showed a significant reduction in SF for combined photon chemoradiation versus photons only. The linear-quadratic fits of combined therapy with carbon ion dose of 0 to 2.5 Gy led to reductions of mean 15% in SF. The LD50 (lethal radiation dose required to reduce cell survival by 50%) for carbon ions only was 0.7 Gy and for carbon ions with gemcitabine 0.6 Gy. The LD50 for photons (with gemcitabine) was 2.8 Gy (2.0 Gy) and for carbon ions (with gemcitabine) 0.7 Gy (0.6 Gy), resulting in a relative biological effectiveness at 10% cell survival (RBE10) of 3.0 (2.7). Carbon ions and photons reduced S phase and increased G2/M phase cell distribution. Isolated treatment with gemcitabine as well as combination with photons led to prolonged S phase transit, whereas combined treatment with carbon ions led to early accumulation in G2/M phase. A significant increase in the sub-G1 population as a hint of relevant number of apoptotic cells was not observed. CONCLUSION: Gemcitabine showed radiosensitizing effects in combination with photons. The combination of gemcitabine and carbon ions had independent additive effects. Carbon ions only had a RBE10 of 3.0, compared to photons only. The combination of gemcitabine, photon, and carbon ions in patients with MEC seems promising and warrants further investigation.

Creation, evolution, and future challenges of ion beam therapy from a medical physicist's viewpoint (Part 2). Chapter 2. Biophysical model, treatment planning system and image guided radiotherapy.

When an ion beam penetrates deeply into the body, its kinetic energy decreases, and its biological effect increases due to the change of the beam quality. To give a uniform biological effect to the target, it is necessary to reduce the absorbed dose with the depth. A bio-physical model estimating the relationship between ion beam quality and biological effect is necessary to determine the relative biological effectiveness (RBE) of the ion beam that changes with depth. For this reason, Lawrence Berkeley Laboratory, National Institute of Radiological Sciences (NIRS) and GSI have each developed their own model at the starting of the ion beam therapy. Also, NIRS developed a new model at the starting of the scanning irradiation. Although the Local Effect Model (LEM) at the GSI and the modified Microdosimetric Kinetic Model (MKM) at the NIRS, the both are currently used, can similarly predict radiation quality-induced changes in surviving fraction of cultured cell, the clinical RBE-weighted doses for the same absorbed dose are different. This is because the LEM uses X-rays as a reference for clinical RBE, whereas the modified MKM uses carbon ion beam as a reference and multiplies it by a clinical factor of 2.41. Therefore, both are converted through the absorbed dose. In PART 2, I will describe the development of such a bio-physical model, as well as the birth and evolution of a treatment planning system and image guided radiotherapy.

Quality assurance and temporal stability of a 1.5 T MRI scanner for MR-guided Photon and Particle Therapy.

PURPOSE: To describe performance measurements, adaptations and time stability over 20 months of a diagnostic MR scanner for integration into MR-guided photon and particle radiotherapy. MATERIAL AND METHODS: For realization of MR-guided photon and particle therapy (MRgRT/MRgPT), a 1.5 T MR scanner was installed at the Heidelberg Ion Beam Therapy Center. To integrate MRI into the treatment process, a flat tabletop and dedicated coil holders for flex coils were used, which prevent deformation of the patient external contour and allow for the use of immobilization tools for reproducible positioning. The signal-to-noise ratio (SNR) was compared for the diagnostic and therapy-specific setup using the flat couch top and flexible coils for the a) head & neck and b) abdominal region as well as for different bandwidths and clinical pulse sequences. Additionally, a quality assurance (QA) protocol with monthly measurements of the ACR phantom and measurement of geometric distortions for a large field-of-view (FOV) was implemented to assess the imaging quality parameters of the device over the course of 20 months. RESULTS: The SNR measurements showed a decreased SNR for the RT-specific as compared to the diagnostic setup of (a) 26% to 34% and (b) 11% to 33%. No significant bandwidth dependency for this ratio was found. The longitudinal assessment of the image quality parameters with the ACR and distortion phantom confirmed the long-term stability of the MRI device. CONCLUSION: A diagnostic MRI was commissioned for use in MR-guided particle therapy. Using a radiotherapy specific setup, a high geometric accuracy and signal homogeneity was obtained after some adaptions and the measured parameters were shown to be stable over a period of 20 months.

Stretching effects on non-adiabatic electron dynamic behavior in poly(dG)-poly(dC) DNA upon the proton irradiation.

The electronic excitations caused by DNA when exposed to ion radiation is essential to DNA damage. In this paper, we investigated the energy deposition and electron excitation process of DNA with reasonable stretching range upon proton irradiation based on time-dependent density functional theory. Stretching changes the strength of hydrogen bonding between the DNA base pairs, which in turn affects the Coulomb interaction between the projectile and DNA. As a semi-flexible molecule, the way of energy deposition is weakly sensitive to the stretching rate of DNA. However, the increase of stretching rate causes the increase of charge density along the trajectory channel, sequentially resulting in an increase in proton resistance along the intruding channel. The Mulliken charge analysis indicates that the guanine base and guanine ribose are ionized, meanwhile the cytosine base and cytosine ribose are reduced at all stretching rates. In a few femtoseconds, there exists an electron flow passing through the guanine ribose, guanine, cytosine base and the cytosine ribose in turn. This electron flow increases electron transfer and DNA ionization, promoting the side chain damage of the DNA upon ion irradiation. Our results provide a theoretical insight for deciphering the physical mechanism of the early stage of the irradiation process, and are also of great significance for the study of particle beam cancer therapy in different biological tissues.

Experience and new prospects of PET imaging for ion beam therapy monitoring.

Pioneering investigations on the usage of positron-emission-tomography (PET) for the monitoring of ion beam therapy with light (protons, helium) and heavier (stable and radioactive neon, carbon and oxygen) ions started shortly after the first realization of planar and tomographic imaging systems, which were able to visualize the annihilation of positrons resulting from irradiation induced or implanted positron emitting nuclei. And while the first clinical experience was challenged by the utilization of instrumentation directly adapted from nuclear medicine applications, new detectors optimized for this unconventional application of PET imaging are currently entering the phase of (pre)clinical testing for more reliable monitoring of treatment delivery during irradiation. Moreover, recent advances in detector technologies and beam production open several new exciting opportunities which will not only improve the performance of PET imaging under the challenging conditions of in-beam applications in ion beam therapy, but will also likely expand its field of application. In particular, the combination of PET and Compton imaging can enable the most efficient utilization of all possible radiative emissions for both stable and radioactive ion beams, while positronium lifetime imaging may enable probing new features of the underlying tumour and normal tissue environment. Thereby, PET imaging will not only provide means for volumetric reconstruction of the delivered treatment and in-vivo verification of the beam range, but can also shed new insights for biological optimization of the treatment or treatment response assessment.

3D high resolution clonogenic survival measurement of xrs-5 cells in low-dose region of carbon ion plans.

PURPOSE: In this study, we performed biological verification measurements of cell survival of a 12C ion irradiation plan employing a high-resolution 3D culture setup. This allowed, in particular, to access the cell inactivation in the low-dose regions close to the target area. MATERIALS AND METHODS: We established the protocol for a 3D culture setup where xrs-5 cells were grown inside a layered matrigel structure in 384-well plates. Their radiosensitivity to conventional and 12C ion radiation was evaluated by irradiating them either with 250 kV X-rays at GSI or with monoenergetic 12C beams of 110 MeV/u at MIT, and compared with those of monolayers. A treatment plan for a rectangular target was prepared using the GSI research treatment planning system TRiP98. xrs-5 cells were seeded in the matrigel-based setup and irradiated in dose fall-off regions using active scanning 12C ion beams. In addition, film dosimetry utilizing radiochromic EBT3 film has been performed to assess the field homogeneity downstream of 384-well V-bottom plates with or without additional agarose coating of the well plate bottom. RESULTS: Dose response curves following X-ray and 12C ion irradiation had linear shape and showed a significant decrease in survival fraction at even moderate doses. Survival measurements in the low-dose regions of the plan for the extended target showed good agreement to the predicted survival fraction. The irradiated film profiles yielded a flat dose distribution without apparent artifacts or inhomogeneities for well plates both with and without agarose coating, confirming the suitability of the experimental setup. CONCLUSIONS: We conclude that the V-bottom 384-well plates in combination with the radiation-sensitive xrs-5 cell line constitute a suitable radiobiological verification tool which can be used especially for low doses. Furthermore, the measured survival of xrs-5 cells show a good agreement with the expected survival in the low-dose out-of-field regions, both laterally and downstream of the target.

Sensitivity correction of fluorescent nuclear track detectors using alpha particles: Determining LET spectra of light ions with enhanced accuracy.

BACKGROUND: Radiation fields encountered in proton therapy (PT) and ion-beam therapy (IBT) are characterized by a variable linear energy transfer (LET), which lead to a variation of relative biological effectiveness and also affect the response of certain dosimeters. Therefore, reliable tools to measure LET are advantageous to predict and correct LET effects. Fluorescent nuclear track detectors (FNTDs) are suitable to measure LET spectra within the range of interest for PT and IBT, but so far the accuracy and precision have been challenged by sensitivity variations between individual crystals. PURPOSE: To develop a novel methodology to correct changes in the fluorescent intensity due to sensitivity variations among FNTDs. This methodology is based on exposing FNTDs to alpha particles in order to derive a detector-specific correction factor. This will allow us to improve the accuracy and precision of LET spectra measurements with FNTDs. METHODS: FNTDs were exposed to alpha particles. Afterward, the detectors were irradiated to monoenergetic protons, 4 He-, 12 C-, and 16 O-ions. At each step, the detectors were imaged with a confocal laser scanning microscope. The tracks were reconstructed and analyzed using in-house developed tools. Alpha-particle tracks were used to derive a detector-specific sensitivity correction factor ( k s , i ${k_{s,i}}$ ). Proton, 4 He-, 12 C-, and 16 O-ion tracks were used to establish a traceable calibration curve that relates the fluorescence intensity with the LET in water ( L E T H 2 O $LE{T_{{{\rm{H}}_2}{\rm{O}}}}$ ). FNTDs from a second batch were exposed and analyzed following the same procedures, to test if k s , i ${k_{s,i}}$ can be used to extend the applicability of the calibration curve to detectors from different batches. Finally, a set of blind tests was performed to assess the accuracy of the proposed methodology without user bias. Throughout all stages, the main sources of uncertainty were evaluated. RESULTS: Based on a sample of 100 FNTDs, our findings show a high sensitivity heterogeneity between FNTDs, with k s , i ${k_{s,i}}$ having values between 0.57 and 2.55. The fitting quality of the calibration curve, characterized by the mean absolute percentage residuals and correlation coefficient, was improved when k s , i ${k_{s,i}}$ was considered. Results for detectors from the second batch show that, if the fluorescence signal is corrected by k s , i ${k_{s,i}}$ , the differences in the predicted L E T H 2 O $LE{T_{{{\rm{H}}_2}{\rm{O}}}}$ with respect to the reference set are reduced from 55%, 141%, 41%, and 186% to 4.2%, 6.5%, 5.0%, and 11.0%, for protons, 4 He-, 12 C-, and 16 O-ions, respectively. The blind tests showed that it is possible to measure the track- and dose-average L E T H 2 O $LE{T_{{{\rm{H}}_2}{\rm{O}}}}$ with an accuracy of 0.3%, 16%, and 9.6% and 1.7%, 28%, and 30% for protons, 12 C-ions and mixed beams, respectively. On average, the combined uncertainty of the measured L E T H 2 O $LE{T_{{{\rm{H}}_2}{\rm{O}}}}$ was 11%, 13%, 21%, and 26% for protons, 4 He-, 12 C-, and 16 O-ions, respectively. These values were increased by a mean factor of 2.0 when k s , i ${k_{s,i}}$ was not applied. CONCLUSIONS: We have demonstrated for the first time that alpha particles can be used to derive a detector-specific sensitivity correction factor. The proposed methodology allows us to measure LET spectra using FNTD-technology, with a degree of accuracy and precision unreachable before with sole experimental approaches.

Radiotherapy with Helium Ions Has the Potential to Improve Both Endocrine and Neurocognitive Outcome in Pediatric Patients with Ependymoma.

Ependymomas are the third most-frequent pediatric brain tumors. To prevent local recurrence, the resection site should be irradiated. Compared to photon radiation treatment, proton therapy often achieves even better results regarding target coverage and organ-sparing. Due to their physical properties, helium ions could further reduce side effects, providing better protection of healthy tissue despite similar target coverage. In our in silico study, 15 pediatric ependymoma patients were considered. All patients underwent adjuvant radiotherapeutic treatment with active-scanned protons at Heidelberg Ion Beam Therapy Center (HIT). Both helium ion and highly conformal IMRT plans were calculated to evaluate the potential dosimetric advantage of ion beam therapy compared to the current state-of-the-art photon-based treatments. To estimate the potential clinical benefit of helium ions, normal tissue complication probabilities (NTCP) were calculated. Target coverage was comparable in all three modalities. As expected, the integral dose absorbed by healthy brain tissue could be significantly reduced with protons by up to -48% vs. IMRT. Even compared to actively scanned protons, relative dose reductions for critical neuronal structures of up to another -39% were achieved when using helium ions. The dose distribution of helium ions is significantly superior when compared to proton therapy and IMRT due to the improved sparing of OAR. In fact, previous studies could clearly demonstrate that the dosimetric advantage of protons translates into a measurable clinical benefit for pediatric patients with brain tumors. Given the dose-response relationship of critical organs at risk combined with NTCP calculation, the results of our study provide a strong rationale that the use of helium ions has the potential to even further reduce the risk for treatment related sequelae.

Depth dose measurements in water for 11C and 10C beams with therapy relevant energies.

Owing to the favorable depth-dose distribution and the radiobiological properties of heavy ion radiation, ion beam therapy shows an improved success/toxicity ratio compared to conventional radiotherapy. The sharp dose gradients and very high doses in the Bragg peak region, which represent the larger physical advantage of ion beam therapy, make it also extremely sensitive to range uncertainties. The use of ß +-radioactive ion beams would be ideal for simultaneous treatment and accurate online range monitoring through PET imaging. Since all the unfragmented primary ions are potentially contributing to the PET signal, these beams offer an improved image quality while preserving the physical and radiobiological advantages of the stable counterparts. The challenging production of radioactive ion beams and the difficulties in reaching high intensities, have discouraged their clinical application. In this context, the project Biomedical Applications of Radioactive ion Beams (BARB) started at GSI (Helmholtzzentrum für Schwerionenforschung GmbH) with the main goal to assess the technical feasibility and investigate possible advantages of radioactive ion beams on the pre-clinical level. During the first experimental campaign 11C and 10C beams were produced and isotopically separated with the FRagment Separator (FRS) at GSI. The ß +-radioactive ion beams were produced with a beam purity of 99% for all the beam investigated (except one case where it was 94%) and intensities potentially sufficient to treat a small animal tumors within few minutes of irradiation time, ∼ 106 particle per spill for the 10C and ∼ 107 particle per spill for the 11C beam, respectively. The impact of different ion optical parameters on the depth dose distribution was studied with a precision water column system. In this work, the measured depth dose distributions are presented together with results from Monte Carlo simulations using the FLUKA software.

Creation, evolution, and future challenges of ion beam therapy from a medical physicist's viewpoint (part 1). Introduction and Chapter 1. accelerator and beam delivery system.

Radiation therapy for cancer using the Bragg peak of an ion beam has been making steady progress after being proposed by Robert Wilson in 1946. At the end of 2020, 12 dedicated treatment devices existed in operation worldwide, and approximately 40,000 patients have been treated with ion beams (mostly carbon ions). To date, ion beam therapy is superior to other treatments for rare cancers in the head and neck as well as bone and soft tissues; however, most recently, evidence submitted in Japan for the 2022 revision of public health insurance shows that ion beam therapy outperforms photon therapy for intractable common cancers such as pancreatic cancer and liver cancer. This may greatly expand its indications. Lawrence Berkeley Laboratory in the United States started research of ion beam therapy, National Institute of Radiological Sciences in Japan built the first dedicated device Heavy Ion Accelerator in Chiba and started systematic clinical research, and GSI in Germany developed the scanning irradiation method and rotating gantry for the first time. This paper presents the history and future challenges of ion beam therapy in three fields: accelerator and beam delivery system, physical/biological model and treatment planning system, and clinical research. This study is divided into three parts describing the achievements and roles of the three laboratories. In Part 1, accelerator and beam delivery system are described.

Dosimetric validation of a GPU-based dose engine for a fast in silico patient-specific quality assurance program in light ion beam therapy.

BACKGROUND: With rapid evolutions of fast and sophisticated calculation techniques and delivery technologies, clinics are almost facing a daily patient-specific (PS) plan adaptation, which would make a conventional experimental quality assurance (QA) workflow unlikely to be routinely feasible. Therefore, in silico approaches are foreseen by means of second-check independent dose calculation systems possibly handling machine log-files. PURPOSE: To validate the in-house developed GPU-dose engine, FRoG, for light ion beam therapy (protons and carbon ions) as a second-check independent calculation system and to integrate machine log-file analysis into the patient-specific quality assurance (PSQA) program. METHODS: Spot sizes, depth-dose distributions, and absolute dose calibrations were configured into FRoG and a set of nine regular-shaped targets in combination with more than 170 clinical treatment fields were tested against pinpoint ionization chamber measurements. Both the treatment planning system DICOM RTplans and machine treatment log-files were used as input for the dose kernel in water, and a 3D local γ (1 mm/2%) index was used as the main evaluation metric. RESULTS: Calculated configuration data matched experimental measurements with submillimetric agreement. For regular-shaped targets, the unsigned average relative difference between calculated and measured dose values was less than 2% for both protons and carbon ions. The mean γ passing rate (PR) was around 98% for both particle species. For clinical treatment beams, DICOM-based recalculations showed a γ-PR more than 99% for both particle species. The same level of agreement was preserved for protons when moving to log-file-based recalculations. A score of around 95% was registered for carbon ion beams, once excluding low-quality machine log-files. Unsigned average relative difference against acquired data was less than 2% also for real clinical beams. CONCLUSIONS: FRoG was proven as an accurate and reliable tool for PSQA in scanning light ion beam therapy. The proposed method allows for an extremely efficient workflow, without compromising the quality of the plan verification procedure.

Particle beam therapy for nasopharyngeal cancer: A systematic review and meta-analysis.

Background/purpose: A systematic review and meta-analysis were performed to better understand the benefits of particle beam therapy for nasopharyngeal cancer (NPC) treatment. The survival outcomes and toxicity of primary and recurrent NPC patients treated with proton or carbon ion beam therapy were investigated. Method: PubMed, Scopus, and Embase were searched between 1 January 2007 to 3 November 2021. The inclusion and exclusion criteria included studies with either primary or recurrent NPC patients, sample size of ≥10 patients, and proton or carbon ion beam therapy as interventions. Twenty-six eligible studies with a total of 1502 patients were included. We used a random-effect meta-analysis to examine the impact of particle beam therapy on primary NPC patients and qualitatively described the results among recurrent patients. The primary outcome was overall survival (OS), while secondary outcomes included progression-free survival (PFS), local control (LC) and toxicity. Results: The pooled OS at 1-year, 2-year and 3-year and 5-year for primary NPC patients who received particle beam therapy were 96 % (95 % confidence interval (CI) = 92 %-98 %), 93 % (95 % CI = 83 %-97 %), 90 % (95 % CI = 73 %-97 %) and 73 % (95 % CI = 52 %-87 %) respectively. The pooled 1-year and 2-year PFS, and LC for these patients were above 90 %. For locally recurrent NPC patients, the 1-year OS rate ranged from 65 % to 92 %, while the 1-year LC rate ranged from 80 % to 88 %. Both proton and carbon ion beam therapy were generally safe among primary and recurrent patients, with ≥G3 late toxicity rates of 20 % or less. Approximately a 5 % mortality rate was reported among recurrent patients. Conclusions: This systematic review and meta-analysis demonstrated particle beam therapy has great potential in treating NPC, yielding excellent survival outcomes with low toxicity. However, further investigations are needed to assess the long-term outcomes and cost-effectiveness of this newer form of radiotherapy.

Linear energy transfer-independent calibration of radiochromic film for carbon-ion beams.

For carbon-ion beams, radiochromic film response depends on the dose and linear energy transfer (LET). For film dosimetry, we developed an LET-independent simple calibration method for a radiochromic film for specific therapeutic carbon-ion beams. The measured film doses were calibrated with a linear function within 5% error. The penumbra positions of the films were consistent with the differences from the planned ones within ~0.4 mm. The results indicated sufficient accuracy for use as a tool for the confirmation of the penumbra position of the fields.

Impact of DNA Repair Kinetics and Dose Rate on RBE Predictions in the UNIVERSE.

Accurate knowledge of the relative biological effectiveness (RBE) and its dependencies is crucial to support modern ion beam therapy and its further development. However, the influence of different dose rates of the reference radiation and ion beam are rarely considered. The ion beam RBE-model within our "UNIfied and VERSatile bio response Engine" (UNIVERSE) is extended by including DNA damage repair kinetics to investigate the impact of dose-rate effects on the predicted RBE. It was found that dose-rate effects increase with dose and biological effects saturate at high dose-rates, which is consistent with data- and model-based studies in the literature. In a comparison with RBE measurements from a high dose in-vivo study, the predictions of the presented modification were found to be improved in comparison to the previous version of UNIVERSE and existing clinical approaches that disregard dose-rate effects. Consequently, DNA repair kinetics and the different dose rates applied by the reference and ion beams might need to be considered in biophysical models to accurately predict the RBE. Additionally, this study marks an important step in the further development of UNIVERSE, extending its capabilities in giving theoretical guidance to support progress in ion beam therapy.

Experimental helium-beam radiography with a high-energy beam: Water-equivalent thickness calibration and first image-quality results.

PURPOSE: A clinical implementation of ion-beam radiography (iRad) is envisaged to provide a method for on-couch verification of ion-beam treatment plans. The aim of this work is to introduce and evaluate a method for quantitative water-equivalent thickness (WET) measurements for a specific helium-ion imaging system for WETs that are relevant for imaging thicker body parts in the future. METHODS: Helium-beam radiographs (αRads) are measured at the Heidelberg Ion-beam Therapy Center with an initial beam energy of 239.5 MeV/u. An imaging system based on three pairs of thin silicon pixel detectors is used for ion path reconstruction and measuring the energy deposition (dE) of each particle behind the object to be imaged. The dE behind homogeneous plastic blocks is related to their well-known WETs between 280.6 and 312.6 mm with a calibration curve that is created by a fit to measured data points. The quality of the quantitative WET measurements is determined by the uncertainty of the measured WET of a single ion (single-ion WET precision) and the deviation of a measured WET value to the well-known WET (WET accuracy). Subsequently, the fitted calibration curve is applied to an energy deposition radiograph of a phantom with a complex geometry. The spatial resolution (modulation transfer function at 10 % -MTF10% ) and WET accuracy (mean absolute percentage difference-MAPD) of the WET map are determined. RESULTS: In the optimal imaging WET-range from ∼280 to 300 mm, the fitted calibration curve reached a mean single-ion WET precision of 1.55 ± $\,{\pm}\,$ 0.00%. Applying the calibration to an ion radiograph (iRad) of a more complex WET distribution, the spatial resolution was determined to be MTF10% = 0.49 ± $\,{\pm}\,$ 0.03 lp/mm and the WET accuracy was assessed as MAPD to 0.21 %. CONCLUSIONS: Using a beam energy of 239.5 MeV/u and the proposed calibration procedure, quantitative αRads of WETs between ∼280 and 300 mm can be measured and show high potential for clinical use. The proposed approach with the resulting image qualities encourages further investigation toward the clinical application of helium-beam radiography.