Search

Purpose To develop and validate combined ion-beam with constant relative biological effectiveness (RBE) (CICR) particle therapy in single field arrangements for improved treatment efficacy, robustness, and normal tissue sparing. Methods and Materials The PRECISE (PaRticle thErapy using single and Combined Ion optimization StratEgies) treatment planning system was developed to investigate clinical viability of CICR treatments. Single-field uniform dose (SFUD) with a single ion (proton [p], helium [He], or carbon [C]) and CICR (C-p and C-He) treatments were generated for 3 patient cases with a clinically prescribed dose of 3 Gy (RBE) per fraction. Spread-out Bragg peak plans were irradiated in homogenous and clinical-like settings using an anthropomorphic head phantom. A dosimetric and biological verification of CICRC-p treatments using a murine glioma cell line (GL261) was performed. Results CICR treatment plans for the 3 patients presented highly uniform physical dose while reducing high dose-averaged linear energy transfer gradients compared with carbon ions alone. When considering uncertainty in tissue parameter (α/β)x assignment and RBE modeling, the CICRC-p treatment exhibited enhanced biophysical stability within the target volume, similar to protons alone. CICR treatments reduced dose to normal tissue surrounding the target, exhibiting similar or improved dosimetric features compared with SFUDHe. For both CICRC-p and SFUD treatments, measurements verified the planned dose in the target within ∼3%. Planned versus measured target RBE values were 1.38 ± 0.02 and 1.39 ± 0.07 ( Conclusions Here, we demonstrate that by combining 2 (or more) ions in a single field arrangement, more robust biological and more conformal dose distributions can be delivered compared with conventional particle therapy treatment planning. This work constitutes the first dosimetric and biological verification of multi-ion particle therapy in homogeneous as well as heterogenous settings.

Background and summary: Among all vulvar cancers, primary adenoid cystic carcinoma (ACC) of Bartholin’s gland is a very rare tumor characterized by a slow growth, a high local aggressiveness, and a remarkable recurrence rate. Due to its rarity, treatment remains a challenge for oncologists and gynecological surgeons. Key message: The present paper reports clinical, radiological, and histological features of ACC of Bartholin’s gland and reviews the literature data on the treatment options with a particular focus on the potential role of particle radiation therapy.

Hepatocellular carcinoma (HCC) often recurs in the liver and requires multiple rounds of treatment. Thus, less-invasive multidisciplinary approaches are essential for preserving liver function, especially in elderly patients. Here, we report a case of an 86 year-old Japanese male patient with HCC who was successfully treated with repeated carbon ion radiotherapy (C-ion RT) and transarterial chemoembolization (TACE). The patient had alcoholic liver cirrhosis with a 60 mm HCC lesion and a satellite lesion in segment 6. The patient underwent initial C-ion RT but developed primary tumor recurrence (segment 6) and a new lesion (segment 2) 24 months later. The patient received TACE for each lesion, followed by an increased dose of C-ion RT for the recurrent primary tumor. Although the primary tumor lesion was well controlled, the patient subsequently developed new lesions, and TACE was repeated. The patient died of bacterial pneumonia 88 months after the initial treatment. His general condition and liver function were well preserved, and no severe adverse events were observed throughout the course of treatment. These results suggest that a less-invasive multidisciplinary approach involving repeated C-ion RT combined with TACE enables preservation of liver function, which may contribute to long-term survival in elderly patients with HCC.

Carbon ion radiotherapy (CIRT) treatment planning is based on relative biological effectiveness (RBE) weighted dose calculations. A large amount of clinical evidence for CIRT was collected in Japan with RBE estimated by the modified microdosimetric kinetic model (MKM) while all European centres apply the first version of the local effect model (LEM). Japanese schedules have been used in Europe with adapted prescription dose and organs at risk (OAR) dose constraints. Recently, less conservative adapted LEM constraints have been implemented in clinical practice. The aim of this study was to analyse the new set of LEM dose constraints for brain parenchyma, brainstem and optic system considering both RBE models and evaluating early clinical data.31 patients receiving CIRT at MedAustron were analysed using the RayStation v9A planning system by recalculating clinical LEM-based plans in MKM. Dose statistics (D1cmBased on derived fits, currently applied LEM constraints matched recommended MKM constraints with deviations between -8% and +3.9%. For particular cases, data did not follow the expected LEM vs MKM trends resulting in outliers. Radiological (asymptomatic) toxicity was detected in two outlier cases.Respecting LEM constraints does not automatically ensure that MKM constraints are met. Constraints for both RBE models need to be fulfilled for future CIRT patients at MedAustron. Careful selection of planning strategies is essential.

Zeitschrift für medizinische Physik 32(1), 6 - 22 (2022). doi:10.1016/j.zemedi.2021.11.003, The advantageous depth dose profile of ion beams together with state of the art beam delivery and treatment planning systems allow for highly conformal tumor treatments in patients. First treatments date back to 1954 at the Lawrence Berkeley Laboratory (LBL) and in Europe, ion beam therapy started in the mid-1990s at the Paul-Scherrer Institute (PSI) with protons and at the Helmholtz Center for Heavy Ion Research (GSI) with carbon ions, followed by the Heidelberg Ion Therapy Center (HIT) in Heidelberg. This review describes the historical development of ion beam therapy in Germany based on the pioneering work at LBL and in the context of simultaneous developments in other countries as well as recent developments., Published by Elsevier, Urban & Fischer, Amsterdam

Medical physics 49(8), 5589 - 5603 (2022). doi:10.1002/mp.15805, Published by AAPM, College Park, Md.

Primary malignant melanoma of the female urethra (PMMFU) is extremely rare, accounting for 0.2% of all melanomas, and fewer than 200 cases have been reported worldwide. Because of the small number of clinical cases and unclear biological characteristics, there is no uniform and standard treatment protocol. We herein describe the treatment of PMMFU using carbon ion radiotherapy. The radiotherapy was delivered at 60.8 Gy (RBE) in 16 fractions, once daily, five times per week. The patient achieved complete tumor disappearance within 1 year after carbon ion radiotherapy and remained disease-free thereafter. She developed acute grade 1 radiation dermatitis and urethritis, which resolved quickly; no other toxic effects were observed. At the time of this writing, her survival duration was 33 months. This case demonstrates that carbon ion radiotherapy may be a good option for primary genitourinary mucosal malignancies.

Background/aim We evaluated the efficacy and safety of carbon-ion radiotherapy (CIRT) alone for Stage III non-small-cell lung cancer (NSCLC). Patients and methods Data of 65 patients (median age=73 years) with Stage III NSCLC who underwent CIRT alone in the QST Hospital, Chiba, Japan, between 1997 and 2015 were retrospectively analysed. The median dose was 72.0 Gy (relative biological effectiveness). Results The median follow-up was 27.6 months (range=1.6-207.7 months). Two-year local control, progression-free survival (PFS), and overall survival (OS) rates were 73.9%, 38.6%, and 54.9%, respectively. Overall, 1 (2%), 4 (6%), and 1 (2%) patient developed Grade 4 (mediastinal haemorrhage), Grade 3 (radiation pneumonitis), and Grade 3 (bronchial fistula) toxicities, respectively. On univariate analysis, clinical T and N stage and CIRT timing were significant predictors of PFS and OS; clinical target volume was a significant predictor of PFS. Conclusion CIRT alone is effective with acceptable toxicity for Stage III NSCLC.

Purpose The purpose of this study was to study the field size effect on the estimated Relative Biological Effectiveness (RBE) for carbon scanning beam irradiation. Methods A silicon-on-insulator (SOI) microdosimeter system developed by the Centre for Medical Radiation Physics, University of Wollongong, Australia, was used for lineal-energy measurements (microdosimetric quantity). The RBE values were derived based on the modified microdosimetric kinetic model (MKM) at different depths in a water phantom in the scanning carbon beam for various scanned areas. Results Our study shows that the difference in RBE values derived from the SOI microdosimeter measurements with the MKM model and from the Treatment Planning System (TPS). The difference of the RBE values is within 6.5 % at the peak point of the spread-out Bragg Peak (SOBP) region. Compared to the spot-beam, RBE values obtained in the scanned-beam with a larger scanned area of 1.0 × 1.0 cm2 have better agreement with which estimated by the TPS. Conclusions This study shows the possibility of using the SOI microdosimeter system as a quality assurance (QA) tool for RBE evaluation in carbon-pencil beam scanning radiotherapy.

Background Although carbon‐ion radiotherapy (C‐ion RT) with concurrent chemotherapy (chemo‐C‐ion RT) is a promising treatment for adenocarcinoma (AC) of the uterine cervix, its long‐term efficacy remains unclear. We evaluated the long‐term significance of concurrent weekly cisplatin and C‐ion RT for locally advanced AC of the uterine cervix. Methods We performed a pooled analysis of patients with stage IIB–IVA AC of the uterine cervix who underwent C‐ion RT alone or chemo‐C‐ion RT between September 2007 and December 2018 at our institution. Patients received 74.4 Gy (relative biological effectiveness) with or without cisplatin (40 mg/m2 per week for up to 5 weeks), underwent no prior pelvic RT or systemic therapy, and had a performance status of 0‐2. Propensity score matching was based on the year of diagnosis, regional lymph node metastasis, and stage. Results The matched cohort contained 26 patients who underwent C‐ion RT and 26 who underwent chemo‐C‐ion RT. The median age and follow‐up period were 57 (range, 28‐79) years and 34 (range, 2‐126) months, respectively. The 5‐year overall survival rate was significantly better in the chemo‐C‐ion RT group (72%) than in the C‐ion RT group (46%; P = .041). The 5‐year distant metastatic‐free rate was also significantly better in the chemo‐C‐ion RT group (66%) than in the C‐ion RT group (41%; P = .048). The incidence of grade ≥ 3 late toxicities was comparable between the two groups. Conclusions Chemo‐C‐ion RT for locally advanced AC of the uterine cervix is associated with a long‐term survival benefit., Chemo‐C‐ion radiotherapy improves survival for uterine cervical adenocarcinoma. Chemo‐C‐ion radiotherapy has improved distant metastatic‐free rates. C‐ion radiotherapy with cisplatin is more effective than C‐ion radiotherapy alone.

Objective Atypical and anaplastic meningiomas, unlike their benign counterparts, are highly aggressive, locally destructive, and likely to recur after treatment. These diseases are difficult to definitively treat with traditional radiotherapy without injuring adjacent brain parenchyma. The physical properties of ion radiotherapy allows for treatment plans that avoid damaging critical neural structures. The objectives of this systematic review were to evaluate the use and efficacy of ion radiotherapy in the treatment of atypical and anaplastic meningiomas. Methods We performed a systematic review of the literature by querying the PubMed and Ovid databases to identify and examine literature addressing the efficacy of ion radiotherapy in maintaining long-term local tumor control for patients with atypical or anaplastic meningiomas. The outcome of interest was rate of local tumor control at 5 years after ion radiotherapy. Results Across the included studies, proton therapy delivered a mean local control rate of 59.62% after 5 years. Carbon ion radiotherapy studies showed local control rates of 95% and 63% at 2 years for grade II and III meningiomas, respectively. In contrast, carbon ion radiotherapy studies that failed to differentiate between atypical and anaplastic meningiomas produced a local control rate of 33% at 2 years. Conclusions Proton and carbon ion radiotherapy maintain comparable rates of local control to conventional photon therapy and allow for more targeted treatment plans that may limit excess radiation damage. Although additional prospective trials are needed, ion therapy represents a burgeoning field in the treatment of atypical and anaplastic meningiomas.

Little information is available on the risk factors for nasolacrimal duct obstruction after radiotherapy for head and neck tumors. We investigated the incidence and predictive dosimetric parameters for nasolacrimal duct obstruction following carbon-ion radiotherapy for head and neck tumors.Twenty-eight patients with head and neck non-squamous cell carcinoma were analyzed in this single-institution prospective study. More than half of the tumors were located in the nasal cavity and maxillary sinus. Carbon-ion radiotherapy consisting of 57.6 or 64.0 Gy(relative biological effectiveness; RBE) in 16 fractions was administered. Nasolacrimal duct obstruction was recorded according to Common Terminology Criteria for Adverse Events version 4.0. Cutoff values were determined using receiver operating characteristic (ROC) curve analysis. VX indicates the volume irradiated with X Gy(RBE).The median follow-up period was 60.3 months. Incidences of Grade 1 and 2 nasolacrimal duct obstructions were 46% (13/28) and 7% (2/28), respectively; no Grade 3 or greater toxicities were recorded. Throughout the dose range, the volumes of the irradiated nasolacrimal ducts were significantly higher in the obstruction-positive patients than in the obstruction-negative patients (p 0.001 for V10, V20, V30, V40, V50, and V60). Cutoff values determined by the ROC curve analysis classified the obstruction-positive patients with an accuracy of96% over the entire range of V10-V60.The incidence and predictive dosimetric parameters for nasolacrimal duct obstruction after carbon-ion radiotherapy were demonstrated in a prospective cohort. These data should help optimize carbon-ion radiotherapy treatments for patients with head and neck tumors.

Proton heavy ion radiotherapy is widely used and currently represents the most advanced radiotherapy technology. However, at present, proton heavy ion radiotherapy chairs in fixed beam radiotherapy rooms do not have a head and neck positioning function. This paper presents a novel design for a proton heavy ion radiotherapy chair with a head and neck positioning device. The design of the posture adjustment mechanism and the head and neck positioning device of the treatment chair is based on U-TRIZ theory and ergonomics, respectively. A positive kinematic analysis of the posture adjusting mechanism was carried out, as well as a workspace analysis of the head and neck positioning device. Finally, positioning error experiment and ergonomic evaluation were performed on a prototype of the head and neck positioning device. The proposed design of the treatment chair satisfies the requirements for posture adjustment and achieves the head and neck positioning function. The experimental results also provide a basis for further optimization of the design.

Background Due to the physical dose distribution characteristic of “Bragg peak” and the biological effect as a kind of high linear energy transfer ray, heavy ion therapy has advantages over conventional photon therapy in both efficacy and safety. Based on the evidence that prostate cancer lesions before treatment are the most common sites of tumor residual or recurrence after treatment, simultaneous integrated boost radiation therapy for prostate cancer has been proven to have the advantage of improving efficacy without increasing toxicities. Methods This study is a prospective phase II randomized controlled clinical trial evaluating the efficacy and safety of functional imaging-guided carbon ion irradiation with simultaneous integrated boost for localized prostate cancer. One hundred and forty patients with localized prostate cancer will be randomized into carbon ion radiotherapy group and simultaneous integrated boost carbon ion radiotherapy group at a 1:1 ratio. The primary endpoint is to compare the incidence of treatment-related grade 2 and higher acute toxicities between the two groups according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. Secondary endpoints are late toxicities, biochemical relapse-free survival, overall survival, progression-free survival, and quality of life. Discussion This study adopts functional imaging-guided simultaneous integrated boost of carbon ion radiotherapy for localized prostate cancer, aiming to evaluate the differences in the severity and incidence of acute toxicities in patients with localized prostate cancer treated with carbon ion radiotherapy and simultaneous integrated boost carbon ion radiotherapy, in order to optimize the carbon ion treatment strategy for localized prostate cancer. Trial registration ClinicalTrials.gov NCT05010343. Retrospectively registered on 18 August 2021

The coronavirus disease 2019 (COVID-19) pandemic has greatly disrupted the normal treatment of patients with liver cancer and increased their risk of death. The weight of therapeutic safety was significantly amplified for decision-making to minimize the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Herein, the safety and effectiveness of carbon ion radiotherapy (CIRT) for unresectable liver cancer (ULC) were evaluated, and Chinese experiences were shared to solve the predicament of ULC treatment caused by SARS-CoV-2. Worldwide studies were collected to evaluate CIRT for ULC as the world has become a community due to the COVID-19 pandemic. We not only searched five international databases including the Cochrane Library, Web of Science, PubMed, Embase, and Scopus but also performed supplementary retrieval with other sources. Chinese experiences of fighting against COVID-19 were introduced based on the advancements of CIRT in China and a prospective clinical trial of CIRT for treating ULC. A total of 19 studies involving 813 patients with ULC were included in the systematic review. The qualitative synthetic evaluation showed that compared with transarterial chemoembolization (TACE), CIRT could achieve superior overall survival, local control, and relative hepatic protection. The systematic results indicated that non-invasive CIRT could significantly minimize harms to patients with ULC and concurrently obtain superior anti-cancer effectiveness. According to the Chinese experience, CIRT allows telemedicine within the hospital (TMIH) to keep a sufficient person-to-person physical distance in the whole process of treatment for ULC, which is significant for cutting off the transmission route of SARS-CoV-2. Additionally, CIRT could maximize the utilization rate of hospitalization and outpatient care (UHO). Collectively, CIRT for ULC patients not only allows TMIH and the maximized UHO but also has the compatible advantages of safety and effectiveness. Therefore, CIRT should be identified as the optimal strategy for treating appropriate ULC when we need to minimize the risk of SARS-CoV-2 infection and to improve the capacity of medical service in the context of the unprecedented COVID-19 crisis.

Introduction: Carbon ion radiotherapy (CIRT) is a novel treatment for prostate cancer (PCa). However, the underlying mechanism for the individualized response to CIRT is still not clear. Metabolic reprogramming is essential for tumor growth and proliferation. Although changes in metabolite profiles have been detected in patients with cancer treated with photon radiotherapy, there is limited data regarding CIRT-induced metabolic changes in PCa. Therefore, the study aimed to investigate the impact of metabolic reprogramming on individualized response to CIRT in patients with PCa.Materials and Methods: Urine samples were collected from pathologically confirmed patients with PCa before and after CIRT. A UPLC-MS/MS system was used for metabolite detection. XCMS online, MetDNA, and MS-DIAL were used for peak detection and identification of metabolites. Statistical analysis and metabolic pathway analysis were performed on MetaboAnalyst.Results: A total of 1,701 metabolites were monitored in this research. Principal component analysis (PCA) revealed a change in the patient's urine metabolite profiles following CIRT. Thirty-five metabolites were significantly altered, with the majority of them being amino acids. The arginine biosynthesis and histidine metabolism pathways were the most significantly altered pathways. Hierarchical cluster analysis (HCA) showed that after CIRT, the patients could be clustered into two groups according to their metabolite profiles. The arginine biosynthesis and phenylalanine, tyrosine, and tryptophan biosynthesis pathways are the most significantly discriminated pathways.Conclusion: Our preliminary findings indicate that metabolic reprogramming and inhibition are important mechanisms involved in response to CIRT in patients with PCa. Therefore, changes in urine metabolites could be used to timely assess the individualized response to CIRT.

Radiotherapy plays a key role in breast cancer treatment, and recent technical advances have been made to improve the therapeutic window by limiting the risk of radiation-induced toxicity or by increasing tumor control. Hadrontherapy is a form a radiotherapy relying on particle beams; compared with photon beams, particle beams have specific physical, radiobiological and immunological properties, which can be valuable in diverse clinical situations. To date, available hadrontherapy techniques for breast cancer irradiation include proton therapy, carbon ion radiation therapy, fast neutron therapy and boron neutron capture therapy. This review analyzes the current rationale and level of evidence for each hadrontherapy technique for breast cancer.

A charged particle therapy was proposed by Robert R. Wilson in 1946 and a clinical study of proton radiotherapy had been started at Lawrence Berkeley National Laboratory in 1954. Clinical studies have been promoted mainly in the United States and Europe. However, in Japan as well, the University of Tsukuba (KEK Campus) and the National Institute of Radiological Sciences (NIRS) started proton radiotherapy around 1980, and NIRS started carbon-ion radiotherapy in 1994. Following pioneering clinical studies, now in Japan, many proton and carbon-ion radiotherapy facilities are in operation, and some vendors are supplying equipment. Among them, charged particle therapy technologies originating in Japan have been developed, such as a respiratory-gated irradiation technology, a spot scanning irradiation technology, and a clinical dose design for ion radiotherapy. I look back on them and discuss the future direction of research and development of the charged particle therapy.

The relative biological efficiency of particle irradiation could be predicted with a wide variety of radiobiological models for various end-points. We validate the forecast of modified Microdosimetric Kinetic Model in vitro using combined data of reference Co-60 radiation and carbon ion plateau data for specific cell line to optimize the survival function in spread-out Bragg Peak obtained with an especially designed ridge filter. We used Geant4 Monte-Carlo software to simulate the fragment contribution along Bragg curve inside water phantom, open-source toolkit Survival to predict the expected linear-quadratic model parameters for each fragment, and in-house software to form the total survival curve in spread-out Bragg Peak. The irradiation was performed at U-70 synchrotron with an especially designed Aluminum ridge filter under the control of PTW and in-house ionization chambers. The cell clonogenic assay was conducted with the B14–150 cell line. The data analysis was accomplished using scipy and CERN ROOT. The clonogenic assay represents the survival in spread-out Bragg Peak at different points and qualitatively follows the modeled survival curve very well. The quantitative difference is within 3σ, and the deviation might be explained by the uncertainties of physical modeling using Monte-Carlo methods. Overall, the obtained results are promising for further usage in radiobiological studies or carbon ion radiotherapy. Shaping the survival curve in the region of interest (i.e., spread-out Bragg Peak) is a comprehensive task that requires high-performance computing approaches. Nevertheless, the method’s potential application is related to the development of next-generation treatment planning systems for ion beams. This can open a wide range of improvements in patient treatment outcome, provide new optimized fractionation regimes or optimized dose delivery schemes, and serve as an entrance point to the translational science approach.

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.

Chromosome aberrations are widely considered among the best biomarkers of radiation health risk due to their relationship with late cancer incidence. In particular, aberrations in peripheral blood lymphocytes (PBL) can be regarded as indicators of hematologic toxicity, which is a major limiting factor of radiotherapy total dose. In this framework, a radiobiological database describing the induction of PBL dicentrics as a function of ion type and energy was developed by means of the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model, which has been previously applied to predict the effectiveness of therapeutic-like ion beams at killing tumour cells. This database was then read by the FLUKA Monte Carlo transport code, thus allowing us to calculate the Relative Biological Effectiveness (RBE) for dicentric induction along therapeutic C-ion beams. A comparison with previous results showed that, while in the higher-dose regions (e.g., the Spread-Out Bragg Peak, SOBP), the RBE for dicentrics was lower than that for cell survival. In the lower-dose regions (e.g., the fragmentation tail), the opposite trend was observed. This work suggests that, at least for some irradiation scenarios, calculating the biological effectiveness of a hadrontherapy beam solely based on the RBE for cell survival may lead to an underestimation of the risk of (late) damage to healthy tissues. More generally, following this work, BIANCA has gained the capability of providing RBE predictions not only for cell killing, but also for healthy tissue damage.

From August 2019 to August 2020, we inserted polyglycolic acid (PGA) spacers and administered carbon ion radiotherapy (CIRT) to three cases of retroperitoneal sarcoma at our hospital. We aimed to investigate its utility and safety for retroperitoneal sarcoma. We analyzed changes in PGA spacer volume and corresponding computed tomography (CT) values in addition to the dose distribution using in-room CT images that were obtained during treatment. We assessed adverse events and investigated the suitability, safety and effectivity of PGA spacer insertion. During treatment, changes in PGA spacer volumes and CT values were confirmed. Volumes increased in patients with a folded PGA spacer, and it increased 1.6-fold by the end of irradiation compared with planning CT. The CT values decreased by 20–50 Hounsfield units at the end of irradiation compared to the planning CT. Dose distribution evaluation showed that the dose to the gastrointestinal tract adjacent to the tumor was maintained below the tolerable dose, and a sufficient dose was delivered to the target by PGA spacer insertion. One case of subileus caused during abdominal surgery for PGA spacer insertion occurred. No other adverse events, such as digestive disorders, were observed. CIRT with PGA spacer insertion for retroperitoneal sarcomas is safe and effective. For cases in which there is no option but to perform irradiation using a PGA spacer, precautionary measures such as verification of dose distributions using CT images are necessary.

This study aimed to explore the prognostic factors associated with acute radiation dermatitis (ARD). A normal tissue complication probability (NTCP) model for ARD in patients with head and neck cancer treated with carbon ion radiation therapy was developed.A total of 187 patients were included in the analysis, and the endpoint was ≥grade 2 ARD. The biological and physical dose-surface parameters associated with ARD were used in the logistic regression model. The mean areas under the receiver operating characteristic curve in the internal cross-validation and Akaike's corrected Information Criterion were examined for model evaluation and selection. The multivariate logistic regression NTCP models were established based on factors with weak correlation.Tumor volume, planning target volume to the skin, radiation technique and all dose-surface parameters were significantly associated with ARD (P.05). Models with high performance for grade 2 to 3 ARD were constructed. The most significant prognostic predictors were SNTCP models for ARD may provide a basis for the development of individualized treatment strategies and reduce the incidence of severe ARD in patients with head and neck cancer receiving carbon ion radiation therapy. Furthermore, biological and physical dose-surface parameter-based models are comparable. However, further validation with more evaluation parameters is warranted.

Photon-based radiotherapy upregulates Notch signaling in cancer, leading to the acquisition of the stem cell phenotype and induction of invasion/migration, which contributes to the development of resistance to therapy. However, the effect of carbon ion radiotherapy (CIRT) on Notch signaling in glioma and its impact on stemness and migration is not explored yet. Human glioma cell lines (LN229 and U251), stable Notch1 intracellular domain (N1ICD) overexpressing phenotype of LN229 cells, and Notch inhibitor resistant LN229 cells (LN229R) were irradiated with either photon (X-rays) or (carbon ion irradiation) CII, and expressions of Notch signaling components were accessed by RT-PCR, Western blotting, and enzymatic assays and flow cytometry. Spheroid forming ability, cell migration, and clonogenic assay were used to evaluate the effect of modulated Notch signaling by irradiation. Our results show that X-ray irradiation induced the expression of Notch signaling components such as Notch receptors, target genes, and ADAM17 activity, while CII reduced it in glioma cell lines. The differential modulation of ADAM17 activity by CII and X-rays affected the cell surface levels of NOTCH1 and NOTCH2 receptors, as they were reduced by X-ray irradiation but increased in response to CII. Functionally, CII reduced the spheroid formation and migration of glioma cells, possibly by downregulating the N1ICD, as stable overexpression of N1ICD rescued these inhibitory effects of CII. Moreover, LN229R that are less reliant on Notch signaling for their survival showed less response to CII. Therefore, downregulation of Notch signaling resulting in the suppression of stemness and impaired cell migration by CII seen here may reduce tumor regrowth and disease dissemination, in addition to the well-established cytotoxic effects.

Introduction. We present a mathematical method to adjust the leaf end position for dose calculation correction in the carbon ion radiation therapy treatment planning system. Methods and Materials. A straggling range algorism of 400 MeV/n carbon ion beam in nine different multileaf collimator (MLC) materials was conducted to calculate the dose 50% point to derive the offset corrections in the carbon ion treatment planning system (ciPlan). The visualized light field edge position in the treatment planning system is denoted as X tang . p , and MLC position ( X mlc . p ) is defined as the source to leaf end midpoint projection on axis for monitor unit calculation. The virtual source position of energy at 400 MeV/n and straggling range in MLC at different field sizes were used to calculate the dose 50% position on axis. On-axis MLC offset (correction) could then be obtained from the position corresponding to 50% of the central axis dose minus the X mlc . p . Results. The exact MLC position in the carbon ion treatment planning system can be used as an offset to do the correction. The offset correction of pure tungsten is the smallest among the others due to its shortest straggling range of carbon ion beam in MLC. The positions of 50% dose of all MLC materials are always located in between X tang . p and X mlc . p under the largest field of 12 cm by 12 cm. Conclusions. MLC offset should be adjusted carefully at different field sizes in the treatment planning systems especially of its small penumbra characteristic in the carbon ion beam. It is necessary to find out the dose 50% position for adjusting MLC leaf edge on-axis location in the treatment planning system to reduce dose calculation error.

Introduction: Giant cell tumor (GCT) of the bone is a benign–malignant intermediate tumor with locally destructive growth and a relatively high local recurrence rate. Neurological symptoms may develop in patients with GCT of the spine, and surgical treatment is prioritized in cases where resection is possible. However, the local recurrence rate of GCT of the bone is higher than that of GCT at other sites owing to the associated surgical challenges, and treatment is often difficult. No study to date has reported long-term remission of recurrent tumors for more than 5 years by treatment with carbon ion beam radiotherapy after resection of GCT of the cervical spine. Patient concerns: A 14-year-old boy who experienced recurrence after surgery for GCT of the cervical spine. Diagnosis: The patient presented with cervical pain, and computed tomography revealed a mass of the C2 vertebral body. He underwent surgery for tumor resection and autologous bone grafting, and the final pathological diagnosis was GCT. The transplanted bone exhibited gradual progression of resorption, and recurrent tumors were observed on computed tomography and magnetic resonance imaging 1 year and 4 months after surgery. Interventions: The patient was started on denosumab at 15 years of age and received carbon ion beam therapy with 70.4 Gy administered in 32 sessions over 7 weeks. Outcomes: No progressive tumor growth was observed, there were no neurological symptoms such as paralysis or pain were noted, and the patient was in remission for 5 years after irradiation. Conclusion: These findings suggest that carbon ion radiotherapy is a safe and effective therapeutic option for patients with recurrent GCT of the cervical spine.

Pengcheng Zhang,1– 4 Boyi Yu,1,2 Xiaodong Jin,1,2 Ting Zhao,1 Fei Ye,1,2 Xiongxiong Liu,1,2 Ping Li,1,2 Xiaogang Zheng,1 Weiqiang Chen,1,2 Qiang Li1,2 1Institute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China; 2University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China; 3The First Hospital of Lanzhou University, Lanzhou, 730000, People’s Republic of China; 4Department of Radiation Oncology, The First Hospital of Lanzhou University, Lanzhou, 730000, People’s Republic of ChinaCorrespondence: Weiqiang Chen; Qiang LiInstitute of Modern Physics, Chinese Academy of Sciences; Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of ChinaEmail chenwq7315@impcas.ac.cn; liqiang@impcas.ac.cnPurpose: Gold nanoparticles (AuNPs) are widely studied as radiosensitizers, but their radiosensitization in carbon ion radiotherapy is unsatisfactory. There is a lack of in vivo data on the radiosensitization of AuNPs under carbon ion irradiation. This study focused on the radiosensitization effect of AuNPs in the mouse melanoma cell line B16-F10 in vitro and in vivo.Materials and Methods: 11-mercaptoundecanoic acid (11-MUA)-coated gold (Au) nanoparticles (mAuNPs) formulations were prepared and characterized. To verify the radiosensitization effect of mAuNPs, hydroxyl radicals were generated in aqueous solution, and the detection of intracellular reactive oxygen species (ROS) and clone survival were carried out in vitro. The tumor growth rate (TGR) and survival of mice were analyzed to verify the radiosensitization effect of mAuNPs in vivo. The apoptosis of tumor cells was detected, and the expression of key proteins in the apoptosis pathway was verified by immunohistochemistry.Results: The intracellular ROS level in B16-F10 cells was enhanced by mAuNPs under carbon ion irradiation. The sensitization rate of mAuNPs was 1.22 with a 10% cell survival rate. Compared with irradiation alone, the inhibitory effect of mAuNPs combined with carbon ion irradiation on tumor growth was 1.94-fold higher, the survival time of mice was prolonged by 1.75-fold, and the number of apoptotic cells was increased by 1.43-fold. The ratio of key proteins Bax and Bcl2 in the apoptosis pathway was up-regulated, and the expression of caspase-3, a key executor of the apoptosis pathway, was up-regulated.Conclusion: In in vivo and in vitro experiments, mAuNPs showed radiosensitivity to carbon ion irradiation. The sensitization effect of mAuNPs on mice tumor may be achieved by activating the mitochondrial apoptosis pathway and increasing tumor tissue apoptosis. To our best knowledge, the present study is the first in vivo evidence for radiosensitization of mAuNPs in tumor-bearing mice exposed to carbon ion irradiation.Keywords: gold nanoparticles, radiosentization, carbon ion irradiation, tumor-bearing mice, apoptosis

Carbon ion radiation therapy (CIRT) is the most advanced radiation therapy (RT) available and offers new opportunities to improve cancer treatment and research. CIRT has a unique physical and biological advantage that allow them to kill tumor cells more accurately and intensively. So far, CIRT has been used in almost all types of malignant tumors, and showed good feasibility, safety and acceptable toxicity, indicating that CIRT has a wide range of development and application prospects. In addition, in order to improve the biological effect of CIRT, scientists are also trying to investigate related sensitizing agents to enhance the killing ability of tumor cells, which has attracted extensive attention. In this review, we tried to systematically review the rationale, advantages and problems, the clinical applications and the sensitizing agents of the CIRT. At the same time, the prospects of the CIRT in were prospected. We hope that this review will help researchers interested in CIRT, sensitizing agents, and radiotherapy to understand their magic more systematically and faster, and provide data reference and support for bioanalysis, clinical medicine, radiotherapy, heavy ion therapy, and nanoparticle diagnostics.

Background/aim The purpose of this study was to compare the dose distribution between scanning carbon-ion radiotherapy (sCIRT) and volumetric-modulated arc therapy with stereotactic body radiation therapy (VMAT-SBRT) for stage I non-small cell lung cancer (NSCLC). Patients and methods Fifteen patients with early-stage NSCLC who underwent sCIRT at Kanagawa Cancer Center between 2018-2020 were enrolled. Dose-volume histogram parameters of the planned target volume and normal organs for sCIRT and VMAT-SBRT were evaluated. Results The homogeneity index of the target volume of sCIRT was significantly lower than that of VMAT-SBRT. The dose of sCIRT was significantly lower than that of VMAT-SBRT at low volumes in the lung, heart, spinal cord, and esophagus. Conclusion The dose distribution of sCIRT for early-stage NSCLC was better than that of VMAT-SBRT.

There are no studies on the risk factors of radiation pneumonitis (RP) after carbon-ion radiotherapy at a dose of 50 Gy (relative biological effectiveness (RBE)) in a single fraction. The objective of this study was to identify factors associated with RP after radiotherapy, including dose–volume parameters. Ninety-eight patients without a history of thoracic radiotherapy who underwent treatment for solitary lung tumors between July 2013 and April 2016 were retrospectively analyzed. Treatment was planned using Xio-N. The median follow-up duration was 53 months, and the median clinical target volume was 32.3 mL. Three patients developed grade 2 RP, and one patient developed grade 3 interstitial pneumonitis. None of the patients developed grade 4 or 5 RP. The dose-volume parameters of the normal lung irradiated at least with 5–30 Gy (RBE), and the mean lung dose was significantly lower in patients with grade 0–1 RP than in those with grade 2–3 RP. Pretreatment with higher SP-D and interstitial pneumonitis were significant factors for the occurrence of symptomatic RP. The present study showed a certain standard for single-fraction carbon-ion radiotherapy that does not increase the risk of RP, however, further validation studies are needed.

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.

In cases of simultaneous chemoradiotherapy (CRT), early recognition of toxic side effects is important, as drug discontinuation may prevent further injury. It appears favorable to undertake further steps to investigate whether patient subgroups behave differently depending on their toxicity profile. We retrospectively analyzed 125 consecutive patients with non-metastasized carcinoma of the head and neck who were treated with CRT (cisplatin 40 mg/m2 weekly) in 2013/2014. Patients were planned to receive six cycles of cisplatin. Statistical analyses were performed using the chi2 test, t-test, Kaplan–Meier method, and the log-rank test, as appropriate. Eighty-six patients did not reach the intended sixth cycle (68.8%; 60.0% of whom were ≥60 years, p

Purpose Although carbon-ion therapy is becoming increasingly attractive to the treatment of tumors, details about the ionization pattern formed by therapeutic carbon-ion beam in tissue have not been fully investigated. In this work, systematic calculations for the nanodosimetric quantities and relative biological effectiveness (RBE) of a clinically relevant carbon-ion beam were studied for the first time. Methods The method combining both track structure and condensed history Monte Carlo (MC) simulations was adopted to calculate the nanodosimetric quantities. Fragments and energy spectra at different positions of the radiation field of a clinically relevant carbon-ion pencil beam were generated by means of MC simulations in water. Nanodosimetric quantities such as mean ionization cluster size ( M 1 ), the first moment of conditional cluster size ( M 1 C 2 ), cumulative probability ( F 2 ), and conditional cumulative probability ( F 3 C 2 ) at these positions were then acquired based on the spectra and the pre-calculated nanodosimetric database created by track structure MC simulations. What's more, a novel approach to calculate RBE based on the said nanodosimetric quantities was introduced. The RBE calculations were then conducted for the carbon-ion beam at different water-equivalent depths. Results Lateral distributions at various water-equivalent depths of both the nanodosimetric quantities and RBE values were obtained. The values of M 1 , M 1 C 2 , F 2 , and F 3 C 2 were 1.49, 2.67, 0.30, and 0.38 at the plateau at the beam central axis and maximized at 2.79, 5.69, 0.47, and 0.68 at the depths around the Bragg peak, respectively. At a given depth, M 1 and F 2 decreased laterally with increasing the distance to the beam central axis while M 1 C 2 and F 3 C 2 remained nearly unchanged at first and then decreased except for M 1 C 2 at the rising edge of the Bragg peak. The calculated RBE values were 1.07 at the plateau and 3.13 around the Bragg peak. Good agreement between the calculated RBE values and experimental data was obtained. Conclusions Different nanodosimetric quantities feature the track structure of therapeutic carbon-ion beam in different manners. Detailed ionization patterns generated by carbon-ion beam could be characterized by nanodosimetric quantities. Moreover the combined method adopted in this work to calculate nanodosimetric quantities is not only valid but also convenient. Nanodosimetric quantities are significantly helpful for the RBE calculations in carbon-ion therapy.

Purpose: We studied lethal and mutagenic bystander effects in normal human fibroblasts irradiated with low-energy-carbon ions.Materials and methods: After cells reached confluence, cells were irrad...

Purpose: Accumulated damage in neural stem cells (NSCs) during brain tumor radiotherapy causes cognitive dysfunction to the patients. Carbon-ion radiotherapy can reduce undesired irradiation of nor...

Background Particle therapy provides steep dose gradients to facilitate dose escalation in challenging anatomical sites which has been shown not only to improve local control but also overall survival in patients with ACC. Cost-effectiveness of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost vs IMRT alone was performed in order to objectivise and substantiate more widespread use of this technology in ACC. Methods Patients with pathologically confirmed ACC received a combination regimen of IMRT plus C12 boost. Patients presenting outside C12 treatment slots received IMRT only. Clinical results were published; economic analysis on patient-level data was carried out from a healthcare purchaser’s perspective based on costs of healthcare utilization. Cost histories were generated from resource use recorded in individual patient charts and adjusted for censoring using the Lin I method. Cost-effectiveness was measured as incremental cost-effectiveness ratio (ICER). Sensitivity analysis was performed regarding potentially differing management of recurrent disease. Results The experimental treatment increased overall costs by € 18,076 (€13,416 – €22,922) at a mean survival benefit of 0.86 years. Despite improved local control, following costs were also increased in the experimental treatment. The ICER was estimated to 26,863 €/LY. After accounting for different management of recurrent disease in the two cohorts, the ICER was calculated to 20,638 €/LY. Conclusion The combined treatment (IMRT+C12 boost) substantially increased initial and overall treatment cost. In view of limited treatment options in ACC, costs may be acceptable though. Investigations into quality of life measures may support further decisions in the future.

Purpose This study aimed to assess the feasibility of carbon ion reirradiation (CIR) for recurrent head and neck cancer (HNC). Methods and Materials This retrospective study included 229 patients with recurrent HNC who were treated with CIR between 2010 and 2017. We assessed progression-free survival, overall survival, pattern of failure, and toxicity. Of the primary tumors, 54.1% were adenoid cystic carcinomas, 26.2% were squamous cell carcinomas, 8.3% were adenocarcinomas, and 11.4% were other tumor entities. Results The median radiation therapy interval was 3.9 years (range, 0.3-46.5 years), and patients received a median dose of 51 Gy (relative biological effectiveness [RBE]; range, 30-66 Gy [RBE]) in 3 Gy (RBE) fractions. The median cumulative lifetime dose after CIR was 132.8 Gy (range, 88.8-155.0 Gy). The median local progression-free survival after CIR was 24.2 months (95% confidence interval, 19.4-29.0 months), and the median overall survival was 26.1 months (95% confidence interval, 21.9-30.3 months). Serious acute toxicity (grade ≥3) after CIR included laryngeal edema, grade 4 (n = 2; 0.9%); dysphagia, grade 3 (n = 3; 1.3%); fistula, grade 3 (n = 1; 0.4%); and impaired hearing, grade 3 (n = 1; 0.4%). Late toxicities of grades 3 or higher (n = 18; 14.5%) included central nervous system necrosis, grades 4/3 (n = 1; 0.8%/n = 5; 4.0%); optic nerve disorder, grades 4/3 (n = 2; 1.6%/n = 2; 1.6%); impaired hearing, grade 3 (n = 5; 4.0%), osteonecrosis, grade 3 (n = 1; 0.8%); and carotid blowout, grade 4 (n = 1; 0.8%). Conclusions In patients with locally recurrent HNC, CIR was a feasible, effective treatment with acceptable toxicity and good local control. Thus, CIR represented a valuable alternative to surgical salvage and palliative chemotherapy in selected patients.

Purpose The purpose of this study was to compare carbon-ion (C-ion), proton and photon radiotherapy (RT) plans with regard to dose reduction of the gastrointestinal (GI) tract by using a greater omentum spacer (GO spacer). Methods We retrospectively retrieved data for ten patients who received the GO spacer as surgical spacer placement for abdominal and pelvic tumors. Simulation plans were created on pre-spacer Computed Tomography (CT) and post-spacer CT for C-ion RT, proton RT and photon RT to compare the dose of the GI tract. The plans were normalized so that at least 95% of the planning target volume (PTV) received 70 Gy (relative biological effectiveness equivalent) delivered in 35 fractions. All plans were created with the lowest possible dose to the GI tract under conditions that meet the dose constraints for the PTV and spinal cord (maximum dose Results D2 cc and V10–70 of the GI tract were significantly lower on post-spacer plans than on pre-spacer plans for all three RT modalities. Regarding post-spacer plans, D2 cc of the GI tract was significantly lower on C-ion RT plans and proton RT plans than on photon RT plans (C-ion vs photon p = 0.001, proton vs photon p = 0.002). However, there was no significant difference between C-ion RT plans and proton RT plans for D2 cc of the GI tract (C-ion vs proton p = 0.992). In the photon RT plan for one patient, D2 cc of the GI tract did not meet Conclusions The GO spacer shows a significant dose reduction effect on the GI tract.

This phase II study's aim was to confirm the efficacy and safety of hypofractionated carbon‐ion radiotherapy in patients with stage I peripheral nonsmall cell lung cancer (NSCLC). The study encompassed 37 patients with histologically proven peripheral stage I NSCLC in the period June 2010‐March 2015. All underwent the planned full dose of carbon‐ion radiotherapy, administered with relative biological effectiveness of 52.8 Gy and 60 Gy (divided into four fractions over 1 week) for T1 and T2a tumors, respectively. The 2‐year local control rate was set as the primary endpoint, while overall survival, progression‐free survival, and the incidence rates of acute and late adverse events were secondary endpoints. The patients were followed up for 56.3 months overall and 62.2 months in the surviving patients, respectively. The actuarial local control rates were 91.2% after 2 years, and 88.1% after 5 years. No differences were found between the T1 and T2a tumors in the 5‐year local control rate (90.9% vs 86.7%, P = .75). The actuarial overall survival rates achieved 91.9% for 2‐year and 74.9% for 5‐year period. T1 tumors showed actuarial 5‐year overall survival rates of 80%, compared to 66.7% in T2a tumors. Two patients with T2a tumors and either severe emphysema or bronchiectasis experienced lung toxicity ≥ grade 2, in contrast to T1 patients who only experienced mild toxicities (lower than grade 2). The findings suggest that carbon‐ion radiotherapy is effective and safe for peripheral stage I NSCLC; however, further clinical evaluations are needed to confirm its therapeutic efficacy. Trial registration: UMIN000003797. Registered 21 June 2010, prospectively registered., The aim of this phase II study was to confirm the feasibility and safety of hypofractionated carbon‐ion radiotherapy for patients with stage I peripheral nonsmall cell lung cancer. The actuarial 2‐year and 5‐year local control rates were 91.2% and 88.1%, respectively. The actuarial 2‐year and 5‐year overall survival rates were 91.9% and 74.9%, respectively.

Background The objective of this investigation is to evaluate the outcomes and toxicity of carbon-ion re-irradiation (CIR) in patients with rare head and neck cancers (HNC). There is a paucity of data regarding treatment approaches in this patient cohort, which we aim to address in this work. Methods Thirty-two (n = 32) consecutive patients with uncommon HNC treated between 2010 and 2017 were retrospectively analyzed in terms of clinical outcomes, patterns of failure, and toxicity. Results Mucoepidermoid carcinoma (MEC) was the most common histology (22%). Patients received a median cumulative dose equivalent in 2 Gy fractions (EQD2) after CIR of 128.6 Gy (range, 105.8–146.5 Gy). The local and distant control rates 1 year after CIR were 66 and 72%. No serious acute or late toxicity (≥ grade 3) after CIR was observed. Conclusions CIR may represent an effective and safe treatment alternative to palliative systemic therapies in these rare indications.