Experimental evidence that carbon-ion radiotherapy utilizes cytotoxic T lymphocyte-mediated anti-tumor immunity for shrinking tumors compared to X-ray therapy.

The therapeutic efficacy of radiotherapy (RT) is primarily driven by two factors: biophysical DNA damage in cancer cells and radiation-induced anti-tumor immunity. However, Anti-tumor immune responses between X-ray RT (XRT) and carbon-ion RT (CIRT) remain unclear. In this study, we, employed mouse models to assess the immunological contribution, especially cytotoxic T-lymphocyte (CTL)-mediated immunity, to the therapeutic effectiveness of XRT and CIRT in shrinking tumors. We irradiated mouse intradermal tumors of B16F10-ovalbumin (OVA) mouse melanoma cells and 3LL-OVA mouse lung cancer cells with carbon-ion beams or X-rays in the presence or absence of CTLs. CTL removal was performed by administration of anti-CD8 monoclonal antibody (mAb) in mice. Based on tumor growth delay, we determined the tumor growth and regression curves. The enhancement ratio (ER) of the slope of regression lines in the presence of CTLs, relative to the absence of CTLs, indicates the dependency of RT on CTLs for shrinking mouse tumors, and the biological effectiveness (RBE) of CIRT relative to XRT were calculated. Tumor growth curves revealed that the elimination of CD8+ CTLs by administrating anti-CD8 mAb accelerated tumor growth compared to the presence of CTLs in both RTs. The ERs were larger in CIRT compared to XRT in the B16F10-OVA tumor models, but not in the 3LL-OVA models, suggesting a greater contribution of CTL-mediated anti-tumor immunity to tumor reduction in CIRT compared to XRT in the B16F10-OVA tumor model. In addition, the RBE values for both models were larger in the presence of CTLs compared to models without CTLs, suggesting that CIRT may utilize CTL-mediated anti-tumor immunity more than X-ray. The findings from this study suggest that although immunological contribution to therapeutic efficacy may vary depending on the type of tumor cell, CIRT utilizes CTL-mediated immunity to a greater extent compared to XRT.

Effectiveness and Safety of Carbon Ion Radiotherapy in Solid Tumors: A Systematic Review and Meta-Analysis.

PURPOSE: This systematic review and meta-analysis aimed to investigate the effectiveness of carbon ion radiotherapy (CIRT) compared to that of conventional radiotherapy in patients with various types of solid tumors. MATERIALS AND METHODS: We systematically searched eight electronic databases from inception until August 2022 in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The comparative effectiveness of the different treatment options was assessed by a random-effects meta-analysis. RESULTS: This review included 34 comparative studies and three treatment groups. Overall, the meta-analysis indicated comparable local control rates between the CIRT and control groups [pooled risk ratio (RR)=1.02, 95% confidence interval (CI) 0.90-1.15]. The local control rate in the CIRT group was higher than that in the photon therapy group, but slightly lower than that in the proton radiation therpy (PRT) group. Additionally, the CIRT group had significantly higher overall survival (OS) (RR=1.19, 95% CI=1.01-1.42) and progression-free survival (PFS) (RR=1.50, 95% CI=1.01-2.21) rates compared to the control group. In the subgroup analysis, survival rates were similar between the CIRT and PRT groups. CONCLUSION: CIRT was associated with improved toxicity, local tumor control, OS, and PFS compared to conventional treatments. Therefore, CIRT was found to be a safe and effective option for achieving local control in patients with solid tumors.

Assessing the Impact of Charged Particle Radiation Therapy for Head and Neck Adenoid Cystic Carcinoma: A Systematic Review and Meta-Analysis.

Purpose: Head and neck adenoid cystic carcinoma (HNACC) is a radioresistant tumor. Particle therapy, primarily proton beam therapy and carbon-ion radiation, is a potential radiotherapy treatment for radioresistant malignancies. This study aims to conduct a meta-analysis to evaluate the impact of charged particle radiation therapy on HNACC. Methods: A comprehensive search was conducted in Pubmed, Cochrane Library, Web of Science, Embase, and Medline until December 31, 2022. The primary endpoints were overall survival (OS), local control (LC), and progression-free survival (PFS), while secondary outcomes included treatment-related toxicity. Version 17.0 of STATA was used for all analyses. Results: A total of 14 studies, involving 1297 patients, were included in the analysis. The pooled 5-year OS and PFS rates for primary HNACC were 78% (95% confidence interval [CI] = 66-91%) and 62% (95% CI = 47-77%), respectively. For all patients included, the pooled 2-year and 5-year OS, LC, and PFS rates were as follows: 86.1% (95% CI = 95-100%) and 77% (95% CI = 73-82%), 92% (95% CI = 84-100%) and 73% (95% CI = 61-85%), and 76% (95% CI = 68-84%) and 55% (95% CI = 48-62%), respectively. The rates of grade 3 and above acute toxicity were 22% (95% CI = 13-32%), while late toxicity rates were 8% (95% CI = 3-13%). Conclusions: Particle therapy has the potential to improve treatment outcomes and raise the quality of life for HNACC patients. However, further research and optimization are needed due to the limited availability and cost considerations associated with this treatment modality.

Carbon ion radiotherapy for mesonephric adenocarcinoma of the uterine cervix: a case report.

BACKGROUND: Mesonephric adenocarcinoma is an extremely rare subtype of uterine cervical cancer that is associated with a poor prognosis and for which a standardized treatment protocol has not been established. Carbon ion radiotherapy (CIRT) is an emerging radiotherapy modality that has been shown to have a favorable anti-tumor effect, even for tumors resistant to conventional photon radiotherapy or chemotherapy. However, there is no report on CIRT outcomes for mesonephric adenocarcinoma of the uterine cervix. CASE PRESENTATION: We treated a 47-year-old Japanese woman with mesonephric adenocarcinoma of the uterine cervix (T2bN0M0 and stage IIB according to the 7th edition of the Union for International Cancer Control and International Federation of Gynecology and Obstetrics, respectively) with CIRT combined with brachytherapy and concurrent chemotherapy. CIRT consisted of whole pelvic irradiation and boost irradiation to the gross tumor; 36.0 Gy (relative biological effectiveness [RBE]) in 12 fractions and 19.2 Gy (RBE) in 4 fractions, respectively, performed once a day, four times per week. Computed tomography-based image-guided adaptive brachytherapy was performed after completion of CIRT, for which the D90 (i.e., the dose prescribed to 90% of the target volume) for the high-risk clinical target volume was 20.4 Gy in a total of 3 sessions in 2 weeks. A weekly cisplatin (40 mg/m2) dose was administered concomitantly with the radiotherapy for a total of five courses. From 4 months post-CIRT, the patient developed metastasis of the lung, with a total of 10 lung metastases over 70 months; these lesions were treated on each occasion by photon stereotactic body radiotherapy and/or systemic therapy. At 8 years from initial treatment (i.e., 2 years after the last treatment), the patient is alive without any evidence of recurrence and maintains a high quality of life. CONCLUSIONS: This is the first report of CIRT for treatment of mesonephric adenocarcinoma of the uterine cervix. The present case indicates the potential efficacy of CIRT in combination with brachytherapy for treatment of this disease.

[Safety Analysis Using Event Tree Analysis for Multi-Ion Therapy].

At the National Institutes for Quantum Science and Technology (QST), a multi-ion therapy using helium, carbon, oxygen, and neon ions has been studied for charged particle therapy with more optimal biological effects. To make multi-ion therapy clinically feasible, a new treatment system was developed to realize the changes of the ion species in each irradiation using the Heavy Ion Medial Accelerator in Chiba (HIMAC). Since radiation therapy is safety-critical, it is necessary to construct a safety system that includes multiple safety barriers in the new treatment system for multi-ion therapy and to perform a safety analysis for the prevention of serious accidents. In this study, we conducted a safety analysis using event tree analysis (ETA) for newly introduced processes in the treatment planning, accelerator, and irradiation system of the multi-ion therapy. ETA is an optimal method to verify multiple safety barriers that are essential for medical safety and to shorten the time for safety analysis by focusing only on the new processes. Through ETA, we clarified the types of malfunctions and human errors that may lead to serious accidents in the new system for multi-ion therapy, and verified whether safety barriers such as interlock systems and human check procedures are sufficient to prevent such malfunctions and human errors. As a result, 6 initial events which may lead to serious accidents were listed in the treatment planning process, 16 initial events were listed in the accelerator system, and 13 initial events were listed in the irradiation system. Among these 35 initial events, 5 cautionary initial events were identified that could lead to serious final events and they had a probability of occurrence higher than 10-4. Meanwhile, the others were all initial events that do not lead to serious accidents, or the initial events that can lead to serious accidents but were considered to have sufficient safety barriers. The safety analysis using ETA successfully identified the system malfunctions and the human errors that can lead to serious accidents, and the multiple safety barriers against them were systematically analyzed. It became clear that the multiple safety barriers were not sufficient for some initial events. We plan to improve the safety barriers for the five cautionary initial events before the start of the clinical trial. Based on these findings, we achieved our objective to conduct a safety analysis for a new treatment system for multi-ion therapy. The safety analysis procedure using ETA proposed by this study will be effective when new systems for radiotherapy are established at QST and other facilities in the future as well.

Biological dose optimization incorporating intra-tumoural cellular radiosensitivity heterogeneity in ion-beam therapy treatment planning.

Objective.Treatment plans of ion-beam therapy have been made under an assumption that all cancer cells within a tumour equally respond to a given radiation dose. However, an intra-tumoural cellular radiosensitivity heterogeneity clearly exists, and it may lead to an overestimation of therapeutic effects of the radiation. The purpose of this study is to develop a biological model that can incorporate the radiosensitivity heterogeneity into biological optimization for ion-beam therapy treatment planning.Approach.The radiosensitivity heterogeneity was modeled as the variability of a cell-line specific parameter in the microdosimetric kinetic model following the gamma distribution. To validate the developed intra-tumoural-radiosensitivity-heterogeneity-incorporated microdosimetric kinetic (HMK) model, a treatment plan with H-ion beams was made for a chordoma case, assuming a radiosensitivity heterogeneous region within the tumour. To investigate the effects of the radiosensitivity heterogeneity on the biological effectiveness of H-, He-, C-, O-, and Ne-ion beams, the relative biological effectiveness (RBE)-weighted dose distributions were planned for a cuboid target with the stated ion beams without considering the heterogeneity. The planned dose distributions were then recalculated by taking the heterogeneity into account.Main results. The cell survival fraction and corresponding RBE-weighted dose were formulated based on the HMK model. The first derivative of the RBE-weighted dose distribution was also derived, which is needed for fast biological optimization. For the patient plan, the biological optimization increased the dose to the radiosensitivity heterogeneous region to compensate for the heterogeneity-induced reduction in biological effectiveness of the H-ion beams. The reduction in biological effectiveness due to the heterogeneity was pronounced for low linear energy transfer (LET) beams but moderate for high-LET beams. The RBE-weighted dose in the cuboid target decreased by 7.6% for the H-ion beam, while it decreased by just 1.4% for the Ne-ion beam.Significance.Optimal treatment plans that consider intra-tumoural cellular radiosensitivity heterogeneity can be devised using the HMK model.

Treatment strategies and molecular mechanism of radiotherapy combined with immunotherapy in colorectal cancer.

Radiotherapy (RT) remodels the tumor immune microenvironment (TIME) and modulates the immune response to indirectly destroy tumor cells, in addition to directly killing tumor cells. RT combined with immunotherapy may significantly enhance the efficacy of RT in colorectal cancer by modulating the microenvironment. However, the molecular mechanisms by which RT acts as an immunomodulator to modulate the immune microenvironment remain unclear. Further, the optimal modalities of RT combined with immunotherapy for the treatment of colorectal cancer, such as the time point of combining RT and immunization, the fractionation pattern and dosage of radiotherapy, and other methods to improve the efficacy, are also being explored parallelly. To address these aspects, in this review, we summarized the mechanisms by which RT modulates TIME and concluded the progress of RT combined with immunization in preclinical and clinical trials. Finally, we discussed heavy ion radiation therapy and the efficacy of prediction markers and other immune combination therapies. Overall, combining RT with immunotherapy to enhance antitumor effects will have a significant clinical implication and will help to facilitate individualized treatment modalities.

Effectiveness of Carbon Ion Radiotherapy for Bone and Soft Tissue Sarcoma in Older Patients.

BACKGROUND/AIM: The aging population is expected to increase the occurrences of bone sarcoma (BS) and soft tissue sarcoma (STS). Carbon ion radiotherapy (CIRT) is reported to be effective for BS and several STSs. However, the effect of CIRT on clinical outcomes, functional prognoses, and quality of life (QOL) in older patients who underwent CIRT has not been reported. Therefore, we aimed to evaluate the effect of CIRT on clinical outcomes, functional prognoses and QOL in older patients with BS or STS. PATIENTS AND METHODS: This retrospective cohort study included 235 patients aged >70 years with BS or STS who underwent CIRT. Overall survival (OS), cancer-specific survival (CSS), and local control (LC) were evaluated in chordoma and non-chordoma patients. Furthermore, factors associated with post-CIRT Toronto Extremity Salvage Score (TESS) and EuroQoL 5-dimension 5-level (EQ-5D-5L) index were assessed. RESULTS: The overall 5-year LC, OS, and CSS rates were 81%, 62%, and 76%, respectively. In the chordoma and non-chordoma groups, the 5-year LC, OS, and CSS rates were 84%, 72%, and 87%; and 77%, 47%, and 60%, respectively. The mean post-CIRT TESS and EQ-5D-5L index were 75% and 0.71, respectively. The TESSs and EQ-5D-5L indices tended to be better among males, younger patients (<76 years old), patients with small tumor volumes, and patients with chordoma. CONCLUSION: CIRT is effective for older patients with BS, especially with chordoma, and STS with good LC and survival rates. Furthermore, post-treatment limb function and QOL were comparable with those of the other treatments and age groups.

Development of porous structure for broadening Bragg-peak in scanning carbon-ion radiotherapy: Monte Carlo simulation and experimental validation.

PURPOSE: The present study aimed to develop a porous structure with plug-ins (PSP) to broaden the Bragg peak width (BPW, defined as the distance in water between the proximal and distal 80% dose) of the carbon ion beam while maintaining a sharp distal falloff width (DFW, defined as the distance along the beam axis where the dose in water reduces from 80% to 20%). METHODS: The binary voxel models of porous structure (PS) and PSP were established in the Monte Carlo code FLUKA and the corresponding physical models were manufactured by 3D printing. Both experiment and simulation were performed for evaluating the modulation capacity of PS and PSP. BPWs and DFWs derived from each integral depth dose curves were compared. Fluence homogeneity of 430 MeV/u carbon-ion beam passing through the PSP was recorded by analyzing radiochromic films at six different locations downstream the PSP in the experiment. Additionally, by changing the beam spot size and incident position on the PSP, totally 48 different carbon-ion beams were simulated and corresponding deviations of beam metrics were evaluated to test the modulating stability of PSP. RESULTS: According to the measurement data, the use of PSP resulted in an average increase of 0.63 mm in BPW and a decrease of 0.74 mm in DFW compared to PS. The 2D radiation field inhomogeneities were lower than 3 % when the beam passing through a ≥ 10 cm PMMA medium. Furthermore, employing a spot size of ≥ 6 mm ensures that beam metric deviations, including BPW, DFW, and range, remain within a deviation of 0.1 mm across various incident positions. CONCLUSION: The developed PSP demonstrated its capability to effectively broaden the BPW of carbon ion beams while maintaining a sharp DFW comparing to PS. The superior performance of PSP, indicates its potential for clinical use in the future.

Dose-averaged LET optimized carbon-ion radiotherapy for head and neck cancers.

This feasibility study confirmed the initial safety and efficacy of a novel carbon-ion radiotherapy (CIRT) using linear energy transfer (LET) painting for head and neck cancer. This study is the first step toward establishing CIRT with LET painting in clinical practice and making it a standard practice in the future.

High-LET charged particles: radiobiology and application for new approaches in radiotherapy.

The number of patients treated with charged-particle radiotherapy as well as the number of treatment centers is increasing worldwide, particularly regarding protons. However, high-linear energy transfer (LET) particles, mainly carbon ions, are of special interest for application in radiotherapy, as their special physical features result in high precision and hence lower toxicity, and at the same time in increased efficiency in cell inactivation in the target region, i.e., the tumor. The radiobiology of high-LET particles differs with respect to DNA damage repair, cytogenetic damage, and cell death type, and their increased LET can tackle cells' resistance to hypoxia. Recent developments and perspectives, e.g., the return of high-LET particle therapy to the US with a center planned at Mayo clinics, the application of carbon ion radiotherapy using cost-reducing cyclotrons and the application of helium is foreseen to increase the interest in this type of radiotherapy. However, further preclinical research is needed to better understand the differential radiobiological mechanisms as opposed to photon radiotherapy, which will help to guide future clinical studies for optimal exploitation of high-LET particle therapy, in particular related to new concepts and innovative approaches. Herein, we summarize the basics and recent progress in high-LET particle radiobiology with a focus on carbon ions and discuss the implications of current knowledge for charged-particle radiotherapy. We emphasize the potential of high-LET particles with respect to immunogenicity and especially their combination with immunotherapy.

Range verification in heavy-ion therapy using a hadron tumour marker.

Objective.A new method to estimate the range of an ion beam in a patient during heavy-ion therapy was investigated, which was previously verified for application in proton therapy.Approach.The method consists of placing a hadron tumour marker (HTM) close to the tumour. As the treatment beam impinges on the HTM, the marker undergoes nuclear reactions. When the HTM material is carefully chosen, the activation results in the emission of several delayed, characteristicγrays, whose intensities are correlated with the remaining range inside the patient. When not just one but two reaction channels are investigated, the ratio between these twoγray emissions can be measured, and the ratio is independent of any beam delivery uncertainties.Main results.A proof-of-principle experiment with an16O ion beam and Ag foils as HTM was successfully executed. The107Ag(16O,x)112Sb and the107Ag(16O,x)114Sb reaction channels were identified as suitable for the HTM technique. When only oneγ-ray emission is measured, the resulting range-uncertainty estimation is at the 0.5 mm scale. When both channels are considered, a theoretical limit on the range uncertainty of a clinical fiducal marker was found to be ±290µm.Significance.Range uncertainty of a heavy-ion beam limits the prescribed treatment plan for cancer patients, especially the direction of the ion beam in relation to any organ at risk. An easy to implement range-verification technique which can be utilized during clinical treatment would allow treatment plans to take full advantage of the sharp fall-off of the Bragg peak without the risk of depositing excessive dose into healthy tissue.

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.

The study of virtual source position with the geometric convergent ratio errors prevention management method of spot scanning beam in carbon ion therapy.

INTRODUCTION: We developed a technique including preventing errors management method capable of dealing with the virtual source position delivered by different carbon ion energies from the pattern of spot scanning beam in this study. MATERIALS AND METHODS: A homemade large-format complementary metal-oxide-semiconductor (CMOS) sensor and Gaf Chromic EBT3 films were used for the virtual source position measurement. The Gaf films were embedded in a self-designed rectangular plastic frame to tighten the films and set up on a treatment couch for irradiation in the air with the film perpendicular to the carbon ion beam at the nominal source-axis-distance (SAD) as well as upstream and downstream from the SAD. The horizontal carbon ion beam with five energies at a machine opening field size was carried out in this study. The virtual source position was determined mainly with a linear regression by back projecting the full width half maximum (FWHM) to zero at a distance upstream from the various source-film-distance and double checks additionally with a geometric convergent method to avoid any mistakes caused by manual measurement on FWHM. RESULTS: The virtual source position for higher carbon ion energy has an obvious longer distance from the SAD since the more carbon ion beam energy, the less spreading affected by the horizontal and vertical magnetism, therefore, the distance of virtual source positions is decreased from SAD with high to low energy. CONCLUSION: The method for investigating the virtual source position in the carbon ion beam in this study can also be used for electrons and the proton. We have developed a technique capable of dealing with the virtual source position with a geometric convergent method to avoid any mistakes in spot scanning carbon ion beam.

Carbon-ion radiotherapy for oligometastatic liver disease: A national multicentric study by the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS).

Reports on the therapeutic efficacy and safety of carbon-ion radiotherapy (C-ion RT) for oligometastatic liver disease are limited, with insufficient evidence. This study aimed to evaluate the clinical outcomes of C-ion RT for oligometastatic liver disease at all Japanese facilities using the nationwide cohort data. We reviewed the medical records to obtain the nationwide cohort registry data on C-ion RT between May 2016 and June 2020. Patients (1) with oligometastatic liver disease as confirmed by histological or diagnostic imaging, (2) with ≤3 synchronous liver metastases at the time of treatment, (3) without active extrahepatic disease, and (4) who received C-ion RT for all metastatic regions with curative intent were included in this study. C-ion RT was performed with 58.0-76.0 Gy (relative biological effectiveness [RBE]) in 1-20 fractions. In total, 102 patients (121 tumors) were enrolled in this study. The median follow-up duration for all patients was 19.0 months. The median tumor size was 27 mm. The 1-year/2-year overall survival, local control, and progression-free survival rates were 85.1%/72.8%, 90.5%/78.0%, and 48.3%/27.1%, respectively. No patient developed grade 3 or higher acute or late toxicity. C-ion RT is a safe and effective treatment for oligometastatic liver disease and may be beneficial as a local treatment option in multidisciplinary treatment.

Validation of robust radiobiological optimization algorithms based on the mixed beam model for intensity-modulated carbon-ion therapy.

Currently, treatment planning systems (TPSs) that can compute the intensities of intensity-modulated carbon-ion therapy (IMCT) using scanned carbon-ion beams are limited. In the present study, the computational efficacy of the newly designed IMCT algorithms was analyzed for the first time based on the mixed beam model with respect to the physical and biological doses; moreover, the validity and effectiveness of the robust radiobiological optimization were verified. A dose calculation engine was independently generated to validate a clinical dose determined in the TPS. A biological assay was performed using the HSGc-C5 cell line to validate the calculated surviving fraction (SF). Both spot control (SC) and voxel-wise worst-case scenario (WC) algorithms were employed for robust radiobiological optimization followed by their application in a Radiation Therapy Oncology Group benchmark phantom under homogeneous and heterogeneous conditions and a clinical case for range and position errors. Importantly, for the first time, both SC and WC algorithms were implemented in the integrated TPS platform that can compute the intensities of IMCT using scanned carbon-ion beams for robust radiobiological optimization. For assessing the robustness, the difference between the maximum and minimum values of a dose-volume histogram index in the examined error scenarios was considered as a robustness index. The relative biological effectiveness (RBE) determined by the independent dose calculation engine exhibited a -0.6% difference compared with the RBE defined by the TPS at the isocenter, whereas the measured and the calculated SF were similar. Regardless of the objects, compared with the conventional IMCT, the robust radiobiological optimization enhanced the sensitivity of the examined error scenarios by up to 19% for the robustness index. The computational efficacy of the novel IMCT algorithms was verified according to the mixed beam model with respect to the physical and biological doses. The robust radiobiological optimizations lowered the impact of range and position uncertainties considerably in the examined scenarios. The robustness of the WC algorithm was more enhanced compared with that of the SC algorithm. Nevertheless, the SC algorithm can be used as an alternative to the WC IMCT algorithm with respect to the computational cost.

MR-guided ion therapy: Detector response in magnetic fields during carbon ion irradiation.

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

Clinical Outcomes of Intensity-modulated Carbon-ion Radiotherapy for Bone and Soft Tissue Tumors.

BACKGROUND/AIM: Carbon-ion radiotherapy (CIRT) for bone and soft tissue tumors (BSTs) has been reported to have favorable clinical outcomes. Intensity-modulated CIRT (IMCT) techniques have been developed to further reduce dose delivery to adjacent organs compared to conventional CIRT. We retrospectively analyzed the clinical results of IMCT for BSTs and investigated treatment efficacy and toxicity. PATIENTS AND METHODS: This study included 9 consecutive BSTs patients who underwent IMCT at the Kanagawa Cancer Center from January 2016 to April 2021. IMCT was administered at a dose of 60.8-70.4 Gy (relative biological effect) in 16 fractions. The time to event was calculated from the initiation of IMCT. Toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 5.0. RESULTS: The median age was 49 (range=16-71) years. The median observation period was 57.6 (range=7.0-77.8) months. There were 7 and 2 cases for IMCT because of proximity to the spinal cord and intestinal tract, respectively. There was one death during the observation period, which occurred 7.0 months after the initiation of treatment. Clinical recurrence occurred in 3 patients at 1.3, 17.8, and 22.4 months after the initiation of treatment, respectively. Acute toxicity of Grade 2 or higher was seen in 2 patients with Grade 2 pharyngeal mucositis. Late toxicities of Grade 2 or higher included 1 case each of Grade 2 neuralgia and peripheral neuropathy, as well as 1 case of Grade 3 fracture. CONCLUSION: IMCT for BSTs showed good local therapeutic efficacy and tolerable toxicity in patients with bone and soft tissue tumors.

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.

Particle beam therapy for pelvic recurrence of colorectal cancer: a registry data analysis in Japan and a systematic review.

The aim of this study was to investigate the efficacy and safety of particle beam therapy (PBT) with proton or carbon ion beam for pelvic recurrence of colorectal cancer (PRCC) by comparing the clinical outcomes of a dataset of prospectively enrolled patients for PBT with those from the literature, which were collected by a systematic review of external X-ray radiotherapy (XRT) and PBT. Patients with PRCC treated at 14 domestic facilities between May 2016 and June 2019 and entered the database for prospective observational follow-up were analyzed. The registry data analyzed included 159 PRCC patients treated with PBT of whom 126 (79%) were treated with carbon ion radiation therapy (CIRT). The 3-year overall survival and local control rate were 81.8 and 76.4%, respectively. Among these PRCC patients, 5.7% had Grade 3 or higher toxicity. Systematic search of PubMed and Cochrane databases published from January 2000 to September 2020 resulted in 409 abstracts for the primary selection. Twelve studies fulfilled the inclusion criteria. With one additional publication, 13 studies were selected for qualitative analysis, including 9 on XRT and 4 on PBT. There were nine XRT studies, which included six on 3D conformal radiotherapy and three on stereotactic body radiation therapy, and four PBT studies included three on CIRT and one on proton therapy. A pilot meta-analysis using literatures with median survival time extractable over a 20-month observation period suggested that PBT, especially CIRT, may be a promising treatment option for PRCC not amenable to curative resection.