Heavy Therapy Research Articles

Design and Magnetic Field Measurement of the Superconducting Magnets for the Next-Generation Rotating Gantry

This paper describes the design and reports the test results of the world's most compact rotating gantry for a heavy-ion therapy system mounted with superconducting bending and focusing magnets. A rotating gantry is cylindrical irradiation equipment with magnets for beam transport and beam scanning that delivers energetic carbon ions at up to 430 MeV/u precisely to a tumor from any direction without changing the posture of the patient. However, because of the high magnetic rigidity of therapeutic carbon ions, the rotating gantry was too big to be installed at general hospitals. Therefore, the superconducting rotating gantry had been developed in collaboration with Yamagata University. In the project, to achieve further downsizing of the rotating gantry, the length of the scanning irradiation system is reduced and the magnetic field of the superconducting magnet is increased to 3.5 T from the 2.88 T of the first superconducting gantry installed in the National Institutes for Quantum and Radiological Science and Technology (QST). As a result, the gantry is downsized to 2/3 of the first superconducting rotating gantry. This next-generation small superconducting rotating gantry has already been installed and is undergoing preclinical commissioning at Yamagata University.

Concept Design of a Superconducting Magnet for a Compact Heavy-Ion Synchrotron

A compact synchrotron is now under development at the National Institutes for Quantum Science and Technology (QST), with the goal of downsizing the heavy-ion therapy system with superconducting magnets conduction-cooled by GM cryocoolers. The synchrotron is required to accelerate several kinds of heavy-ion beams from 4 MeV/u to 430 MeV/u. A superconducting magnet with both dipole and quadrupole coils is adopted to generate a dipole field from 0.3 to 3.5 T and a quadrupole field from 0.1 to 1.5 T/m with a ramp rate of 0.6 T/s. A coil winding pattern and iron yoke are optimized to achieve field homogeneity in the required area. For the small-scale synchrotron, the coil ends are optimized with a novel parameter combining the beta function and multipole errors considering the beam dynamics.

Deciphering the Biological Effects of Radiotherapy in Cancer Cells.

Radiotherapy remains an effective conventional method of treatment for patients with cancer. However, the clinical efficacy of radiotherapy is compromised by the development of radioresistance of the tumor cells during the treatment. Consequently, there is need for a comprehensive understanding of the regulatory mechanisms of tumor cells in response to radiation to improve radiotherapy efficacy. The current study aims to highlight new developments that illustrate various forms of cancer cell death after exposure to radiation. A summary of the cellular pathways and important target proteins that are responsible for tumor radioresistance and metastasis is also provided. Further, the study outlines several mechanistic descriptions of the interaction between ionizing radiation and the host immune system. Therefore, the current review provides a reference for future research studies on the biological effects of new radiotherapy technologies, such as ultra-high-dose-rate (FLASH) radiotherapy, proton therapy, and heavy-ion therapy.

Thermal characteristics of a helium-free superconducting magnet system for a fast-ramping heavy-ion synchrotron

A compact synchrotron has been proposed for the next generation heavy-ion therapy system at the National Institutes for Quantum Science and Technology (QST). In this synchrotron, four 90-degree superconducting bending magnets designed on the basis of the superconducting magnet for the rotating-gantry currently operated at QST are adopted to achieve a compact size. These NbTi superconducting bending magnets are conduction-cooled by several Gifford–McMahon (GM) cryocoolers and are designed to generate both the dipole field of 3.5 T and the quadrupole field of 1.5 T/m to operate at a ramp rate of 0.7 T/s. It is a challenge to remove the heat generated from AC losses at such a fast ramp rate, and keep the superconducting magnets from quenching during the continuous operation without using liquid helium. In this paper, we studied the feasibility for realizing a fast-ramping synchrotron by using a helium-free superconducting magnet system for heavy-ion therapy. Using the numerical models, we estimated the AC losses including eddy current loss in mechanical structures, iron loss and loss in superconductor to be about 212 J in a cycle duration of 20 s for each 90-degree superconducting bending magnet, and it was possible to eliminate that amount of AC losses by using GM cryocoolers. To validate the transient temperature rising during the continuous operation, a dynamic simulation was performed using the estimated AC losses as input, and the peak temperature at thermal equilibrium was evaluated to be lower than 5 K for a practical operation scenario of heavy-ion therapy irradiation.

Investigation on the activity distribution of positron products in PMMA target irradiated by carbon ion beam

In the heavy ion radiotherapy, the dose distribution is an important index to ensure the therapeutic effect. But it can not be directly measured during a treatment. Positron-emitting radionuclides (10 C, 11 C, and 15 O et al.) produced in the treatment process are deposited along the path and the end of the beam trajectory, so the positron activity distribution can be used to monitor the dose distribution of carbon ions. In this paper, we present results of measurements of positron activity distributions with a developed scanner system. Then the relationship between the activity distribution of positrons and the dose distribution of carbon ions is studied. The research shows that the activity distribution of positrons is quite similar to that of carbon ions in the direction of penetration depth. The activity peak position of positrons is smaller than the dose peak position of carbon ions, and this difference increases along with the increase of carbon ion beam energy. These experimental results are consistent with the GATE simulation results. It is found that the detector system can distinguish shift of peak position of 3 mm that corresponds change of a particle energy of 4 MeV/u. This indicates that the positron scanner system had been successfully developed for heavy ion therapy equipment.

Induced radiation studies and personnel dose assessment in a carbon ion therapy facility

Carbon ions have become the most widely used particles in heavy-ion tumor therapy due to favorable physical and biological characteristics. The beam delivery system (BDS) and tumor tissues are directly bombarded with accelerated carbon ions, resulting in activation products in the components and the patient’s body. The results of an experimental study and a Monte-Carlo simulation for the radioactivity induced in a treatment room under a uniform scanning mode were presented in this study. They indicated that the multi-leaf collimator (MLC) and the patient’s body were the main sources of induced radioactivity. The half-lives of the main produced radionuclides ranged from a few minutes to tens of minutes for single irradiation and from dozens of days to hundreds of days for long-term irradiation. The personal dose of medical staff working in the treatment room and the additional dose of the patient from the induced radioactivity were estimated. Finally, some suggestions were made to reduce the unwanted radiation exposure of the medical staff, patients, and carers.

A European Collaboration to Investigate Superconducting Magnets for Next Generation Heavy Ion Therapy

Next generation ion therapy magnets both for gantry and for accelerator (synchrotron) are under investigation in a recently launched European collaboration that, in the frame of the European H2020 HITRI <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">plus</i> and I.FAST programmes, has obtained some funding for work packages on superconducting magnets. Design and technology of superconducting magnets will be developed for ion therapy synchrotron and -especially- gantry, taking as reference beams of 430 MeV/nucleon ions (C-ions) with 10 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">10</sup> ions/pulse. The magnets are about 60–90 mm diameter, 4 to 5 T <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">peak</i> field with a field change of about 0.3 T/s and good field quality. The paper will illustrate the organization of the collaboration and the technical program. Various superconductor options (LTS, MgB <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> or HTS) and different magnet shapes, like classical CosTheta or innovative Canted CosTheta (CCT), with curved multifunction (dipole and quadrupole), are under evaluation, CCT being the baseline. These studies should provide design inputs for a new superconducting gantry design for existing facilities and, on a longer time scale, for a brand-new hadron therapy centre to be placed in the South East Europe (SEEIIST project).

Impact of Regorafenib on Endothelial Transdifferentiation of Glioblastoma Stem-like Cells.

Simple SummaryGlioblastomas (GBM) are the most frequent and aggressive adult brain tumours with a poor prognosis despite heavy therapy that combines surgical resection and radio-chemotherapy. There is a real therapeutic failure concerning these tumours and it highlights the need for new efficient and usable molecules in these particular and not easily reachable cancers. GBM are also characterised by abnormal and abundant vascularisation, of which some vessels originate from transdifferentiation of GBM stem cells (GSC) to tumour-derived endothelial cells (TDEC). As this mechanism was described as essential for tumour growth, we evaluated the impact of regorafenib, a multikinase inhibitor with anti-angiogenic and anti-tumourigenic activity on transdifferentiation but also directly on GSC. Regorafenib significantly decreases GSC proliferation in vitro but also in vivo. Regorafenib also inhibits transdifferentiation by decreasing phenotypic and functional endothelial features of TDEC obtained from non-irradiated GSC but also of TDEC obtained from irradiated GSC. All these results confirm that regorafenib clearly impacts GSC tumour formation and transdifferentiation and may therefore be a promising therapeutic option in combination with chemo/radiotherapy for the treatment of these highly aggressive brain tumours.Glioblastomas (GBM) are aggressive brain tumours with a poor prognosis despite heavy therapy that combines surgical resection and radio-chemotherapy. The presence of a subpopulation of GBM stem cells (GSC) contributes to tumour aggressiveness, resistance and recurrence. Moreover, GBM are characterised by abnormal, abundant vascularisation. Previous studies have shown that GSC are directly involved in new vessel formation via their transdifferentiation into tumour-derived endothelial cells (TDEC) and that irradiation (IR) potentiates the pro-angiogenic capacity of TDEC via the Tie2 signalling pathway. We therefore investigated the impact of regorafenib, a multikinase inhibitor with anti-angiogenic and anti-tumourigenic activity, on GSC and TDEC obtained from irradiated GSC (TDEC IR+) or non-irradiated GSC (TDEC). Regorafenib significantly decreases GSC neurosphere formation in vitro and inhibits tumour formation in the orthotopic xenograft model. Regorafenib also inhibits transdifferentiation by decreasing CD31 expression, CD31+ cell count, pseudotube formation in vitro and the formation of functional blood vessels in vivo of TDEC and TDEC IR+. All of these results confirm that regorafenib clearly impacts GSC tumour formation and transdifferentiation and may therefore be a promising therapeutic option in combination with chemo/radiotherapy for the treatment of highly aggressive brain tumours.

Please Place Your Seat in the Full Upright Position: A Technical Framework for Landing Upright Radiation Therapy in the 21st Century.

Delivering radiotherapy to patients in an upright position can allow for increased patient comfort, reduction in normal tissue irradiation, or reduction of machine size and complexity. This paper gives an overview of the requirements for the delivery of contemporary arc and modulated radiation therapy to upright patients. We explore i) patient positioning and immobilization, ii) simulation imaging, iii) treatment planning and iv) online setup and image guidance. Treatment chairs have been designed to reproducibly position seated patients for treatment and can be augmented by several existing immobilisation systems or promising emerging technologies such as soft robotics. There are few solutions for acquiring CT images for upright patients, however, cone beam computed tomography (CBCT) scans of upright patients can be produced using the imaging capabilities of standard Linacs combined with an additional patient rotation device. While these images will require corrections to make them appropriate for treatment planning, several methods indicate the viability of this approach. Treatment planning is largely unchanged apart from translating gantry rotation to patient rotation, allowing for a fixed beam with a patient rotating relative to it. Rotation can be provided by a turntable during treatment delivery. Imaging the patient with the same machinery as used in treatment could be advantageous for online plan adaption. While the current focus is using clinical linacs in existing facilities, developments in this area could also extend to lower-cost and mobile linacs and heavy ion therapy.

Fixed Beamline Optimization for Intensity Modulated Carbon-Ion Therapy.

A major obstacle for the adoption of heavy ion therapy is the cost and technical difficulties to construct and maintain a rotational gantry. Many heavy ion treatment facilities instead choose to construct fixed beamlines as a compromise, which we propose to mitigate with optimized treatment couch angle. We formulate the integrated beam orientation and scanning spot optimization problem as a quadratic cost function with a group sparsity regularization term. The optimization problem is efficiently solved using fast iterative shrinkage-thresholding algorithm (FISTA). To test the method, we created the fixed beamline plans with couch rotation (FBCR) and without couch rotation (FB) for intensity modulated carbon-ion therapy (IMCT) and compared with the ideal scenario where both the couch and gantry have 360 degrees of freedom (GCR). FB, FBCR, and GCR IMCT plans were compared for ten pancreas cases. The FBCR plans show comparable PTV coverage and OAR doses for each pancreas case. In conclusion, the dosimetric limitation of fixed beams in heavy ion radiotherapy may be largely mitigated with integrated beam orientation optimization of the couch rotation.

Flourish of Proton and Carbon Ion Radiotherapy in China.

Proton and heavy ion therapy offer superior relative biological effectiveness (RBE) in the treatment of deep-seated tumors compared with conventional photon radiotherapy due to its Bragg-peak feature of energy deposition in organs. Many proton and carbon ion therapy centers are active all over the world. At present, five particle radiotherapy institutes have been built and are receiving patient in China, mainly including Wanjie Proton Therapy Center (WPTC), Shanghai Proton Heavy Ion Center (SPHIC), Heavy Ion Cancer Treatment Center (HIMM), Chang Gung Memorial Hospital (CGMH), and Ruijin Hospital affiliated with Jiao Tong University. Many cancer patients have benefited from ion therapy, showing unique advantages over surgery and chemotherapy. By the end of 2020, nearly 8,000 patients had been treated with proton, carbon ion or carbon ion combined with proton therapy. So far, there is no systemic review for proton and carbon ion therapy facility and clinical outcome in China. We reviewed the development of proton and heavy ion therapy, as well as providing the representative clinical data and future directions for particle therapy in China. It has important guiding significance for the design and construction of new particle therapy center and patients’ choice of treatment equipment.

Inhibition of DNA synthesis and cancer therapies.

Cancer is a worldwide problem afflicting 19 million people. Inhibition of DNA synthesis has been a cornerstone of anticancer therapy. A variety of chemotherapy drugs have been developed and many of these are aimed at inhibiting DNA synthesis, as they damage DNA, form DNA adduct and interfere with DNA synthesis. Another type of chemotherapy interferes with the synthesis of nucleotide pools. There are also other types of drugs that inhibit topoisomerases resulting in the interference with DNA replication and transcription. Significant progress has been made regarding radiation therapy that includes X-ray (and γ-ray), proton therapy and heavy ion therapy. The Auger therapy is a type of radiation therapy that differs from X-ray, proton or heavy ion therapy. The method relies on the use of high Z elements such as gadolinium, iodine, gold or silver. Irradiation of these elements results in the release of electrons including the Auger electrons that have strong DNA damaging effect. Tamanoi et al. developed novel nanoparticles containing gadolinium or iodine to place high Z elements at the periphery of the nucleus thus localizing them close to DNA. Irradiation with monochromatic X-ray resulted in the formation of double-strand DNA breaks leading to the destruction of tumor mass. Comparison of conventional X-ray therapy and the Auger therapy is discussed.

Implementation of a rapid response system at an isolated radiotherapy facility through simulation training

A rapid response system is required in a radiotherapy department for patients experiencing a critical event when access to an emergency department is poor due to geographic location and the...

Commissioning of carbon-ion radiotherapy for moving targets at the Osaka Heavy-Ion Therapy Center.

PurposeHerein, we report the methods and results of the Hitachi carbon‐ion therapy facility commissioning to determine the optimum values of the magnitude of movement and repaint number in respiratory‐gated irradiation.MethodsA virtual‐cylinder target was created using the treatment‐planning system (VQA Plan), and measurements were performed to study the effects of respiratory movements using a two‐dimensional ionization‐chamber array detector and a phantom with movable wedge and stage. For simulations, we selected a 10 × 10 × 10 cm3 cubic irradiation pattern with a uniform physical dose and two actual cases of liver‐cancer treatments, whose prescribed doses were 60 Gy(RBE)/4 fraction (Case 1) and 60 Gy(RBE)/12 fraction (Case 2). We employed two types of repainting methods, one produced by the algorithm of VQA Plan (VQA algorithm) and the other by ideal repainting. The latter completely repeats all spots with set number of repaintings. We performed flatness calculations and gamma analysis to evaluate the effects of each condition.ResultsFrom the measurements, the gamma passing rates for which the criteria were 3%/3 mm exceeded 95% for displacements in the head‐to‐tail direction if the repaint number was greater than 3 and the magnitude of the residual motions was less than 5.0 mm. In simulations with the cubic irradiation pattern, the gamma passing rates (with criteria of 2%/2 mm) exceeded 95% when the magnitude of the residual motions was 3.0 mm and the repaint number was greater than 3. When the repaint number was set to 4 in the VQA with the actual liver cases, the flatness results for Case 2 was minimal. For ideal repainting, the flatness results for all ports fell within ∼3.0% even when the magnitude of the residual motions was 5.0 mm if the repaint number was 6. However, the flatness was less than 3.0% for almost all ports if the magnitude of the residual motions was less than 3.0 mm with a repaint number of 4 in case of both types of repaint methods.ConclusionsAt our facility, carbon‐ion radiotherapy can be provided safely to a moving target with residual motions of 3.0 mm magnitude and with a repaint number of 4.

Intra- and inter-fraction relative range verification in heavy-ion therapy using filtered interaction vertex imaging

Heavy-ion therapy, particularly using scanned (active) beam delivery, provides a precise and highly conformal dose distribution, with maximum dose deposition for each pencil beam at its endpoint (Bragg peak), and low entrance and exit dose. To take full advantage of this precision, robust range verification methods are required; these methods ensure that the Bragg peak is positioned correctly in the patient and the dose is delivered as prescribed. Relative range verification allows intra-fraction monitoring of Bragg peak spacing to ensure full coverage with each fraction, as well as inter-fraction monitoring to ensure all fractions are delivered consistently. To validate the proposed filtered interaction vertex imaging (IVI) method for relative range verification, a 16O beam was used to deliver 12 Bragg peak positions in a 40 mm poly-(methyl methacrylate) phantom. Secondary particles produced in the phantom were monitored using position-sensitive silicon detectors. Events recorded on these detectors, along with a measurement of the treatment beam axis, were used to reconstruct the sites of origin of these secondary particles in the phantom. The distal edge of the depth distribution of these reconstructed points was determined with logistic fits, and the translation in depth required to minimize the χ 2 statistic between these fits was used to compute the range shift between any two Bragg peak positions. In all cases, the range shift was determined with sub-millimeter precision, to a standard deviation of the mean of 220(10) μm. This result validates filtered IVI as a reliable relative range verification method, which should be capable of monitoring each energy step in each fraction of a scanned heavy-ion treatment plan.

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

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

Radioactive Beams for Image-Guided Particle Therapy: The BARB Experiment at GSI.

Several techniques are under development for image-guidance in particle therapy. Positron (β+) emission tomography (PET) is in use since many years, because accelerated ions generate positron-emitting isotopes by nuclear fragmentation in the human body. In heavy ion therapy, a major part of the PET signals is produced by β+-emitters generated via projectile fragmentation. A much higher intensity for the PET signal can be obtained using β+-radioactive beams directly for treatment. This idea has always been hampered by the low intensity of the secondary beams, produced by fragmentation of the primary, stable beams. With the intensity upgrade of the SIS-18 synchrotron and the isotopic separation with the fragment separator FRS in the FAIR-phase-0 in Darmstadt, it is now possible to reach radioactive ion beams with sufficient intensity to treat a tumor in small animals. This was the motivation of the BARB (Biomedical Applications of Radioactive ion Beams) experiment that is ongoing at GSI in Darmstadt. This paper will present the plans and instruments developed by the BARB collaboration for testing the use of radioactive beams in cancer therapy.

PO-1529 HITRIplus project: building a pan-European heavy ion therapy research community

PO-1529 HITRIplus project: building a pan-European heavy ion therapy research community

Hi’Beam-A: A Pixelated Beam Monitor for the Accelerator of a Heavy-Ion Therapy Facility

In this article, a noninterceptive and high-accuracy beam position monitor, named Hi'Beam-A, has been designed for the accelerator of a heavy-ion therapy facility. The Hi'Beam-A consists of the detector subsystem and the readout subsystem. In the detector subsystem, the microchannel plate multiplies the ionized charge in the high vacuum chamber, and the novel Topmetal silicon pixel sensor directly collects the charge. The readout subsystem processes the data and calculates the beam position. Beam test results show that the Hi'Beam-A reaches an accuracy of 5 μm. This article will present the design, characterization, and beam test of Hi'Beam-A.

Geant4 based applications to space physics, nuclear waste-based muon tomography and heavy ion therapy. Review

Geant4 based applications to space physics, nuclear waste-based muon tomography and heavy ion therapy. Review