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Mayo Clinic Florida will initially open with the capability to treat with a single horizontal port for carbon ion therapy. Carbon ion therapy is traditionally done using a multi fixed port treatment approach. In this study, for nine treatment sites, clinically approved treatment plan of Osaka Heavy Ion Therapy Center was compared to a treatment plan using only a horizontal port. The treatment sites evaluated in this study were prostate cancer, pancreatic cancer, cervical cancer, recurrent rectal cancer, liver cancer, head and neck cancer, bone cancer (sarcoma and chordoma), and lung cancer. As expected, the prostate plans are identical and are only included for completeness. The DVH results for the pancreas and cervical cancer were very similar. The results for recurrent rectal, head and neck, sarcoma, chordoma, and lung cancer indicate that a single horizontal port with couch roll and yaw will accommodate certain medial targets but will be challenging to treat for laterally located targets without creative mitigations. [ABSTRACT FROM AUTHOR]

Objective. The highly conformal carbon-ion radiotherapy is associated with an increased sensitivity of the dose distributions to internal changes in the patient during the treatment course. Hence, monitoring methodologies capable of detecting such changes are of vital importance. We established experimental setup conditions to address the sensitivity of a monitoring approach based on secondary-fragment tracking for detecting clinically motivated air cavity dimensions in a homogeneous head-sized PMMA phantom in 40 mm depth. Approach. The air cavities were positioned within the entrance channel of a treatment field of 50 mm diameter at three lateral positions. The measured secondary-fragment emission profiles were compared to a reference measurement without cavities. The experiments were conducted at the Heidelberg Ion-Beam Therapy Center in Germany at typical doses and dose rates. Main results. Significances above a detectability threshold of 2 σ for the larger cavities (20 mm diameter and 4 mm thickness, and 20 mm diameter and 2 mm thickness) across the entire treatment field. The smallest cavity of 10 mm diameter and 2 mm thickness, which is on the lower limit of clinical interest, could not be detected at any position. We also demonstrated that it is feasible to reconstruct the lateral position of the cavity on average within 2.8 mm, once the cavity is detected. This is sufficient for the clinicians to estimate medical effects of such a cavity and to decide about the need for a control imaging CT. Significance. This investigation defines well-controlled reference conditions for the evaluation of the performance of any kind of treatment monitoring method and its capability to detect internal changes within head-sized objects. Four air cavities with volumes between 0.31 cm3 and 1.26 cm3 were narrowed down around the detectability threshold of this secondary-fragment-based monitoring method. [ABSTRACT FROM AUTHOR]

Background/Aim: In the pencil beam scanning carbon-ion radiotherapy, spot positions are arranged in three dimensions throughout the entire target region. Therefore, dose deviations can occur due to spot position errors in the target. However, performing three-dimensional measurements for routine patient-specific quality assurance (PSQA) is difficult because a simple measurement method has not been established. This study aimed to establish a three-dimensional dose verification method using beam delivery log data. Materials and Methods: Pencil beam dose distributions in water were generated through Monte Carlo (MC) calculations. Treatment beam dose distribution was calculated by superposing the pencil beam dose distributions, considering given spot positions and monitor units (referred to as semi-MC, SMC). The aim of this study was to perform gamma analysis (GA) using dose distributions of log data-based SMC instead of measured dose for PSQA. To verify SMC, the SMC depth-dose curves were compared with the measured dose. To assess the equivalence between the proposed and measurement-based methods, pass rates of two-dimensional GA were compared. Furthermore, a threedimensional GA was performed to investigate clinically suitable criteria. Results: The SMC dose curves were consistent with measured dose, with a deviation <5%. In two-dimensional GA, pass rates for the proposed method were generally lower than those for measurement-based method. The results of the three-dimensional GA indicated that the proposed method, with criteria of 3%-3 mm and 3%-2 mm, had capabilities comparable to the measurement-based method. Conclusion: The developed three-dimensional log data-based PSQA method with criteria of 3%-3 mm and 3%-2 mm is clinically applicable. [ABSTRACT FROM AUTHOR]

Background: A recent phase I/II study determined the optimal dose of definitive carbon-ion radiotherapy (CIRT) for cT1bN0M0 esophageal cancer. This study aimed to further confirm the efficacy and feasibility of the recommended dose fractionation of CIRT with long-term follow-up results in a larger sample size. Methods: This single center retrospective study evaluated patients with cT1bN0M0 esophageal squamous cell carcinoma treated with the recommended dose fractionation of 50.4 Gy relative biological effectiveness in 12 fractions, between 2012 and 2022. Results: Thirty-eight patients underwent CIRT at our hospital. Although eight (21.1%) patients were older than 80 years, 15 (39.5%) had high surgical risk, and seven (18.4%) were at high risk for chemotherapy, all patients underwent CIRT as scheduled. Grade 3 esophagitis occurred in eight (21.1%) patients and grade 3 pneumonia in one (2.6%) patient in this study, but no grade 4 adverse events occurred. The only grade 3 late adverse event was pneumonia in one patient (2.6%). The 5-year overall survival rate, local control rate, and disease-free survival rates were 76.6% (95% CI, 90.9–62.4), 74.9% (95% CI, 90.7–59.0), and 66.4% (95% CI, 83.3–49.5), respectively. Additionally, post CIRT recurrence was as follows: seven (18.4%) patients had recurrence in another part of the esophagus, three (7.9%) in the primary site, three (7.9%) in lymph nodes outside the irradiated area, and one (2.6%) patient had liver metastasis. Conclusions: Our study demonstrates that CIRT using the recommended dose fractionation is feasible and effective for cT1bN0M0 esophageal squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusions In‐vivo monitoring methods of carbon ion radiotherapy (CIRT) includes explorations of nuclear reaction products generated by carbon‐ion beams interacting with patient tissues. Our research group focuses on in‐vivo monitoring of CIRT using silicon pixel detectors. Currently, we are conducting a prospective clinical trial as part of the In‐Vivo Monitoring project (InViMo) at the Heidelberg Ion Beam Therapy Center (HIT) in Germany. We are using an innovative, in‐house developed, non‐contact fragment tracking system with seven mini‐trackers based on the Timepix3 technology developed at CERN.This article focuses on the implementation of the mini‐tracker in Monte Carlo (MC) based on FLUKA simulations to monitor secondary charged nuclear fragments in CIRT. The main objective is to systematically evaluate the simulation accuracy for the InViMo project.The implementation involved integrating the mini‐tracker geometry and the scoring mechanism into the FLUKA MC simulation, utilizing the finely tuned HIT beam line. The systematic investigation included varying mini‐tracker angles (from 15∘$15^\circ$ to 45∘$45^\circ$ in 5∘$5^\circ$ steps) during the irradiation of a head‐sized phantom with therapeutic carbon‐ion pencil beams. To evaluate our implemented FLUKA framework, a comparison was made between the experimental data and data obtained from MC simulations. To ensure the fidelity of our comparison, experiments were performed at the HIT using the parameters and setup established in the simulations.Our research demonstrates high accuracy in reproducing characteristic behaviors and dependencies of the monitoring method in terms of fragment distributions in the mini‐tracker, track angles, emission profiles, and fragment numbers. Discrepancies in the number of detected fragments between the experimental data and the data obtained from MC simulations are less than 4% for the angles of interest in the InViMo detection system.Our study confirms the potential of our simulation framework to investigate the performance of monitoring inter‐fractional anatomical changes in patients undergoing CIRT using secondary nuclear charged fragments escaping from the irradiated patient. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Radiotherapy is considered an alternative treatment for unresectable or pharmacologically resistant desmoid‐type fibromatosis. While it results in relatively good local control, the risk of secondary malignancy remains a concern. Case We present a case of secondary osteosarcoma after carbon‐ion radiation therapy (CIRT). A 31‐year‐old male patient presented with left thigh pain. The tumor was located between the left gluteus maximus and gluteus medius and extended to the vastus lateralis and biceps femoris. It was diagnosed as desmoid‐type fibromatosis after needle biopsy. The patient was treated with several medications, including a cyclooxygenase 2 inhibitor and tamoxifen; however, his left thigh pain did not improve. He was treated with CIRT 1 year after diagnosis (67.2 Gy [relative biological effectiveness] 16fr/4wks). He developed osteosarcoma of the left femur 8 years later. He underwent chemotherapy and tumor excision with disarticulation of the left hip. Pulmonary metastasis was detected 6 and 17 months after the definitive surgery and excised using metastasectomy. However, he died due to the recurrence of multiple pulmonary metastases 29 months after the definitive surgery. Conclusions In this case, we believe that the low radiation dose to the femur may have caused secondary malignancy.

Carbon-ion radiotherapy (CIRT) offers superior dose distributions and greater biological effectiveness than conventional photon-based radiotherapy (RT). Due to its higher linear energy transfer and relative biological effectiveness, CIRT is particularly effective against radioresistant tumors and those located near critical organs. Since the first dedicated CIRT facility was established in Japan in 1994, CIRT has demonstrated remarkable efficacy against various malignancies, including head and neck tumors, skull base and upper cervical spine tumors, non-small-cell lung cancer, hepatocellular carcinoma, pancreatic cancer, prostate cancer, and bone and soft tissue sarcomas. This narrative review provides a comprehensive overview of the current status of CIRT, highlighting its clinical indications and future directions. According to clinical studies, CIRT achieves high local control rates with manageable toxicity across multiple cancer types. For instance, in head and neck tumors (e.g., adenoid cystic carcinoma and mucosal melanoma), CIRT has achieved local control rates exceeding 80%. In early-stage non-small-cell lung cancer, CIRT has resulted in local control rates over 90% with minimal toxicity. Moreover, CIRT has shown promise in treating challenging cases of hepatocellular carcinoma and pancreatic cancer, where conventional therapies are limited. Nonetheless, the global adoption of CIRT remains limited due to high costs and complexity. Future directions include conducting randomized controlled trials to establish high-level evidence, integrating new technologies such as ultrahigh-dose-rate (FLASH) therapy, and expanding CIRT facilities globally with strategic planning and cost-effectiveness analyses. If these challenges are addressed, CIRT is poised to play a transformative role in cancer treatment, improving survival rates and the quality of life.

Abstract Background Radiation-induced liver damage (RILD) occasionally occurs following carbon-ion radiotherapy (CIRT) for liver tumors, such as hepatocellular carcinoma (HCC), in patients with impaired liver function disease. However, the associated risk factors remain unknown. The present study aimed to determine the risk factors of RILD after CIRT. Methods We retrospectively analyzed 108 patients with HCC treated with CIRT at the Osaka Heavy Ion Therapy Center between December 2018 and December 2022. RILD was defined as a worsening of two or more points in the Child–Pugh score within 12 months following CIRT. The median age of the patients was 76 years (range 47–95 years), and the median tumor diameter was 41 mm (range 5–160 mm). Based on the pretreatment liver function, 98 and 10 patients were categorized as Child–Pugh class A and B, respectively. We analyzed patients who received a radiation dose of 60 Gy (relative biological effectiveness [RBE]) in four fractions. The median follow-up period was 9.7 months (range 2.3–41.1 months), and RILD was observed in 11 patients (10.1%). Results Multivariate analysis showed that pretreatment Child–Pugh score B (p = 0.003, hazard ratio [HR] = 6.90) and normal liver volume spared from

Background: Local recurrence in locally advanced pancreatic cancer (LAPC) after carbon‐ion radiotherapy (CIRT) may partly attribute to low dose‐averaged linear energy transfer (LETd), despite high CIRT dose. Purpose: This study aimed to investigate the approaches to up‐modulate the CIRT LETd and to evaluate the corresponding oxygen enhancement ratio (OER) reduction. Methods: 10 LAPCs that had been irradiated by CIRT with 67.5 Gy (RBE) in 15 fractions were selected. Their original plans were taken as the control plan for the LETd and OER investigations. Our considerations for up‐modulating LETd were: (1) to deliver high doses to gross tumor volume core (GTVcore), while keeping dose constraints of the gastrointestinal (GI) tract in tolerance; (2) to put more Bragg‐peak (BP) within the modulated targets; (3) to increase the BP density, high doses were necessary; (4) CIRT LETd could be effectively increased to small volumes; and (5) simultaneous integrated boost technique (SIB) could achieve the aforementioned tasks. The LETd and the corresponding OER distributions of each type of SIB plan were evaluated. Results: We delivered up to 100 Gy (RBE) to GTVcore using SIB. The mean LETd of GTV increased significantly by 21.3% from 47.8 to 58.0 keV/μm (p < 0.05). Meanwhile, the mean OER of GTVcore decreased by 6.6%, from 1.51 to 1.41 (p < 0.05). The GI LETdS in all modulated plans were not more than those in the original plans. Conclusions: SIB could effectively increase CIRT LETd to LAPC, thus producing reduced OER, which may effectively overcome the radioresistance of LAPCs. [ABSTRACT FROM AUTHOR]

Dose verification of treatment plans is an essential step in radiotherapy workflows. In this work, we propose a novel method of treatment planning based on nanodosimetric quantity-weighted dose (NQWD), which could realize biological representation using pure physical quantities for biological-oriented carbon ion-beam treatment plans and their direct verification. The relationship between nanodosimetric quantities and relative biological effectiveness (RBE) was studied with the linear least-squares method for carbon-ion radiation fields. Next, under the framework of the matRad treatment planning platform, NQWD was optimized using the existing RBE-weighted dose (RWD) optimization algorithm. The schemes of NQWD-based treatment planning were compared with the RWD treatment plans in term of the microdosimetric kinetic model (MKM). The results showed that the nanodosimetric quantity F3 − 10 had a good correlation with the radiobiological effect reflected by the relationship between RBE and F3 − 10. Moreover, the NQWD-based treatment plans reproduced the RWD plans generally. Therefore, F3 − 10 could be adopted as a radiation quality descriptor for carbon-ion treatment planning. The novel method proposed herein not only might be helpful for rapid physical verification of biological-oriented ion-beam treatment plans with the development of experimental nanodosimetry, but also makes the direct comparison of ion-beam treatment plans in different institutions possible. Thus, our proposed method might be potentially developed to be a new strategy for carbon-ion treatment planning and improve patient safety for carbon-ion radiotherapy. [ABSTRACT FROM AUTHOR]

A few reports have discussed the influence of inter-fractional position error and intra-fractional motion on dose distribution, particularly regarding a spread-out Bragg peak. We investigated inter-fractional and intra-fractional prostate position error by monitoring fiducial marker positions. In 2020, data from 15 patients with prostate cancer who received carbon-ion beam radiotherapy (CIRT) with gold markers were investigated. We checked marker positions before and during irradiation to calculate the inter-fractional positioning and intra-fractional movement and evaluated the CIRT dose distribution by adjusting the planning beam isocenter and clinical target volume (CTV) position. We compared the CTV dose coverages (CTV receiving 95% [V95%] or 98% [V98%] of the prescribed dose) between skeletal and fiducial matching irradiation on the treatment planning system. For inter-fractional error, the mean distance between the marker position in the planning images and that in a patient starting irradiation with skeletal matching was 1.49 ± 1.11 mm (95th percentile = 1.85 mm). The 95th percentile (maximum) values of the intra-fractional movement were 0.79 mm (2.31 mm), 1.17 mm (2.48 mm), 1.88 mm (4.01 mm), 1.23 mm (3.00 mm), and 2.09 mm (8.46 mm) along the lateral, inferior, superior, dorsal, and ventral axes, respectively. The mean V95% and V98% were 98.2% and 96.2% for the skeletal matching plan and 99.5% and 96.8% for the fiducial matching plan, respectively. Fiducial matching irradiation improved the CTV dose coverage compared with skeletal matching irradiation for CIRT for prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Radiation-induced liver damage (RILD) occasionally occurs following carbon-ion radiotherapy (CIRT) for liver tumors, such as hepatocellular carcinoma (HCC), in patients with impaired liver function disease. However, the associated risk factors remain unknown. The present study aimed to determine the risk factors of RILD after CIRT. Methods: We retrospectively analyzed 108 patients with HCC treated with CIRT at the Osaka Heavy Ion Therapy Center between December 2018 and December 2022. RILD was defined as a worsening of two or more points in the Child–Pugh score within 12 months following CIRT. The median age of the patients was 76 years (range 47–95 years), and the median tumor diameter was 41 mm (range 5–160 mm). Based on the pretreatment liver function, 98 and 10 patients were categorized as Child–Pugh class A and B, respectively. We analyzed patients who received a radiation dose of 60 Gy (relative biological effectiveness [RBE]) in four fractions. The median follow-up period was 9.7 months (range 2.3–41.1 months), and RILD was observed in 11 patients (10.1%). Results: Multivariate analysis showed that pretreatment Child–Pugh score B (p = 0.003, hazard ratio [HR] = 6.90) and normal liver volume spared from < 30 Gy RBE (VS30 < 739 cm3) (p = 0.009, HR = 5.22) were significant risk factors for RILD. The one-year cumulative incidences of RILD stratified by Child–Pugh class A or B and VS30 < 739 cm3 or ≥ 739 cm3 were 10.3% or 51.8% and 39.6% or 9.2%, respectively. Conclusion: In conclusion, the pretreatment Child–Pugh score and VS30 of the liver are significant risk factors for RILD following CIRT for HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Late radiation-induced lumbosacral neuropathy (RILSN) is a rare, debilitating, but potentially avoidable morbidity associated with carbon-ion therapy (CIRT) for pelvic sarcomas/chordomas. This toxicity increases significantly if the long length of sacral nerves is exposed to CIRT doses > 70 Gy (RBE) [Japanese RBE model]. We propose a sacral-nerve-sparing optimized CIRT strategy (SNSo-CIRT) to minimize the risk of RILSN. This strategy is composed of (a) Contouring of individual sacral nerve roots between L5–S3 levels until sciatic nerve. (b) Restriction of doses to sacral nerves outside of high dose CTV (HD-CTV) (i.e., 'sacral nerves-to-spare') to doses to 5% of volume (DRBE|LEM-I|D5%) < 69 Gy (RBE). (c) Evaluation of robustness of SNSo-CIRT. With this strategy, doses to sacral nerves-to-spare were restricted to DRBE|LEM-I|D5% < 69 Gy (RBE) for 95% of patients. Patients who developed RILSN despite the application of the sacral-nerve-sparing strategy had significantly higher DRBE-filtered dose-averaged linear energy transfer (LETd) on sacral nerves-to-spare. DRBE-filtered-LETd can be optimized along with DRBE for SNSo-CIRT. To minimize radiation-induced lumbosacral neuropathy (RILSN), we employed sacral-nerve-sparing optimized carbon-ion therapy strategy (SNSo-CIRT) in treating 35 patients with pelvic sarcomas/chordomas. Plans were optimized using Local Effect Model-I (LEM-I), prescribed DRBE|LEM-I|D50% (median dose to HD-PTV) = 73.6 (70.4–76.8) Gy (RBE)/16 fractions. Sacral nerves were contoured between L5-S3 levels. DRBE|LEM-I to 5% of sacral nerves-to-spare (outside HD-CTV) (DRBE|LEM-I|D5%) were restricted to <69 Gy (RBE). The median follow-up was 25 months (range of 2–53). Three patients (9%) developed late RILSN (≥G3) after an average period of 8 months post-CIRT. The RILSN-free survival at 2 years was 91% (CI, 81–100). With SNSo-CIRT, DRBE|LEM-I|D5% for sacral nerves-to-spare = 66.9 ± 1.9 Gy (RBE), maintaining DRBE|LEM-I to 98% of HD-CTV (DRBE|LEM-I|D98%) = 70 ± 3.6 Gy (RBE). Two-year OS and LC were 100% and 93% (CI, 84–100), respectively. LETd and DRBE with modified-microdosimetric kinetic model (mMKM) were recomputed retrospectively. DRBE|LEM-I and DRBE|mMKM were similar, but DRBE-filtered-LETd was higher in sacral nerves-to-spare in patients with RILSN than those without. At DRBE|LEM-I cutoff = 64 Gy (RBE), 2-year RILSN-free survival was 100% in patients with <12% of sacral nerves-to-spare voxels receiving LETd > 55 keV/µm than 75% (CI, 54–100) in those with ≥12% of voxels (p < 0.05). DRBE-filtered-LETd holds promise for the SNSo-CIRT strategy but requires longer follow-up for validation. [ABSTRACT FROM AUTHOR]

Radiation-induced organizing pneumonia is a rare complication of radiation therapy for thoracic cancer. Carbon-ion radiotherapy, an emerging treatment modality for early-stage lung cancer treatment, can also cause lung injuries. However, as cases of radiation-induced organizing pneumonia caused by carbon-ion radiotherapy for lung cancer have not been reported, its clinical features remain unclear. A 69-year-old woman was referred to our hospital 11 months after being diagnosed with early lung cancer due to refractory pneumonitis induced by carbon-ion radiotherapy. She had developed fever and dyspnea 4 months after undergoing carbon-ion radiotherapy and was subsequently diagnosed with radiation pneumonitis. The administration of oral prednisolone resulted in improvement. However, she relapsed each time the dose of prednisolone was tapered. She was diagnosed with radiation-induced organizing pneumonia caused by carbon-ion radiotherapy for lung cancer based on the clinical course and the results of the examination performed at our hospital. An improvement was observed after administering methylprednisolone (1000 mg/d) for 3 days. The dose of oral prednisolone was slowly tapered over a period of ≥6 months with no relapse. Organizing pneumonia caused by carbon-ion radiotherapy for lung cancer is treatable with corticosteroids; however, tapering the dose of corticosteroids may lead to relapse.

Abstract Background Recent advances in chemotherapy and chemoradiotherapy have enabled conversion surgery (CS) to be performed for selected patients with initially unresectable locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). Many studies indicate CS might extend the survival of patients with initially unresectable LA PDAC. However, several clinical questions concerning CS remain, such as the optimal preoperative treatment. Carbon-ion radiotherapy (CIRT) is a unique radiotherapy that offers higher biological effectiveness than conventional radiotherapy. Here, we report a long-term survival case with initially unresectable LA PDAC who underwent CS after chemotherapy followed by CIRT. Case presentation The patient was a 72-year-old Japanese woman with unresectable LA pancreatic head cancer with tumor contact to the superior mesenteric artery (SMA). She underwent four courses of chemotherapy (gemcitabine plus nanoparticle albumin-bound paclitaxel). However, the lesion did not shrink and tumor contact with the SMA did not improve after chemotherapy. Because the probability of achieving curative resection was judged to be low, she underwent radical dose CIRT, and chemotherapy was continued. She complained of vomiting 2 months after CIRT. Although imaging studies showed no tumor growth or metastasis, a duodenal obstruction which was speculated to be an adverse effect of CIRT was observed. She could not eat solid food and a trans-nasal feeding tube was inserted. Therapeutic intervention was required to enable enteral nutrition. We proposed several treatment options. She chose resection with the expectation of an anti-tumor effect of chemotherapy and CIRT rather than course observation with tube feeding or bypass surgery. Therefore, subtotal-stomach-preserving pancreatoduodenectomy with portal vein resection was performed as CS. Pathological examination of the resected specimen revealed an R0 resection with a histological response of Evans grade IIA. Postoperatively, she recovered uneventfully. Adjuvant chemotherapy with tegafur/gimeracil/oteracil (S1) was administrated. At the time of this report, 5 years have passed since the initial consultation and she has experienced no tumor recurrence. Conclusions The present case suggests that multidisciplinary treatment consisting of a combination of recent chemotherapy and CIRT may be beneficial for unresectable LA PDAC. However, further studies are required to assess the true efficacy of this treatment strategy.

Simple Summary: Ablative radiotherapy for central early stage non-small cell lung cancer (NSCLC) is controversial in its feasibility and optimal dose prescription due to the risk of severe pneumonia and adverse events associated with mediastinal organs. Carbon-ion radiotherapy (CIRT) is a promising modality of radiotherapy with steep and linear dose distribution and high biological efficacy. We retrospectively analyzed the long-term results of ablative CIRT using 68.4 Gy in 12 fractions for central early stage NSCLC. Irradiation doses to lungs and mediastinal organs such as bronchus and esophagus were controlled and no serious mediastinal organ-related adverse events occurred. In addition, the efficacy was not inferior to that reported in previous studies, including photon SBRT or proton radiotherapy. This means that our CIRT regimen is expected to have a relatively high safety profile for central NSCLC with tumor and organ at risk (OAR) proximity. The aim of this study is to assess the efficacy and safety of ablative carbon ion radiotherapy (CIRT) for early stage central non-small cell lung cancer (NSCLC). We retrospectively reviewed 30 patients who had received CIRT at 68.4 Gy in 12 fractions for central NSCLC in 2006–2019. The median age was 75 years, and the median Karnofsky Performance Scale score was 90%. All patients had concomitant chronic obstructive pulmonary disease, and 20 patients (67%) were considered inoperable. In DVH analysis, the median lung V5 and V20 were 15.5% and 10.4%, and the median Dmax, D0.5cc, D2cc of proximal bronchial tree was 65.6 Gy, 52.8 Gy, and 10.0 Gy, respectively. At a median follow-up of 43 months, the 3-year overall survival, disease-specific survival, and local control rates were 72.4, 75.8, and 88.7%, respectively. Two patients experienced grade 3 pneumonitis, but no grade ≥3 adverse events involving the mediastinal organs occurred. Ablative CIRT is feasible and effective for central NSCLC and could be considered as a treatment option, especially for patients who are intolerant of other curative treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with lung cancer complicated by interstitial pneumonia (IP) often lose treatment options early because of concerns about acute exacerbation of IP. Carbon-ion radiotherapy (CIRT) is expected to provide both superior tumor control and low toxicity owing to its superior dose concentration; however, it is not yet a well-established therapy. In this study, we confirmed that 50 Gy single-fraction CIRT can be performed even in IP-complicated lung cancer with acceptable efficacy and tolerability. Lung dose is a significant predictor of overall survival, indicating the need for further efforts to reduce lung dose. Patients with lung cancer complicated by interstitial pneumonia (IP) often lose treatment options early owing to acute exacerbation of IP concerns. Carbon-ion radiotherapy (CIRT) can provide superior tumor control and low toxicity at high dose concentrations. We conducted a retrospective analysis of the efficacy and tolerability of a single-fraction CIRT using 50 Gy for IP-complicated lung cancer. The study included 50 consecutive patients treated between April 2013 and September 2022, whose clinical stage of lung cancer (UICC 7th edition) was 1A:1B:2A:2B = 32:13:4:1. Of these, 32 (64%) showed usual interstitial pneumonia patterns. With a median follow-up of 23.5 months, the 3-year overall survival (OS), cause-specific survival, and local control rates were 45.0, 75.4, and 77.8%, respectively. The median lung V5 and V20 were 10.0 and 5.2%, respectively (mean lung dose, 2.6 Gy). The lung dose, especially lung V20, showed a strong association with OS (p = 0.0012). Grade ≥ 2 pneumonia was present in six patients (13%), including two (4%) with suspected grade 5. CIRT can provide a relatively safe and curative treatment for patients with IP-complicated lung cancer. However, IP increases the risk of severe radiation pneumonitis, and further studies are required to assess the appropriate indications. [ABSTRACT FROM AUTHOR]

The aim of this retrospective study was to identify clinical predictors of early biochemical recurrence (BCR) in patients with high-risk prostate cancer (PCa) treated with carbon-ion radiotherapy (CIRT) and androgen deprivation therapy (ADT). A total of 670 high-risk PCa patients treated with CIRT and ADT were included in the study. Early BCR was defined as recurrence occurring during adjuvant ADT after CIRT or within 2 years after completion of ADT. Univariate and multivariate analyses were performed to identify clinical predictors of early BCR. Patients were also classified according to the Systemic Therapy in Advancing or Metastatic Prostate cancer (STAMPEDE) PCa classification. Early BCR was observed in 5.4% of the patients. Multivariate analysis identified clinical T3b stage and ≥75% positive biopsy cores as clinical predictors of early BCR after CIRT and ADT. The STAMPEDE PCa classification was also significantly associated with early BCR based on univariate analysis. These predictors can help clinicians identify patients who are at risk of early BCR. In the future, combination therapy of ADT with abiraterone may be an option for high-risk PCa patients who are at risk of early BCR, based on the results of the STAMPEDE study.

Abstract Background and Aims Hepatocellular carcinoma (HCC) patients with Child‐Pugh (CP)‐B not eligible for surgery nor other focal therapy options due to impaired liver function, have very limited treatment options. This study aims to retrospectively investigate the toxicity and efficacy of Carbon‐ion radiotherapy (C‐ion RT) on HCC with CP‐B patients. Materials and Methods Patients with CP‐B, no extrahepatic metastasis, and treated with C‐ion RT between May 2000 and March 2020 were retrospectively extracted and included in this study. Results Sixty‐nine lesions of 58 patients were included. The median follow‐up duration was 20.5 (2.7–108) months. During follow‐up, recurrence was observed in 43 patients, including 2 local recurrences and 39 intrahepatic recurrences beyond the irradiation field. A grade 3 acute hepatotoxicity was observed in one patient during the observation period. No acute or late adverse event of grade ≥4 was observed. Overall survival was 80.4% and 46.0% at 1 and 2 years, respectively, and the median survival time was 22.6 months. Local control rate was 96.4% at both 1 and 2 years, and progression‐free survival was 38.6% and 6.9% at 1 and 2 years, respectively, with a median of 9.7 months. Conclusion The C‐ion RT showed low toxicity and good local effect in patients with HCC and CP‐B. Therefore, C‐ion RT could be an appropriate treatment for patients with HCC with poor liver function.

Introduction: Carbon-ion radiotherapy (C-ion RT) is associated with favorable clinical outcomes for the pelvic recurrence of rectal cancer. However, few long-term follow-up studies after C-ion RT have been conducted. Hence, we performed an updated analysis of a prospective clinical trial of C-ion RT for the postoperative pelvic recurrence of rectal cancer. Materials and methods: The study included 28 patients. Inclusion criteria were patients with confirmed pelvic recurrence of rectal cancer without distant metastasis; those who underwent curative resection of their primary disease and regional lymph nodes without gross or microscopic residual disease; and those who had radiographically measurable tumors. The total dose of C-ion RT for all the patients was 73.6 Gy (relative biological effectiveness) administered in 16 fractions. Results: The median follow-up duration in all patients and those who survived were 51.2 and 69.2 months, respectively. The follow-up rate at the time of analysis was 96.4%. The 5-year overall survival and local control rates were 50% and 83%, respectively. Four patients had local recurrence, and 17 died of rectal cancer. Regarding late toxicities, two patients developed grade 3 pelvic infection, and nine developed grade 2 peripheral neuropathy. Conclusion: Our updated analysis of a prospective clinical trial of C-ion RT for postoperative pelvic recurrence of rectal cancer confirmed its long-term efficacy and safety. These results suggest that C-ion RT may be a safe and effective treatment option for the postoperative pelvic recurrence of rectal cancer.

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

Purpose: To investigate the efficacy and safety of particle beam radiotherapy (PBRT) in the management of patients with WHO grade 2 and 3 meningiomas. Methods: Thirty-six consecutive and non-selected patients with WHO grade 2 (n = 28) and grade 3 (n = 8) meningiomas were treated at the Shanghai Proton and Heavy Ion Center, from May 2015 to March 2022. The median age of the cohort at PBRT was 48 years. There were 25 and 11 patients treated with PBRT in the setting of newly diagnosed diseases and progressive/recurrent diseases, respectively. PBRT was utilized as re-irradiation in 5 patients. Proton radiotherapy (PRT) and carbon-ion radiotherapy (CIRT), with a median dose of 60 Gy-Equivalent (GyE), were provided to 30 and 6 patients, respectively. Results: With a median follow-up of 23.3 months, the local control rates were 92.0%, 82.0%, and 82.0% at 1, 2, and 3 years for the entire cohort, respectively. Patients with WHO grade 2 meningiomas (100%, 94.1%, 94,1% at 1,2,3 years) had a much better local control than those with WHO grade 3 meningiomas (50%, 25%, 25% at 1,2,3 years; P < 0.001). Three patients, all with WHO grade 3 meningiomas, had deceased at the time of this analysis. Multivariate analyses revealed that WHO grade (grade 2 vs. 3) (p = 0.016) was a significant prognosticator for local control. No severe toxicities (G3 or above) were observed. Conclusions: Treatment-induced efficacy and toxicities to PBRT in WHO grade 2 and 3 meningiomas were both highly acceptable. Longer follow-up is needed to evaluate the long-term outcome in terms of disease control, survival, as well as potential late effects. [ABSTRACT FROM AUTHOR]

The aim of this retrospective study was to identify clinical predictors of early biochemical recurrence (BCR) in patients with high-risk prostate cancer (PCa) treated with carbon-ion radiotherapy (CIRT) and androgen deprivation therapy (ADT). A total of 670 high-risk PCa patients treated with CIRT and ADT were included in the study. Early BCR was defined as recurrence occurring during adjuvant ADT after CIRT or within 2 years after completion of ADT. Univariate and multivariate analyses were performed to identify clinical predictors of early BCR. Patients were also classified according to the Systemic Therapy in Advancing or Metastatic Prostate cancer (STAMPEDE) PCa classification. Early BCR was observed in 5.4% of the patients. Multivariate analysis identified clinical T3b stage and ≥75% positive biopsy cores as clinical predictors of early BCR after CIRT and ADT. The STAMPEDE PCa classification was also significantly associated with early BCR based on univariate analysis. These predictors can help clinicians identify patients who are at risk of early BCR. In the future, combination therapy of ADT with abiraterone may be an option for high-risk PCa patients who are at risk of early BCR, based on the results of the STAMPEDE study. [ABSTRACT FROM AUTHOR]

Simple Summary: Carbon-ion radiotherapy (CIRT) is a potentially curative treatment for unresectable pelvic sarcomas/chordomas. Tumor control remains suboptimal in large pelvic sarcomas/chordomas compared with the control of small tumors. We hypothesized that lower dose-averaged LET (LETd) distribution in the majority of large tumors could be one of the contributing factors for local relapse. The high-LETd region lies at the end of the beam range. As the tumor size increases, the volume of tumor covered by high LETd decreases. A statistically significant difference was observed in LETd distribution between small and large pelvic sarcomas/chordomas. To improve the high-LETd component in large tumors, LETd optimization using 'distal patching' was explored in a planning setting (not implemented clinically). Distal patching significantly increased (a) median LETd in the targets, (b) LETdmin in low-LETd regions of the targets, (c) the GTV fraction receiving LETd of ≥50 keV/µm, and (d) the high-LETd component in the central region of the GTV, without significant compromise in relative biological effectiveness (RBE)-weighted absorbed-dose (DRBE) distribution. To improve outcomes in large sarcomas/chordomas treated with CIRT, there has been recent interest in LET optimization. We evaluated 22 pelvic sarcoma/chordoma patients treated with CIRT [large: HD-CTV ≥ 250 cm3 (n = 9), small: HD-CTV < 250 cm3 (n = 13)], DRBE|LEM-I = 73.6 (70.4–73.6) Gy (RBE)/16 fractions, using the local effect model-I (LEM-I) optimization and modified-microdosimetric kinetic model (mMKM) recomputation. We observed that to improve high-LETd distribution in large tumors, at least 27 cm3 (low-LETd region) of HD-CTV should receive LETd of ≥33 keV/µm (p < 0.05). Hence, LETd optimization using 'distal patching' was explored in a treatment planning setting (not implemented clinically yet). Distal-patching structures were created to stop beams 1–2 cm beyond the HD-PTV-midplane. These plans were reoptimized and DRBE|LEM-I, DRBE|mMKM, and LETd were recomputed. Distal patching increased (a) LETd50% in HD-CTV (from 38 ± 3.4 keV/µm to 47 ± 8.1 keV/µm), (b) LETdmin in low-LETd regions of the HD-CTV (from 32 ± 2.3 keV/µm to 36.2 ± 3.6 keV/µm), (c) the GTV fraction receiving LETd of ≥50 keV/µm, (from <10% to >50%) and (d) the high-LETd component in the central region of the GTV, without significant compromise in DRBE distribution. However, distal patching is sensitive to setup/range uncertainties, and efforts to ascertain robustness are underway, before routine clinical implementation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgery is the standard treatment for stage I non-small-cell lung cancer (NSCLC), but is often difficult to perform in elderly patients due to their comorbidities and inferior physical status. Stereotactic body radiotherapy (SBRT) is expected to be an alternative treatment and is becoming widely used. Meanwhile, carbon ion radiotherapy (CIRT) is being recognized as an attractive treatment option with potentially lower toxicity for elderly patients with co-morbidities. The aim of this retrospective study was to assess the efficacy and safety of the two modalities for NSCLC in the elderly using Japanese multicenter data. The data on SBRT and single CIRT in consecutive patients ≥80 years of age suggested that the two modalities were comparable in terms of efficacy, at least in Japan during the study period; single CIRT was associated with a lower incidence of severe radiation pneumonitis, indicating a potentially safer treatment. The emergence of an aging society and technological advances have made radiotherapy, especially stereotactic body radiotherapy (SBRT), a common alternative to surgery for elderly patients with early stage non-small-cell lung cancer (NSCLC). Carbon-ion radiotherapy (CIRT) is also an attractive treatment option with potentially lower toxicity for elderly patients with comorbidities. We compared the clinical outcomes of the two modalities using Japanese multicenter data. SBRT (n = 420) and single-fraction CIRT (n = 70) data for patients with stage I NSCLC from 20 centers were retrospectively analyzed. Contiguous patients ≥ 80 years of age were enrolled, and overall survival (OS), disease-specific survival (DSS), local control (LC), and adverse event rates were compared. The median age was 83 years in both groups and the median follow-up periods were 28.5 and 42.7 months for SBRT and CIRT, respectively. The 3-year OS, DSS, and LC rates were 76.0% vs. 72.3% (p = 0.21), 87.5% vs. 81.6% (p = 0.46), and 79.2% vs. 78.2% (p = 0.87), respectively, for the SBRT vs. CIRT groups. Regarding toxicity, 2.9% of the SBRT group developed grade ≥ 3 radiation pneumonitis, whereas none of the CIRT group developed grade ≥ 2 radiation pneumonitis. SBRT and CIRT in elderly patients showed similar survival and LC rates, although CIRT was associated with less severe radiation pneumonitis. [ABSTRACT FROM AUTHOR]

We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatocellular carcinoma (HCC) patients with Child‐Pugh (CP)‐B not eligible for surgery nor other focal therapy options due to impaired liver function, have very limited treatment options. This study aims to retrospectively investigate the toxicity and efficacy of Carbon‐ion radiotherapy (C‐ion RT) on HCC with CP‐B patients. Materials and Methods: Patients with CP‐B, no extrahepatic metastasis, and treated with C‐ion RT between May 2000 and March 2020 were retrospectively extracted and included in this study. Results: Sixty‐nine lesions of 58 patients were included. The median follow‐up duration was 20.5 (2.7–108) months. During follow‐up, recurrence was observed in 43 patients, including 2 local recurrences and 39 intrahepatic recurrences beyond the irradiation field. A grade 3 acute hepatotoxicity was observed in one patient during the observation period. No acute or late adverse event of grade ≥4 was observed. Overall survival was 80.4% and 46.0% at 1 and 2 years, respectively, and the median survival time was 22.6 months. Local control rate was 96.4% at both 1 and 2 years, and progression‐free survival was 38.6% and 6.9% at 1 and 2 years, respectively, with a median of 9.7 months. Conclusion: The C‐ion RT showed low toxicity and good local effect in patients with HCC and CP‐B. Therefore, C‐ion RT could be an appropriate treatment for patients with HCC with poor liver function. [ABSTRACT FROM AUTHOR]

Abstract Background To evaluate the clinical relative biological effectiveness (RBE) of carbon‐ion radiotherapy (C‐ion RT) for prostate cancer. Methods The records of 262 patients with low‐risk prostate cancer (median age, 65 [47–80] years) treated with C‐ion RT at QST Hospital, National Institutes for Quantum Science and Technology in Japan during 2000–2018 were reviewed retrospectively. Four different protocol outcomes and prostate‐specific antigen (PSA) responses were evaluated. The median follow‐up was 8.4 years. The Kaplan–Meier method was used to estimate the biochemical or clinical failure‐free rate (BCFFR). Clinical RBE was calculated using the tumor control probability model. Results The 5‐, 7‐, and 10‐year BCFFRs were 91.7%, 83.8%, and 73.2%, respectively. The 10‐year BCFFRs of patients who received C‐ion RT at 66 Gy (RBE) in 20 fractions, 63 Gy (RBE) in 20 fractions, and 57.6 Gy (RBE) in 16 fractions were 81.4%, 70.9%, and 68.9%, respectively. The PSA level and density during follow‐up were better in the patients treated with the lower fraction size. A higher PSA nadir and shorter time to PSA nadir were risk factors for biochemical or clinical failure by multivariate Cox regression. The tumor control probability analysis showed that the estimated clinical RBE values to achieve an 80% BCFFR at 10 years for 20, 16, and 12 fractions were 2.19 (2.18–2.24), 2.16 (2.14–2.23), and 2.12 (2.09–2.21), respectively. Conclusions Using clinical data from low‐risk prostate cancer patients, we showed the clinical RBE of C‐ion RT decreased with increasing dose per fraction.

Carbon-ion radiotherapy (CIRT) for prostate cancer is both safe and efficacious; beam range calculations use relative stopping power ratio, which is derived from computed tomography (CT) values. However, hip prostheses are made of high atomic number materials and show severe artifacts on CT images. Therefore, it is not possible to accurately calculate dose distribution for CIRT in patients with prostate cancer with hip prostheses. Here, we describe the management of a 77-year-old man with prostate cancer who had previously undergone bilateral hip replacement. CIRT, in combination with androgen deprivation therapy, was recommended as definitive treatment for prostate cancer. Planning CT, magnetic resonance (MRI), and CT images with metal artifact reduction (MAR) were acquired for CIRT planning. MRI and MAR images were superimposed on the planning CT to delineate target volume and organs at risk. The radiation treatment plan consisted of a total dose of 51.6 Gy (relative biological effect) to be delivered in 12 fractions over 3 weeks, and the patient was irradiated in the supine and prone positions with a vertical beam, on alternating days. CIRT was completed as scheduled. No adverse events were observed during treatment or at 3 months after treatment initiation. While we show that CIRT may be a treatment option for patients with prostate cancer with bilateral hip prostheses, further studies are needed to evaluate treatment efficacy and late toxicity and to determine how CIRT can be administered to patients with prostate cancer with bilateral hip prostheses.

Simple Summary: The efficacy of carbon-ion radiotherapy (CIRT) alone vs. multimodality therapy, including surgery, chemoradiotherapy, and intraoperative radiotherapy for previously irradiated locally recurrent rectal cancer, has not been evaluated. A total of 85 patients receiving 70.4 Gy (RBE) in 16 fractions of CIRT were compared with 86 patients receiving 30 Gy in 15 fractions of chemoradiation, resection, and intraoperative electron radiotherapy. CIRT demonstrated improved two- and five-year overall survival (83.1% and 46.8% vs. 62.5% and 25.7% for CMT), with statistically equivalent local recurrence and disease progression, with reduced treatment toxicity and decreased patient cost. A prospective comparison is warranted. No standard treatment paradigm exists for previously irradiated locally recurrent rectal cancer (PILRRC). Carbon-ion radiotherapy (CIRT) may improve oncologic outcomes and reduce toxicity compared with combined modality therapy (CMT). Eighty-five patients treated at Institution A with CIRT alone (70.4 Gy/16 fx) and eighty-six at Institution B with CMT (30 Gy/15 fx chemoradiation, resection, intraoperative electron radiotherapy (IOERT)) between 2006 and 2019 were retrospectively compared. Overall survival (OS), pelvic re-recurrence (PR), distant metastasis (DM), or any disease progression (DP) were analyzed with the Kaplan–Meier model, with outcomes compared using the Cox proportional hazards model. Acute and late toxicities were compared, as was the 2-year cost. The median time to follow-up or death was 6.5 years. Median OS in the CIRT and CMT cohorts were 4.5 and 2.6 years, respectively (p ≤ 0.01). No difference was seen in the cumulative incidence of PR (p = 0.17), DM (p = 0.39), or DP (p = 0.19). Lower acute grade ≥ 2 skin and GI/GU toxicity and lower late grade ≥ 2 GU toxicities were associated with CIRT. Higher 2-year cumulative costs were associated with CMT. Oncologic outcomes were similar for patients treated with CIRT or CMT, although patient morbidity and cost were lower with CIRT, and CIRT was associated with longer OS. Prospective comparative studies are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Anatomical variations may distort the carbon-ion beam, leading to dose degradation during treatment. Thus, a robust-beam arrangement is important for patients with pancreatic cancer with carbon-ion radiotherapy. Our study aimed to investigate the angular dependency of water equivalent thickness (WET) variation for pancreatic cancer and to evaluate the robustness of accumulated doses with WET-based beam configurations. We found that posterior oblique beams in the supine position and anteroposterior beams in the prone position were the most robust to WET changes, and the robustness of the accumulated dose was significantly improved by using WET-based beam configurations. The findings may provide a reference for robust beam selection in clinical practice. Carbon-ion radiotherapy (CIRT) is one of the most effective radiotherapeutic modalities. This study aimed to select robust-beam configurations (BC) by water equivalent thickness (WET) analysis in passive CIRT for pancreatic cancer. The study analyzed 110 computed tomography (CT) images and 600 dose distributions of eight patients with pancreatic cancer. The robustness in the beam range was evaluated using both planning and daily CT images, and two robust BCs for the rotating gantry and fixed port were selected. The planned, daily, and accumulated doses were calculated and compared after bone matching (BM) and tumor matching (TM). The dose-volume parameters for the target and organs at risk (OARs) were evaluated. Posterior oblique beams (120–240°) in the supine position and anteroposterior beams (0° and 180°) in the prone position were the most robust to WET changes. The mean CTV V95% reductions with TM were −3.8% and −5.2% with the BC for gantry and the BC for fixed ports, respectively. Despite ensuring robustness, the dose to the OARs increased slightly with WET-based BCs but remained below the dose constraint. The robustness of dose distribution can be improved by BCs that are robust to ΔWET. Robust BC with TM improves the accuracy of passive CIRT for pancreatic cancer. [ABSTRACT FROM AUTHOR]

In particle therapy, bioabsorbable polyglycolic acid (PGA) spacer was developed to reduce the healthy organ irradiation dose, especially in the gastrointestinal tract. The PGA spacer is safe and effective; however, there are no reports that have confirmed whether the PGA spacer which inserted in the body actually stops the carbon-ion (C-ion) beams. Here, we visualized and confirmed that the PGA spacer stops the C-ion beams in the body based on the dose distribution using auto-activation positron emission tomography (AAPET). A 59-year-old dedifferentiated retroperitoneal liposarcoma patient underwent C-ion radiotherapy (C-ion RT) on referral. A month before C-ion RT initiation, the patient underwent PGA spacer placement. Postoperatively, the patient received 4.4 Gy (RBE) per fraction of C-ion RT, followed by AAPET. AAPET revealed lower positron emitter concentrations at the distal tissue ventral to the PGA spacer than in the planning target volume. In observing the efficacy of the PGA spacer, the AAPET images and the average count per second of the positron emitter suggested that the PGA spacer stopped the C-ion beams in the body in accordance with the dose distribution. Therefore, AAPET was useful in confirming the PGA spacer’s effectiveness in this study, and the PGA spacer stopped the C-ion beams.

Background/Aim: The curative treatment for solitary fibrous tumors (SFTs) consists of surgery. However, surgery for SFTs in the skull base is difficult due to the anatomy and curative surgery may not be possible. Carbon-ion radiotherapy (C-ion RT) might be useful in the treatment of inoperable SFTs in the skull base because of its biological and physical nature. This study presents the clinical outcomes of Cion RT for an inoperable SFT of the skull base. Case Report: A 68-year-old female patient experienced hoarseness, deafness on the right side, right facial nerve paralysis, and dysphagia. Magnetic resonance imaging revealed a tumor located in the right cerebello-pontine angle with destruction of the petrous bone, and immunohistochemical studies of the biopsy specimen showed a grade 2 SFT. Firstly, the patient underwent tumor embolization and surgery. However, 5 months after surgery, magnetic resonance imaging revealed regrowth of residual tumor. Subsequently, the patient was referred to our hospital for C-ion RT because curative surgery was unsuitable. The patient received 64 Gy (relative biological effectiveness) of Cion RT in 16 fractions. Two years after C-ion RT, the tumor showed a partial response. The patient was still alive at the last follow-up without evidence of local recurrence, distant metastasis, or late toxicities. Conclusion: These findings suggest that C-ion RT is a suitable treatment option for inoperable SFTs of the skull base. [ABSTRACT FROM AUTHOR]

Background: Compelling evidence shows the association between the relative biological effectiveness (RBE) of carbon‐ion radiotherapy (CIRT) and the dose averaged linear energy transfer (LETd). However, the ability to calculate the LETd in commercially available treatment planning systems (TPS) is lacking. Purpose: This study aims to develop a method of calculating the LETd of CIRT plans that could be robustly carried out in RayStation (V10B, Raysearch, Sweden). Methods: The calculation used the fragment spectra in RayStation for the CIRT treatment planning. The dose‐weighted averaging procedure was supported by the microdosimetric kinetic model (MKM). The MKM‐based pencil beam dose engine (PBA, v4.2) for calculating RBE‐weighted doses was reformulated to become a LET‐weighted calculating engine. A separate module was then configured to inversely calculate the LETd from the absorbed dose of a plan and the associated fragment spectra. In this study, the ion and energy‐specific LET table in the LETd module was further matched with the values decoded from the baseline data of the Syngo TPS (V13C, Siemens, Germany). The LETd distributions of several monoenergetic and modulated beams were calculated and validated against the values derived from the Syngo TPS and the published data. Results: The differences in LETds of the monoenergetic beams between the new method and the traditional method were within 3% in the entrance and Bragg‐peak regions. However, a larger difference was observed in the distal region. The results of the modulated beams were in good agreement with the works from the published literature. Conclusions: The method presented herein reformulates the MKM dose engine in the RayStation TPS to inversely calculate LETds. The robustness and accuracy were demonstrated. [ABSTRACT FROM AUTHOR]

Background: There is currently no established imaging method for assessing liver reserve capacity prior to carbon-ion radiotherapy (CIRT) for liver tumors. In order to perform safe CIRT, it is essential to estimate the post-therapeutic residual reserve capacity of the liver. Purpose: To evaluate the ability of pre-treatment 99mTc-galactosyl human serum albumin (99mTc-GSA) scintigraphy to accurately estimate the residual liver reserve capacity in patients treated with CIRT for liver tumors. Materials and methods: This retrospective study evaluated patients who were performed CIRT for liver tumors between December 2018 and September 2020 and underwent 99mTc-GSA scintigraphy before and 3 months after CIRT, and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI within 1 month before CIRT were evaluated. The maximal removal rate of 99mTc-GSA (GSA-Rmax) was analyzed for the evaluation of pre-treatment liver reserve capacity. Then, the GSA-Rmax of the estimated residual liver (GSA-RL) was calculated using liver SPECT images fused with the Gd-EOB-DTPA-enhanced MRI. GSA-RL before CIRT and GSA-Rmax at 3 months after CIRT were compared using non-parametric Wilcoxon signed-rank test and linear regression analysis. Results: Overall, 50 patients were included (mean age ± standard deviation, 73 years ± 11; range, 29–89 years, 35 men). The median GSA-RL was 0.393 [range, 0.057–0.729] mg/min, and the median GSA-Rmax after CIRT was 0.369 [range, 0.037–0.780] mg/min (P =.40). The linear regression equation representing the relationship between the GSA-RL and GSA-Rmax after CIRT was y = 0.05 + 0.84x (R2 = 0.67, P <.0001). There was a linear relationship between the estimated and actual post-treatment values for all patients, as well as in the group with impaired liver reserve capacity (y = − 0.02 + 1.09x (R2 = 0.62, P =.0005)). Conclusions: 99mTc-GSA scintigraphy has potential clinical utility for estimating the residual liver reserve capacity in patients undergoing carbon-ion radiotherapy for liver tumors. Trial registration: UMIN000038328, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000043545. [ABSTRACT FROM AUTHOR]

Background: To evaluate the clinical relative biological effectiveness (RBE) of carbon‐ion radiotherapy (C‐ion RT) for prostate cancer. Methods: The records of 262 patients with low‐risk prostate cancer (median age, 65 [47–80] years) treated with C‐ion RT at QST Hospital, National Institutes for Quantum Science and Technology in Japan during 2000–2018 were reviewed retrospectively. Four different protocol outcomes and prostate‐specific antigen (PSA) responses were evaluated. The median follow‐up was 8.4 years. The Kaplan–Meier method was used to estimate the biochemical or clinical failure‐free rate (BCFFR). Clinical RBE was calculated using the tumor control probability model. Results: The 5‐, 7‐, and 10‐year BCFFRs were 91.7%, 83.8%, and 73.2%, respectively. The 10‐year BCFFRs of patients who received C‐ion RT at 66 Gy (RBE) in 20 fractions, 63 Gy (RBE) in 20 fractions, and 57.6 Gy (RBE) in 16 fractions were 81.4%, 70.9%, and 68.9%, respectively. The PSA level and density during follow‐up were better in the patients treated with the lower fraction size. A higher PSA nadir and shorter time to PSA nadir were risk factors for biochemical or clinical failure by multivariate Cox regression. The tumor control probability analysis showed that the estimated clinical RBE values to achieve an 80% BCFFR at 10 years for 20, 16, and 12 fractions were 2.19 (2.18–2.24), 2.16 (2.14–2.23), and 2.12 (2.09–2.21), respectively. Conclusions: Using clinical data from low‐risk prostate cancer patients, we showed the clinical RBE of C‐ion RT decreased with increasing dose per fraction. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the leading causes of death among cancer patients worldwide. Carbon‐ion radiotherapy is a radical nonsurgical treatment with high local control rates and no serious adverse events. N6‐methyladenosine (m6A) modification is one of the most common chemical modifications in eukaryotic messenger RNA (mRNA) and has important effects on the stability, splicing, and translation of mRNAs. Recently, the regulatory role of m6A in tumorigenesis has been recognized more and more. However, the dysregulation of m6A and its role in carbon‐ion radiotherapy of non‐small‐cell lung cancer (NSCLC) remains unclear. In this study, we found that the level of methyltransferase‐like 3 (METTL3) and its mediated m6A modification were elevated in NSCLC cells with carbon‐ion radiotherapy. Knockdown of METTL3 in NSCLC cells impaired proliferation, migration, and invasion in vitro and in vivo. Moreover, we found that METTL3‐mediated m6A modification of mRNA inhibited the decay of H2A histone family member X (H2AX) mRNA and enhanced its expression, which led to enhanced DNA damage repair and cell survival. [ABSTRACT FROM AUTHOR]

Abstract Background There are limited studies on the risk of secondary cancers after carbon‐ion radiotherapy (CIRT). We assessed the incidence of secondary cancers in patients treated with CIRT for cervical cancer. We also evaluated the incidence of secondary cancers in patients who received standard photon radiotherapy (RT) throughout the same period. Methods This retrospective study included patients with cervical cancer who underwent curative RT at our hospital. All cancers discovered for the first time after RT were classified as secondary cancers. To compare the risk of secondary cancers among cervical cancer survivors to the general population, standardized incidence ratios (SIRs) were calculated. Results The analysis included a total of 197 and 417 patients in the CIRT and photon RT groups, respectively. The total person‐years during the observation period were 1052.4 in the CIRT group and 2481.5 in the photon RT group. The SIR for all secondary cancers was 1.1 (95% confidence interval [CI], 0.6–2.1) in the CIRT group and 1.4 (95% CI, 1.0–2.1) in the photon RT group. The 10‐year cumulative incidence of all secondary cancers was 9.5% (95% CI, 4.0–21.5) in the CIRT group and 9.4% (95% CI, 6.2–14.1) in the photon RT group. The CIRT and photon RT groups were not significantly different in incidence (p = 0.268). Conclusions The incidence of secondary cancers after CIRT for cervical cancer was similar to that after photon RT. Validation of our findings after long‐term observation is warranted.

• Linear energy transfer affect local control of lung cancer with carbon-ion radiotherapy. • LET d in iGTV in the local recurrence group was lower than the local control group. • LET d distribution within iGTV should be routinely assessed in CIRT for lung cancer. High linear energy transfer (LET) radiation exhibits stronger tumor-killing effect. However, the correlation between LET and the therapeutic efficacy in Carbon-ion radiotherapy (CIRT) for locally advanced non-small-cell lung cancer (LA-NSCLC) is currently not clear. This study aimed to investigate the relationship between the dose-averaged LET (LET d) distribution within tumor and local recurrence for LA-NSCLC treated with CIRT. An analysis of 62 consecutive patients with LA-NSCLC who underwent CIRT from 2018 to 2022 was conducted. The LET d distribution was calculated based on their treated plans, and the correlation between local recurrence and LET d , relative biological effectiveness (RBE)-weighted doses (D RBE) and clinical factors was investigated. Receiver operating characteristic (ROC) curve, log-rank test, and Cox regression analysis were performed based on that. 16 patients were defined as local recurrence. Overall survival (OS) and local control (LC) at 24 months were 76.9 % and 73.2 %, respectively. The mean LET d in internal gross tumor volume (iGTV) in the local recurrence group was 48.7 keV/µm, significantly lower than the mean LET d of 53.2 keV/µm in the local control group (p = 0.016). No significant difference was observed in D RBE between the local recurrence and local control groups. ROC curve analysis indicated that a percentage of 88 % of volume in iGTV receiving at least 40 keV/µm (V 40 k e V / μ m) is the optimal threshold for predicting local recurrence (Area under curve (AUC) = 0.7636). The log-rank test and Cox regression analysis revealed that the LET d value covering 98 % volume of iGTV ( LET d 98 %) was a significant risk factor for LC (p = 0.020). Our study revealed an association between LET d distribution and local recurrence in patients with LA-NSCLC. These findings suggest that lower LET d may increase the probability of local recurrence. We suggest that LET d distribution within iGTV should be routinely assessed in CIRT for lung cancer. [ABSTRACT FROM AUTHOR]

• The establishment of an optimal, effective, and safe CIRT protocol for SNMM is crucial. • The CTV designs and doses for SNMM were investigated in this study. • Extended CTV was observed to be appropriate for CIRT of SNMM. • At least 40 Gy to the subclinical region was recommended. No guidelines exist for the clinical target volume (CTV) and radiotherapy dose in sinonasal mucosal melanoma (SNMM). Thus, we aimed to determine the carbon-ion radiotherapy (CIRT) CTV and dose for SNMM. In total, 135 patients with SNMM who received CIRT were reviewed. The relative biological effectiveness-weighted dose was 57.6 or 64 Gy in 16 fractions. CTV was classified into small CTV, which included the gross tumor and visible melanosis with a certain margin, and extended CTV, which included the tumor site and adjacent anatomical structures. Local recurrence (LR) patterns were pattern I, II, and III, defined as recurrence over the gross tumor, visible melanosis and subclinical area, which would be covered if extended CTV was applied, and outside the extended CTV, respectively. The 5-year LR rate was 35.3 %. The prescribed dose was not a significant risk factor for pattern I LR; however, 57.6 Gy for a large tumor was insufficient for local control. Using an extended CTV was significantly associated with a lower risk of pattern II LR, and these recurrences did not occur in regions that received > 40 Gy. The 5-year pattern III LR rate was 6.4 %. Utilizing an extended CTV in CIRT for SNMM is appropriate even for small tumors. Using a smaller CTV after an extended CTV of at least 40 Gy is recommended to reduce adverse events. Although the optimal dose for gross tumors remains unclear, the latest technology with 64 Gy showed good outcomes. [ABSTRACT FROM AUTHOR]

In ion beam radiotherapy (IBRT), the secondary neutrons contribute to whole-body exposure, potentially increasing the risk of radiation-induced cancer. The energy range of neutrons generated in the IBRT treatment room spreads from thermal to a few hundred MeV, with those between 0.1 and a few hundred MeV playing a crucial role in the ambient dose equivalent. This study introduces a novel approach for measuring the ambient dose equivalent that focuses on the neutron energy spectrum in the IBRT treatment room. Distinguished by the use of a hydrogen-filled proportional counter and a single moderator, this new method overcomes the weakness of the traditional Bonner Sphere Spectrometer by reducing the complexity and time required for measurements. By deriving the neutron energy spectrum, the neutron ambient dose equivalent can be accurately calculated. Our validation demonstrated that the neutron ambient dose equivalents derived using our method closely agree with the actual values, with discrepancies within 4%, underscoring the feasibility of this innovative approach to neutron dosimetry in the IBRT treatment room. • A new concept for the experimental determination of neutron H *(10) is proposed. • The H *(10) is determined based on the energy spectrum through a single measurement. • This method overcomes the weakness of the conventional measurement method. • Our validation showed that this method reproduces the actual values well. • These findings affirm the practicality of the method in the IBRT treatment room. [ABSTRACT FROM AUTHOR]

Abstract Background Carbon-ion radiotherapy (CIRT) for esophageal cancer has been receiving significant attention given its high local control rates and minimal damage to normal tissues. However, the efficacy and safety of salvage surgery after CIRT for esophageal cancer remain unclear. We report the case of a patient who underwent salvage thoracoscopic surgery after CIRT. Case presentation A 51-year-old woman underwent upper gastrointestinal endoscopy and a type 0-IIa + 0-IIc esophageal squamous cell carcinoma located 27–29 cm from the patient’s incisors, classified as clinical stage I (T1bN0M0), was detected. She received CIRT (50.4 Gy [relative biological effectiveness, RBE]/12 fr) for localized esophageal cancer and achieved complete remission after 4 months. Six years after CIRT, follow-up endoscopic examination demonstrated a type 0-IIa + 0-IIc tumor in the previously treated area. In addition, a type 0-IIa lesion located 20–22 cm from the incisors was found. We diagnosed localized ESCC, classified as clinical stage I (T1bN0M0). Salvage thoracoscopic surgery was performed in the prone position with five access ports. Although the esophagus tightly adhered to the thoracic descending aorta and left main bronchus with severe fibrosis, the esophagus could be separated from the surrounding organs with careful forceps manipulation. The operation time and blood loss were 8 h 45 min and 253 mL, respectively. The patient was discharged from our hospital 17 days after the salvage surgery without any complications. Pathological findings revealed two squamous cell carcinomas. Both tumors were localized in the lamina propria mucosa, and lymph node metastasis was not detected. The tumors were diagnosed as pathological stage IA (pT1aN0M0) according to the TNM criteria. Moreover, pathological examinations showed severe fibrosis of the previously irradiated tissues compared to the normal esophagus located outside of the irradiation field. Following the surgery, the patient had no recurrence for 1 year and 6 months. Conclusions Thoracoscopic radical esophagectomy can be performed as salvage surgery. Careful and discreet surgery is integral to perform salvage surgery after CIRT since CIRT may cause severe adhesions and fibrosis in the irradiated field.

Aim: Carbon‐ion radiotherapy (C‐ion RT) has shown potential as a curative treatment for patients with hepatocellular carcinoma (HCC). However, no reports have compared the effectiveness of C‐ion RT and radiofrequency ablation (RFA). This study aimed to compare clinical outcomes between C‐ion RT and RFA for patients with early‐stage HCC. Methods: Medical records of consecutive patients with HCC (single lesion ≤5 cm or two to three lesions ≤3 cm) who received either C‐ion RT or RFA as initial treatment were retrospectively reviewed. Propensity score matching (PSM) was used to adjust for clinical factors between both groups. Results: A total of 560 patients were included, among whom 69 and 491 received C‐ion RT and RFA, respectively. After PSM (C‐ion RT, 54 patients; RFA, 95 patients), both groups were well balanced. Carbon‐ion radiotherapy had significantly lower cumulative intrasubsegmental recurrence rate after PSM compared to RFA (p = 0.004) (2‐year, 12.6% vs. 31.7%; 5‐year, 15.5% vs. 49.6%, respectively). However, no significant difference in cumulative local recurrence rate, stage progression‐free survival, or overall survival (OS) was observed between both groups. In the RFA group, 6 of 491 patients (1.2%) showed grade 3 adverse events, whereas no grade 3 or higher adverse events were observed in the C‐ion RT group. Conclusion: Carbon‐ion radiotherapy provided a lower cumulative intrasubsegmental recurrence rate, but a comparable cumulative local recurrence rate, stage progression‐free survival, and OS compared to RFA. Thus, C‐ion RT appears to be one of the effective treatment options for early‐stage HCC when RFA is deemed not indicated. [ABSTRACT FROM AUTHOR]

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

Carbon‐ions are charged particles with a high linear energy transfer, and therefore, they make a better dose distribution with greater biological effects on the tumors compared with photons and protons. Since prostate cancer, renal cell carcinoma, and retroperitoneal sarcomas such as liposarcoma and leiomyosarcoma are known to be radioresistant tumors, carbon‐ion radiotherapy, which provides the advantageous radiobiological properties such as an increasing relative biological effectiveness toward the Bragg peak, a reduced oxygen enhancement ratio, and a reduced dependence on fractionation and cell‐cycle stage, has been tested for these urological tumors at the National Institute for Radiological Sciences since 1994. To promote carbon‐ion radiotherapy as a standard cancer therapy, the Japan Carbon‐ion Radiation Oncology Study Group was established in 2015 to create a registry of all treated patients and conduct multi‐institutional prospective studies in cooperation with all the Japanese institutes. Based on accumulating evidence of the efficacy and feasibility of carbon‐ion therapy for prostate cancer and retroperitoneal sarcoma, it is now covered by the Japanese health insurance system. On the other hand, carbon‐ion radiotherapy for renal cell cancer is not still covered by the insurance system, although the two previous studies showed the efficacy. In this review, we introduce the characteristics, clinical outcomes, and perspectives of carbon‐ion radiotherapy and our efforts to disseminate the use of this new technology worldwide. [ABSTRACT FROM AUTHOR]

In particle therapy, bioabsorbable polyglycolic acid (PGA) spacer was developed to reduce the healthy organ irradiation dose, especially in the gastrointestinal tract. The PGA spacer is safe and effective; however, there are no reports that have confirmed whether the PGA spacer which inserted in the body actually stops the carbon-ion (C-ion) beams. Here, we visualized and confirmed that the PGA spacer stops the C-ion beams in the body based on the dose distribution using auto-activation positron emission tomography (AAPET). A 59-year-old dedifferentiated retroperitoneal liposarcoma patient underwent C-ion radiotherapy (C-ion RT) on referral. A month before C-ion RT initiation, the patient underwent PGA spacer placement. Postoperatively, the patient received 4.4 Gy (RBE) per fraction of C-ion RT, followed by AAPET. AAPET revealed lower positron emitter concentrations at the distal tissue ventral to the PGA spacer than in the planning target volume. In observing the efficacy of the PGA spacer, the AAPET images and the average count per second of the positron emitter suggested that the PGA spacer stopped the C-ion beams in the body in accordance with the dose distribution. Therefore, AAPET was useful in confirming the PGA spacer's effectiveness in this study, and the PGA spacer stopped the C-ion beams. [ABSTRACT FROM AUTHOR]