Particle Radiotherapy Research Articles

TMET-13. SPATIAL METABOLOMIC CHANGES OF NUCLEOTIDE IN THE BRAINS OF ORTHOTOPIC MOUSE GLIOMA MODEL AFTER BORON NEUTRON CAPTURE THERAPY (BNCT)

Abstract Glioblastoma is the most lethal primary brain tumor. Boron Neutron Capture Therapy (BNCT) is a tumor-selective particle radiation therapy, in which high-LET α-particles and recoil 7Li are produced by the capture reaction between 10B and thermal neutrons and it has extended the prognosis of glioblastomas [Kawabata S, et al., Neuro-Oncology Advances 3(1), 1–9, 2021]. Augmented synthesis and use of nucleotide triphosphates is critical and universal metabolic dependency of tumor cells [Mullen, N.J., Singh, P.K. Nat Rev Cancer 23, 275–294 (2023)]. However, the effects of BNCT on metabolism of purine and pyrimidine in brain tumors and the surrounding normal brain are unknown. We spatially investigated metabolomic change in brains of orthotopic mouse glioma model, before and 2, 7, and 14 days after BNCT using mass spectrometry imaging (MSI). By separating tumor and non-tumor areas and performing Partial Least Squares Regression calculations, we have successfully visualized tumor-specific metabolites including adenine (ATP, ADP) and uridine (UTP, UDP-glucose, UDP-GlcNAc) with MSI. Of note, the signal of top-scored tumor specific metabolite, UDP-GlcNAc dramatically decreased and disappeared as the tumor regressed. Furthermore, the signal of ADP which was supposed to be released from tumor, colocalized with invading tumors along with corpus callosum. The value of adenylate energy charge, ([ATP]+0.5[ADP]/[ATP]+[ADP]+[AMP]) in the surrounding normal brain of the untreated tumor-bearing mouse increased up to 0.37 and decreased gradually down to 0.32 with BNCT, approaching to the value of normal control mouse brain, 0.27. These metabolomic changes reflected the tumor-killing effect and restoration of energy charge of surrounding normal brain by BNCT and have potential significance for development of biomarker or diagnosis.

Determination of RBE of 450 MeV/nucleon carbon ions using the micronucleus test and survival of mice after irradiation in different regions of the Bragg curve

Purpose Determination of the value of relative biological effectiveness (RBE) of heavy charged ions in vivo is an important task for their optimal use in particle radiotherapy. The aim of this study was to determine the RBE value of a beam of carbon ions with an energy of 450 MeV/nucleon in different regions of the Bragg curve in irradiation of mice at low, medium, and high doses in comparison with X-ray radiation. Materials and methods SHK mice (n = 330) were irradiated in three regions of the Bragg curve in the dose range of 0–1.5 Gy for cytogenetic damage detection and at a dose of 6.5 Gy for determination of 30-day survival. For irradiation of mice in the Bragg peak, two widths of a spread-out Bragg peak (SOBP) were used: 10 mm (LET ∼100 keV/µm) and 30 mm (LET ∼39 keV/µm). Results The RBE value was 0.8–0.9 before the Bragg peak (LET ∼15 keV/µm) and 0.8 after the peak (LET ∼5 keV/µm), and did not depend on the determination method, despite the differences in LET values. The RBE value determined by the micronucleus test was 1.1–1.7 for the 10-mm-wide SOBP and 1.0–1.3 for the 30-mm-wide SOBP, with the highest RBE value obtained in the low-dose region upon irradiation of mice in the 10-mm-wide Bragg peak. The RBE values in the high-dose region determined by the 30-day survival test lay in the range from 1.4 to 2.6 depending on the width of the Bragg peak and the chosen criterion for calculating the value. The RBE values in the 10-mm-wide Bragg peak (LET ∼100 keV/µm) were higher than those in the 30-mm-wide Bragg peak (LET ∼39 keV/µm) at all used criteria. Conclusions The present findings suggest that there is the complex relationship between LET and organism response to accelerated charged particle radiation, and the contribution of specific factors and mechanisms must be further considered.

Cobaltabis(Dicarbollide) [o-COSAN]- for Boron Neutron Capture Therapy of Head and Neck Cancer: Biodistribution and Irradiation Studies in an Experimental Oral Cancer Model.

Boron neutron capture therapy (BNCT) is a tumor-selective particle radiotherapy that combines preferential boron accumulation in tumors and neutron irradiation. Based on previous studies in tumor-bearing mice, this study evaluated the biodistribution of the sodium salt of cobaltabis(dicarbollide) (Na[3,3'-Co(C2B9H11)2], abbreviated as Na[o-COSAN]) in the hamster cheek pouch oral cancer model and the Na[o-COSAN]/BNCT therapeutic effect on tumors and induced radiotoxicity. The synthesis and comprehensive characterization of 10B-enriched trimethylammonium salt of nido-[7,8-C210B9H12]-o-carborane, along with the cesium and sodium salts of [o-10COSAN] cobaltabis(dicarbollide) are reported here for the first time. Hamsters bearing tumors were injected with Na[o-COSAN] (7.5 mg B/kg) and euthanized at different time-points after injection (30 min, 2, 3, 5, and 18 h post-administration) to evaluate boron uptake in different tissues/organs. Based on these results, tumor-bearing animals were treated with Na[10B-o-COSAN]/BNCT (7.5 mg B/kg b.w., 3 h), prescribing 5 Gy total in absorbed dose to the precancerous tissue surrounding tumors, i.e., the dose-limiting tissue. Na[o-10COSAN] exhibited no toxicity. Although biodistribution studies employing Na[o-COSAN] have shown low absolute boron concentration in the tumor (approx. 11 ppm), Na[o-10COSAN]/BNCT induced a high and significant therapeutic effect on tumors versus the control group (cancerized, untreated animals). Moreover, only half of the animals exhibited severe mucositis in the precancerous dose-limiting tissue after BNCT, which resolved completely at 21 days after irradiation. Na[o-10COSAN] would be potentially useful to treat head and neck cancer with BNCT.

Robot-Assisted Resection of Exposed Colon With TaTME After Heavy Ion Radiotherapy for Locally Recurrent Rectal Cancer: A Case Report

Introduction Heavy ion radiotherapy has shown promising results in treating pelvic recurrence of rectal cancer. We report a case in which a patient underwent robot-assisted low anterior resection with transanal mesorectal excision (TaTME) following heavy ion radiotherapy, owing to challenges associated with spacer placement. Case presentation A 54-year-old man was diagnosed with upper rectal cancer. He underwent robot-assisted low anterior resection. Eight courses of CapeOX were administered as postoperative adjuvant chemotherapy. Immediately after completion of adjuvant chemotherapy (8 months postoperatively), computed tomography (CT) scan revealed a 30-mm large nodule on the dorsal surface of the oral anastomotic intestine, which was detected by positron emission tomography–CT. Given that the tumor had an indistinct border with the sacrum and its superior margin extended to the second sacrum, it was concluded that a combined sacral resection was not advisable, and heavy ion radiotherapy was indicated. Robot-assisted low anterior resection combined with TaTME was performed approximately 2 months after heavy particle radiotherapy [73.6 Gy (relative biological effectiveness)/16 sessions]. CT scan conducted 3 months after irradiation revealed substantial shrinkage of the recurrent tumor. Conclusion Robot-assisted resection of exposed colon with TaTME after heavy ion radiotherapy is regarded as an effective strategy for treating locally recurrent rectal cancer.

Key Notes on Fixed Point Programming in Particle Radiotherapy

Key Notes on Fixed Point Programming in Particle Radiotherapy

Particle therapy in gastrointestinal cancer-a narrative review.

Radiation therapy is one of the main pillars in the treatment of gastrointestinal (GI) cancers, especially esophageal and anorectal malignancies. The worldwide standard of care is yet an irradiation with photons. Though not commonly used, charged particles offer some physical advantages with a highly conformal dose distribution, which allows an even better sparing of organs at risk. In addition to dosimetric advantages, heavy-ion beams like carbon ions may offer an additional set of biological advantages. Because particle therapy is not standard of care, data are scarce-especially concerning the use in GI malignancies. The aim of this review is to provide a compact overview of the currently available literature. PubMed and Web of Science databases were searched for publications on particle radiotherapy in GI cancer (e.g., proton therapy in esophageal cancer, carbon ion radiotherapy in pancreatic cancer). Here we present a review of the current data on particle therapy with regard to esophageal, pancreatic, hepatic and anorectal malignancies. Data on particle therapy in GI cancer are scarce. Nevertheless, the current literature shows some promising results. Further clinical evidence, especially randomized trials, is crucial to augment the role of particle radiotherapy in GI cancer.

Pilot study to assess the early cardiac safety of carbon ion radiotherapy for intra- and para-cardiac tumours.

Modern photon radiotherapy effectively spares cardiac structures more than previous volumetric approaches. Still, it is related to non-negligible cardiac toxicity due to the low-dose bath of surrounding normal tissues. However, the dosimetric advantages of particle radiotherapy make it apromising treatment for para- and intra-cardiac tumours. In the current short report, we evaluate the cardiac safety profile of carbon ion radiotherapy (CIRT) for radioresistant intra- and para-cardiac malignancies in areal-world setting. We retrospectively analysed serum biomarkers (TnI, CRP and NT-proBNP), echocardiographic, and both 12-lead and 24-hour Holter electrocardiogram (ECG) data of consecutive patients with radioresistant intra- and para-cardiac tumours irradiated with CIRT between June 2019 and September 2022. In the CIRT planning optimization process, to minimize the delivered doses, we contoured and gave ahigh priority to the cardiac substructures. Weekly re-evaluative 4D computed tomography scans were carried out throughout the treatment. Atotal of 16patients with intra- and para-cardiac localizations of radioresistant tumours were treated up to atotal dose of 70.4 Gy relative biological effectiveness (RBE) and amean heart dose of 2.41 Gy(RBE). We did not record any significant variation of the analysed serum biomarkers after CIRT nor significant changes of echocardiographic features, biventricular strain, or 12-lead and 24-hour Holter ECG parameters during 6months of follow-up. Our pilot study suggests that carbon ion radiotherapy is apromising radiation technique capable of sparing off-target side effects at the cardiac level. Alarger cohort, long-term follow-up and further prospective studies are needed to confirm these findings.

Safety of particle radiotherapy in patients with cardiac implantable electronic devices: Review of literature.

Safety of particle radiotherapy in patients with cardiac implantable electronic devices: Review of literature.

480 Addressing the education and training needs of RTT in particle radiation therapy

480 Addressing the education and training needs of RTT in particle radiation therapy

Tumor Redox‐Responsive Minimalist B/Fe Nano‐Chains for Chemodynamically Enhanced Ferroptosis and Synergistic Boron Neutron Capture Therapy

AbstractBoron neutron capture therapy (BNCT) as a binary targeted particle radiotherapy strategy has shown potent anti‐cancer potential. However, biological barriers and restricted blood supply pose challenges in achieving adequate boron concentration within deep‐seated tumor lesions. BNCT with other anti‐cancer therapies, such as X‐ray radiotherapy and photothermal therapy, is devised to address the limitations of BNCT efficiency. However, the potential risk of organ‐accumulating toxicity and treatment complexity of dual exogenous activation hinders its development. To address this problem, newly redox‐responsive boron nano‐chains (RBNC) are reported that combine BNCT and endogenous chemodynamic therapy (CDT)‐enhanced ferroptosis. RBNC specifically activates nanoparticle size conversion (large‐to‐small) in response to GSH/H2O2 in the tumor microenvironment, releasing boron delivery agents boron quantum dots (BQD) and Fe3+. RBNC exhibits negligible systemic toxicity while demonstrating high boron accumulation at tumor. Meanwhile, the introduction of Fe3+ not only produces ·OH through reaction with H2O2, but also depletes GSH and reduces GPX4 activity in tumors, resulting in amplified intracellular oxidative stress and chemodynamically enhanced ferroptosis. Thus, the work provides a strategy to solve the problem of insufficient boron concentration and poor targeting of boron delivery agents and fill the gaps of BNCT combined with CDT and ferroptosis.

Robot-assisted system for non-invasive wide-range flexible eye positioning and tracking in particle radiotherapy.

Particle (proton, carbon ion, or others) radiotherapy for ocular tumors is highly dependent on precise dose distribution, and any misalignment can result in severe complications. The proposed eye positioning and tracking system (EPTS) was designed to non-invasively position eyeballs and is reproducible enough to ensure accurate dose distribution by guiding gaze direction and tracking eye motion. Eye positioning was performed by guiding the gaze direction with separately controlled light sources. Eye tracking was performed by a robotic arm with cameras and a mirror. The cameras attached to its end received images through mirror reflection. To maintain a light weight, certain materials, such as carbon fiber, were utilized where possible. The robotic arm was controlled by a robot operating system. The robotic arm, turntables, and light source were actively and remotely controlled in real time. The videos captured by the cameras could be annotated, saved, and loaded into software. The available range of gaze guidance is 360° (azimuth). Weighing a total of 18.55kg, the EPTS could be installed or uninstalled in 10s. The structure, motion, and electromagnetic compatibility were verified via experiments. The EPTS shows some potential due to its non-invasive wide-range flexible eye positioning and tracking, light weight, non-collision with other equipment, and compatibility with CT imaging and dose delivery. The EPTS can also be remotely controlled in real time and offers sufficient reproducibility. This system is expected to have a positive impact on ocular particle radiotherapy.

MR-PVHEE: A novel magnetic resonance-guided parallel-beam very high-energy electron radiotherapy system

PurposeMR-guided very high-energy electron (VHEE) radiotherapy can combine the imaging advantages of MR with the dosimetry advantages of VHEE radiotherapy, which is of significant clinical value. However, VHEEs are highly susceptible to the Lorentz force generated by the MR magnetic field, and coupling MR and VHEEs is challenging. Here, we present a novel MR-guided parallel-beam VHEE (MR-PVHEE) radiotherapy system and confirm its feasibility and effectiveness. MethodThe proposed MR-PVHEE radiotherapy system includes an ingenious coupling model of MR and VHEEs and an electromagnetic steering parameters commissioning (ESP-COM) method for accurate delivery. First, by generating parallel VHEE (PVHEE) beamlets that point in the same direction as the MR main magnetic field, the coupling model based on triple-stage electromagnetic steering can significantly lessen the twisting and deflecting of the VHEE beamlets' delivery trajectory caused by the MR magnetic field. The dosimetric advantage of VHEEs will be enhanced by delicately utilizing the MR magnetic field to constrain lateral scatter. Then, the ESP-COM method based on Bayesian black-box optimization for the PVHEE beamlets is designed by constructing a cost function using the position and direction information of particles in phase space and optimizing the parameters to deliver the beamlets accurately to the target spots. Finite element electromagnetic modeling and Monte Carlo particle transport simulation are used to validate the MR-PVHEE. ResultsMR-PVHEE can generate the PVHEE beamlets in the same direction as the MR magnetic field and accurately deliver them to the target spots. The average position error is within 0.5 mm, and the average direction error is about 0.5°, which can meet the requirements of clinical treatment accuracy. MR-PVHEE can reduce the VHEE lateral penumbra and increase the dose drop gradient. ConclusionFor the first time, MR and VHEE radiotherapy are successfully coupled in this study, and the innovative MR-PVHEE radiotherapy system can elicit new modalities for MR-guided charged particle radiotherapy and spatially fractionated radiotherapy.

Potential Benefits of Combining Proton or Carbon Ion Therapy with DNA Damage Repair Inhibitors.

The use of charged particle radiotherapy is currently increasing, but combination therapy with DNA repair inhibitors remains to be exploited in the clinic. The high-linear energy transfer (LET) radiation delivered by charged particles causes clustered DNA damage, which is particularly effective in destroying cancer cells. Whether the DNA damage response to this type of damage is different from that elicited in response to low-LET radiation, and if and how it can be targeted to increase treatment efficacy, is not fully understood. Although several preclinical studies have reported radiosensitizing effects when proton or carbon ion irradiation is combined with inhibitors of, e.g., PARP, ATR, ATM, or DNA-PKcs, further exploration is required to determine the most effective treatments. Here, we examine what is known about repair pathway choice in response to high- versus low-LET irradiation, and we discuss the effects of inhibitors of these pathways when combined with protons and carbon ions. Additionally, we explore the potential effects of DNA repair inhibitors on antitumor immune signaling upon proton and carbon ion irradiation. Due to the reduced effect on healthy tissue and better immune preservation, particle therapy may be particularly well suited for combination with DNA repair inhibitors.

Long-term outcomes after particle radiation therapy in patients with nasopharyngeal adenoid cystic carcinoma

BackgroundNasopharyngeal adenoid cystic carcinoma (NACC) is a relatively rare salivary gland tumor that is generally associated with poor outcomes. High-dose radiotherapy is a key treatment for patients with NACC. This study reported the long-term efficacy and safety of particle beam radiation therapy (PBRT) for NACC.Methods and materialsTwenty-six patients with nonmetastatic NACC who received definitive PBRT alone were included in this retrospective study. The majority of patients (92.3%) had locally advanced disease. Twenty-five (96.15%) patients received intensity-modulated proton radiotherapy (IMPT) followed by a carbon ion radiotherapy (CIRT) boost, and one patient received CIRT alone. Overall survival (OS), local control (LC), regional control (RC), and distant metastasis control (DMC) rates were calculated via the Kaplan-Meier method.ResultsThe median follow-up time was 46.95 months for the entire cohort. Seven patients experienced local recurrence, and one patient experience neck lymph node recurrence. The 3- and 4-year OS, LC, RC, and DMC rates were 100% and 91.7%, 92.3% and 84.6%, 95.8% and 87.8%, and 90.2% and 71.3%, respectively. A total of 91.3% of the patients achieved complete remission of gross tumors at 1 year after PBRT. Severe acute toxicity was observed in only two patients. A grade 4 decrease in visual acuity was observed in one patient with orbital apex invasion. No late grade 3 or 5 toxicity was observed.ConclusionDefinitive PBRT provided a satisfactory 4-year OS for patients with locally advanced NACC. The toxicity was acceptable and mild. Further follow-up is necessary to confirm the efficacy and safety of definitive PBRT for patients with NACC.

Ionization Detail Parameters for DNA Damage Evaluation in Charged Particle Radiotherapy: Simulation Study Based on Cell Survival Database.

Details of excitation and ionization acts hide a description of the biological effects of charged particle traversal through living tissue. Nanodosimetry enables the introduction of novel quantities that characterize and quantify the particle track structure while also serving as a foundation for assessing biological effects based on this quantification. This presents an opportunity to enhance the planning of charged particle radiotherapy by taking into account the ionization detail. This work uses Monte Carlo simulations with Geant4-DNA code for a wide variety of charged particles and their radiation qualities to analyze the distribution of ionization cluster sizes within nanometer-scale volumes, similar to DNA diameter. By correlating these results with biological parameters extracted from the PIDE database for the V79 cell line, a novel parameter R2 based on ionization details is proposed for the evaluation of radiation quality in terms of biological consequences, i.e., radiobiological cross section for inactivation. By incorporating the probability p of sub-lethal damage caused by a single ionization, we address limitations associated with the usually proposed nanodosimetric parameter Fk for characterizing the biological effects of radiation. We show that the new parameter R2 correlates well with radiobiological data and can be used to predict biological outcomes.

Evaluation of Helium Ion Radiotherapy in Combination with Gemcitabine in Pancreatic Cancer In Vitro.

Pancreatic cancer is one of the most aggressive and lethal cancers. New treatment strategies are highly warranted. Particle radiotherapy could offer a way to overcome the radioresistant nature of pancreatic cancer because of its biological and physical characteristics. Within particles, helium ions represent an attractive therapy option to achieve the highest possible conformity while at the same time protecting the surrounding normal tissue. The aim of this study was to evaluate the cytotoxic efficacy of helium ion irradiation in pancreatic cancer in vitro. Human pancreatic cancer cell lines AsPC-1, BxPC-3 and Panc-1 were irradiated with photons and helium ions at various doses and treated with gemcitabine. Photon irradiation was performed with a biological cabin X-ray irradiator, and helium ion irradiation was performed with a spread-out Bragg peak using the raster scanning technique at the Heidelberg Ion Beam Therapy Center (HIT). The cytotoxic effect on pancreatic cancer cells was measured with clonogenic survival. The survival curves were compared to the predicted curves that were calculated via the modified microdosimetric kinetic model (mMKM). The experimental relative biological effectiveness (RBE) of helium ion irradiation ranged from 1.0 to 1.7. The predicted survival curves obtained via mMKM calculations matched the experimental survival curves. Mainly additive cytotoxic effects were observed for the cell lines AsPC-1, BxPC-3 and Panc-1. Our results demonstrate the cytotoxic efficacy of helium ion radiotherapy in pancreatic cancer in vitro as well as the capability of mMKM calculation and its value for biological plan optimization in helium ion therapy for pancreatic cancer. A combined treatment of helium irradiation and chemotherapy with gemcitabine leads to mainly additive cytotoxic effects in pancreatic cancer cell lines. The data generated in this study may serve as the radiobiological basis for future experimental and clinical works using helium ion radiotherapy in pancreatic cancer treatment.

Translational research of boron neutron capture therapy for spinal cord gliomas using rat model

Boron neutron capture therapy (BNCT) is a type of targeted particle radiation therapy with potential applications at the cellular level. Spinal cord gliomas (SCGs) present a substantial challenge owing to their poor prognosis and the lack of effective postoperative treatments. This study evaluated the efficacy of BNCT in a rat SCGs model employing the Basso, Beattie, and Bresnahan (BBB) scale to assess postoperative locomotor activity. We confirmed the presence of adequate in vitro boron concentrations in F98 rat glioma and 9L rat gliosarcoma cells exposed to boronophenylalanine (BPA) and in vivo tumor boron concentration 2.5 h after intravenous BPA administration. In vivo neutron irradiation significantly enhanced survival in the BNCT group when compared with that in the untreated group, with a minimal BBB scale reduction in all sham-operated groups. These findings highlight the potential of BNCT as a promising treatment option for SCGs.

Combined ion beam irradiation platform and 3D fluorescence microscope for cellular cancer research.

To improve particle radiotherapy, we need a better understanding of the biology of radiation effects, particularly in heavy ion radiation therapy, where global responses are observed despite energy deposition in only a subset of cells. Here, we integrated a high-speed swept confocally-aligned planar excitation (SCAPE) microscope into a focused ion beam irradiation platform to allow real-time 3D structural and functional imaging of living biological samples during and after irradiation. We demonstrate dynamic imaging of the acute effects of irradiation on 3D cultures of U87 human glioblastoma cells, revealing characteristic changes in cellular movement and intracellular calcium signaling following ionizing irradiation.

Novel concept of "sequential particle radiotherapy" with atezolizumab plus bevacizumab for hepatocellular carcinoma with portal vein tumor thrombus.

Owing to the high objective response rate of atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC), the concept of sequential conversion to local treatment has recently become mainstream. The conversion concept is mainly applied to Barcelona Clinic for Liver Cancer (BCLC) stage B cases, and radiotherapy is rarely considered as a conversion local treatment. We herein report three patients who were treated with the novel concept of "sequential particle radiotherapy," consisting of Atez/Bev therapy followed by particle radiotherapy (PRT) for HCC with advanced portal vein tumor thrombus (Vp3/4 PVTT). All patients achieved partial response radiologically and were switched to PRT. All patients were recurrence free at 1year after the introduction of Atez/Bev therapy without any additional treatment. This upcoming combination strategy includes the advocacy of sequential concepts for BCLC stage C cases and the introduction of PRT as a local treatment after Atez/Bev.

Patterns of Temporal Lobe Reaction and Radiation Necrosis after Particle Radiotherapy in Patients with Skull Base Chordoma and Chondrosarcoma-A Single-Center Experience.

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