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Highlights • We analyzed 224 LRRC patients treated with C-ion RT at three institutions. • The median follow-up period from the initiation of C-ion RT was 62 months. • The OS rates were 73% at 3 years and 51% at 5 years. • Grade 3 acute (n = 3) and grade 3 late (n = 12) toxicity was observed. • C-ion RT for LRRC showed relatively favorable outcomes and limited toxicity. Abstract Purpose We investigated the efficacy and safety of carbon-ion radiotherapy (C-ion RT) for locally recurrent rectal cancer (LRRC). Patients and methods Data from patients with LRRC treated with C-ion RT from November 2003 to December 2014 at three institutions were retrospectively analyzed. The endpoints of this clinical trial were overall survival (OS), local control (LC), and acute/late toxicity. Results A total of 224 patients' data were collected. The prescribed dose was 70.4 Gy (relative biological effectiveness [RBE]-weighted absorbed dose) or 73.6 Gy (RBE) in 16 fractions. The median follow-up period from the initiation of C-ion RT was 62 months (range 6–169 months). The OS rates were 73% (95% confidence interval [CI], 67%–79%) at 3 years and 51% (95%CI 44%–58%) at 5 years. The LC rates were 93% (95%CI 88%–96%) at 3 years, and 88% (95%CI 82%–93%) at 5 years. Grade 3 acute toxicity was observed in three patients: gastrointestinal toxicity (n = 1) and pelvic infection (n = 2). Grade 3 late toxicity was observed in 12 patients: skin reaction (n = 2), gastrointestinal toxicity (n = 2), neuropathy (n = 1), and pelvic infection (n = 7). There was no grade 4 or 5 acute or late toxicity. Conclusions This first multi-institutional analysis of C-ion RT for LRRC indicated relatively favorable outcomes with limited toxicities. [ABSTRACT FROM AUTHOR]

Introduction: We evaluated treatment outcomes of CIRT in an active raster-scanning technique alone or in combination with IMRT for lacrimal gland tumors. Methods: A total of 24 patients who received CIRT for a malignant lacrimal gland tumor at the HIT between 2009 and 2018 were analyzed retrospectively for LC, OS, and distant progression-free survival (DPFS) using Kaplan–Meier estimates. Toxicity was assessed according to the CTCAE version 5. Results: Median follow-up was 30 months and overall median LC, OS, and DPFS 24 months, 36 months, and 31 months, respectively. Two-year LC, OS, and DPFS of 93%, 96%, and 87% with CIRT was achieved for all patients. Local failure occurred only in patients with ACC and after a median follow-up of 30 months after the completion of RT (n=5, 21%; P=0.09). We identified a significant negative impact of a macroscopic tumor disease, which was diagnosed on planning CT or MRI before RT, on LC (P=0.026). In contrast, perineural spread (P=0.661), T stage (P=0.552), and resection margins in operated patients (P=0.069) had no significant impact on LC. No grade ≥3 acute or grade >3 chronic toxicity occurred. Late grade 3 side effects were identified in form of a wound-healing disorder 3 months after RT in one patient and temporal lobe necrosis 6 months after RT in another (n=2, 8%). Conclusion: Accelerated hypofractionated active raster-scanning CIRT for relative radioresistant malignant lacrimal gland tumors results in adequate LC rates and moderate acute and late toxicity. Nevertheless, LC for ACC histology remains challenging and risk factors for local recurrence are still unclear. Further follow-up is necessary to evaluate long-term clinical outcome. [ABSTRACT FROM AUTHOR]

The efficacy and safety of carbon‐ion radiotherapy (CIRT) for locally advanced non‐small‐cell lung cancer (LA‐NSCLC) remain unclear. We reported the clinical outcomes of CIRT for LA‐NSCLC. Data for 141 eligible patients who received CIRT between 1995 and 2015 were retrospectively analyzed. Local control (LC), locoregional control (LRC), progression‐free survival (PFS) and overall survival (OS) were calculated using the Kaplan‐Meier method. The median age was 75.0 years. Overall, 21 (14.9%), 57 (40.4%), 43 (30.5%) and 20 (14.2%) patients had T1, T2, T3 and T4 disease, respectively. Moreover, 51 (36.2%), 45 (31.9%), 40 (28.4%) and 5 (3.5%) patients had N0, N1, N2 and N3 disease, respectively. Furthermore, 34 (24.1%), 42 (29.8%), 45 (31.9%) and 20 (14.2%) patients had stages IIA, IIB, IIIA and ΙΙΙB disease, respectively. Overall, 62 (44.0%), 60 (42.6%), 8 (5.7%) and 11 (7.8%) patients had adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and others, respectively. The median dose was 72.0 Gy (relative biological effectiveness). No patient received concurrent chemotherapy. Median follow‐up periods were 29.3 (1.6‐207.7) and 40.0 (10.7‐207.7) months for all patients and survivors, respectively. Two‐year LC, PFS and OS rates were 80.3%, 40.2% and 58.7%, respectively. Overall, 1 (0.7%), 5 (3.5%) and 1 (0.7%) patient developed Grades 4 (mediastinal hemorrhage), 3 (radiation pneumonitis) and 3 (bronchial fistula) toxicities, respectively. Multivariate analysis showed adenocarcinoma and N2/3 classification as significant poor prognosticators of PFS. CIRT is an effective treatment with acceptable toxicity for LA‐NSCLC, especially for elderly patients or patients with severe comorbidities who cannot be treated with surgery or chemoradiotherapy. Carbon‐ion radiotherapy is an effective treatment option with acceptable toxicity for LA‐NSCLC. It is especially useful for elderly patients and those with severe comorbidities. [ABSTRACT FROM AUTHOR]

Background: We conducted a retrospective multicenter study to assess the clinical outcomes of carbon‐ion radiotherapy (CIRT) for head and neck malignancies (Japan Carbon‐Ion Radiation Oncology Study Group [J‐CROS] study: 1402 HN). We aimed to evaluate the safety and efficacy of CIRT in patients with external auditory canal (EAC) and middle ear (ME) carcinomas. Methods: Thirty‐one patients treated with CIRT at four Japanese institutions were analyzed. Fourteen patients (45.2%) had squamous cell carcinomas, 13 (41.9%) had adenoid cystic carcinomas, and four (12.9%) had other types. Nineteen (61.3%), six (19.4%), three (9.7%), and three (9.7%) patients had T4, T3, T2, and T1 disease, respectively. All patients had N0M0 status. The median radiation dose was 64 Gy (relative biological effectiveness) in 16 fractions. The median gross tumor volume was 33.3 mL. Results: The median follow‐up period was 18.4 months (range, 5.1‐85.6). The 1‐ and 3‐year local control and overall survival rates were 75.0% and 55.0% and 79.3% and 58.7%, respectively. Regarding grade 3 or higher toxicities, three patients (9.7%) had grade 3 dermatitis, one (3.2%) had grade 3 mucositis, and two (6.5%) had grade 3 central nervous necrosis (ie, radiation‐induced brain necrosis). No grade 4 or worse reactions were observed. Conclusion: CIRT was effective for EAC and ME carcinomas. Carbon‐ion radiotherapy showed high local control rate (a), progression‐free survival rate (b) and overall survival rate (c). [ABSTRACT FROM AUTHOR]

To shorten the treatment procedure and increase the treatment efficiency, we performed planning studies to evaluate the 4D dose (4DD) distributions of different number of irradiation fields with the fixed treatment ports of scanning carbon-ion beam delivery. We enrolled 10 lung cancer patients treated with respiratory-gated scanning carbon-ion therapy. 4-field, 3-field, and 2-field plans were generated with fixed treatment ports by rotating the beam angle with a 20∼40-degree difference. For each field, the range-adapted internal target volume (raITV) was calculated. The prescription dose of 50 Gy (RBE)-weighted dose with 1 fraction was optimized on the reference phase (T50). The 4DD distributions were calculated for each patient, and dose metrics of CTV dose coverage and OARs sparing were evaluated. p < 0.05 was considered to be statistically significant by Wilcoxon signed-rank test. The sufficient CTV-D95 > 97.8% could be achieved for all the three types of treatment plan. The Dmax of skin was increased (= 19.1 ± 5.7 Gy (RBE)) for the 2-field plans as compared to 4-field plans (= 14.2 ± 6.6 Gy (RBE), p = 0.006), which is still acceptable for clinical use (<35 Gy (RBE)). And there were no differences (p > 0.076) of V20 of lung (= 15.5 ± 6.6%, 16.2 ± 7.0%, 15.6 ± 6.3%) and Dmax of spinal cord (= 3.0 ± 2.9, 3.4 ± 3.9, 3.3 ± 4.3 Gy (RBE)) among the three types of plans. Lung treatment plans under the fixed orthogonal beam ports with zero-degree couch pitch angle is feasible for clinical use to further increase the treatment efficiency and throughput. • The 4-field versus 2-field carbon ion treatment plans were compared for the first time. • The range-adapted ITV and fast rescanning protocols were used in the 4D dose distribution calculation. • Both the target dose coverage and OAR sparing were clinical acceptable under 2-field plans. [ABSTRACT FROM AUTHOR]

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., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tatsuya Ohno received research funding from Hitachi. All other authors declare no conflict of interest., (© 2023 The Authors.)

Background/aim: Dose distributions of carbon-ion radiotherapy (C-ion RT) have been created with the relative biological effectiveness (RBE) of human salivary gland cells (HSG). However, no dose distributions have been created using various tumor cell-specific RBE values. Hence, we conducted in vitro experiments to determine the RBE of human osteosarcoma cells (U2OS) and used this RBE value (RBE U2OS ) to calculate the dose distribution for C-ion RT., Materials and Methods: To obtain RBE values for various linear energy transfer (LET) levels, we exposed U2OS cells to different doses of X-rays and varying doses and LET levels of C-ion beams (13, 30, 50, and 70 keV/μm). Subsequently, we converted the RBE of HSG (RBE HSG ) to RBE U2OS in the treatment planning system and reconstructed the dose distribution for a typical osteosarcoma case. We performed a dose-volume histogram (DVH) analysis, evaluating the percentage of the minimum dose that covered 98%, 50%, and 2% (D 98% , D 50% , and D 2% , respectively), as well as the homogeneity index [HI; calculated as (D 2% -D 98% )/D 50% ]., Results: The RBE U2OS values for C-ion beams with LET of 13, 30, 50, and 70 keV/μm were 1.77, 2.25, 2.72, and 4.50, respectively. When comparing DVH parameters with the planning target volume, we observed the following values: D 98% , D 50% , D 2% , and HI for RBE HSG were 64.1, 70.1, 72.4 Gy (RBE), and 0.12, respectively. For RBE U2OS , these values were 86.2, 95.0, 107.9 Gy (RBE), and 0.23, respectively., Conclusion: We utilized RBE U2OS to calculate the dose distribution of carbon ion radiotherapy, revealing potential degradation in dose distribution and particularly worsening of the HI., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Abstract Purpose The Union of Light Ion Centers in Europe (ULICE) program addressed the need for uniting scientific results for carbon-ion radiation therapy obtained by several institutions worldwide in different fields of excellence, and translating them into a real benefit to the community. Particularly, the concepts for dose/volume parameters developed in photon radiotherapy cannot be extrapolated to high linear energy transfer particles. Methods and Materials The ULICE-WP2 taskforce included radiation oncologists involved in carbon-ion radiation therapy and International Commission on Radiation Units and Measurements, radiation biologists, expert physicists in the fields of carbon-ion radiation therapy, microdosimetry, biological modeling and image-guided radiotherapy. Consensual reports emerged from multiple discussions within both the restricted group and the wider ULICE community. Public deliverables were produced and disseminated to the European Commission. Results Here we highlight the disparity in practices between treating centers, then address the main topics to finally elaborate specific recommendations. Although it appears relatively simple to add geometrical margins around the clinical target volume to obtain the planning target volume as performed in photon radiotherapy, this procedure is not appropriate for carbon-ion radiation therapy. Due to the variation of the radiation quality in depth, there is no generic relative biological effectiveness value for carbon-ions outside of an isolated point, for a given fractionation and specific experimental conditions. Absorbed dose and "equieffective dose" for specified conditions must always be reported. Conclusions This work contributed to the development of standard operating procedures for carbon-ion radiation therapy clinical trials. These procedures are now being applied, particularly in the first phase III international, multicenter trial (PHRC Étoile). [ABSTRACT FROM AUTHOR]

Background: This multi‐institutional retrospective study focused on the clinical outcome of carbon‐ion radiotherapy (C‐ion RT) for non‐squamous cell malignant tumors of the nasopharynx. Methods: The Japan Carbon‐ion Radiation Oncology Study Group collected and analyzed data for 43 patients with non‐squamous cell malignant tumors of the nasopharynx treated with C‐ion RT at four institutions in Japan. Results: Twenty‐nine patients had adenoid cystic carcinomas, seven had malignant melanomas, three had adenocarcinomas, two had mucoepidermoid carcinomas, and two had other pathologies. Twenty‐six of the 43 patients (61%) had T4 tumors. The most common dose‐fractionation schedule was 64 Gy (relative biological effectiveness) in 16 fractions. The median follow‐up period was 30 months. The 2‐year local control (LC) and overall survival (OS) rates were 88% and 84%, respectively. For late toxicity, one patient developed grade 4 optic nerve disorder and two developed grade 5 pharyngeal hemorrhage. Actual incidence of grade 3 or higher late adverse events was 19%, and included cranial nerve dysfunction, jaw bone necrosis, central nervous system necrosis, and ear inflammation. Conclusions: C‐ion RT provided good LC and OS rates with acceptable toxicity for treatment of non‐squamous cell malignant tumors of the nasopharynx. This is the first study of 43 patients with non‐squamous cell malignant tumors of the nasopharynx treated with carbon‐ion radiotherapy. Carbon‐ion radiotherapy provided good LC and OS rates with acceptable toxicity even though non‐squamous cell malignant tumors of the nasopharynx often show refractoriness to the conventional therapy. [ABSTRACT FROM AUTHOR]

Highlights • We analyzed 64 LAPC patients treated with C-ion RT at single institution. • The median survival time and 2-year OS were 25.1 months and 53%. • Only four patients experienced acute grade 3 toxicities. • C-ion RT for LAPC showed relatively favorable outcome and limited toxicity. Abstract Purpose The aim of this study was to evaluate the efficacy and safety of carbon-ion radiotherapy (C-ion RT) for unresectable locally advanced pancreatic cancer (LAPC). Methods and materials Patients with LAPC treated with definitive C-ion RT between April 2014 and July 2017 were analyzed retrospectively. The prescribed dose was 55.2 Gy (relative biological effectiveness [RBE] weighted absorbed dose) in 12 fractions. Overall survival (OS), local control (LC), progression free survival (PFS), and toxicity were evaluated. Results Sixty-four patients were enrolled. All patients completed planned course of C-ion RT. The median follow-up time for survivors from the initiation of C-ion RT was 24.4 months (range, 5.1–46.1 months). Median survival time was 25.1 months. Two-year OS, LC, and PFS were 53% (95% confidence interval [CI], 39%–66%), 82% (95% CI, 66%–91%), and 23% (95% CI, 14%–36%), respectively. Four patients experienced acute grade 3 toxicities including 3 gastrointestinal (GI) toxicities. There was no grade 3 or more late toxicity. Conclusions The clinical results of C-ion RT for LAPC at our institution were comparable to those of a recent multi-institutional analysis. [ABSTRACT FROM AUTHOR]

Abstract The efficacy and safety of carbon ion radiotherapy (C-ion RT) for locoregional recurrence after surgery for pancreatic cancer were retrospectively evaluated. The results for 30 patients showed that C-ion RT was performed safely with relatively long overall survival, good local control, and minimal toxicity. [ABSTRACT FROM AUTHOR]

Long‐term oncological outcomes for primary renal cell carcinoma (RCC) treated with carbon‐ion radiotherapy (CIRT) are poorly understood. Patients with primary RCC were treated with 12 or 16‐fraction CIRT at The Hospital of the National Institute of Radiological Sciences outside of clinical trials. Outcome data were pooled and retrospectively analyzed for toxicity, local control, and disease‐free, cancer‐specific, and overall survival. From 1997 to 2014, 19 RCC patients (11 with T1aN0M0, 4 with T1bN0M0, and 4 with inoperable advanced stage [T4N0M0, T3aN1M0, and T1aN0M1]) were treated with CIRT and followed up for a median of 6.6 (range, 0.7‐16.5) years; 9 of these patients were inoperable because of comorbidities or advanced‐stage disease. Diagnoses were confirmed by imaging in 11 patients and by biopsy in the remaining 8. In 4 of 5 patients with definitive renal comorbidities, including diabetic nephropathy, sclerotic kidney or solitary kidney pre‐CIRT progressed to grade 4 chronic kidney disease (CKD). In contrast, the remaining 14 patients without definitive renal comorbidities did not progress to grade 3 or higher CKD. Furthermore, although 1 case of grade 4 dermatitis was observed, there were no other grade 3 or higher non‐renal adverse events. Local control rate, and disease‐free, cancer‐specific, and overall survival rates at 5 years of all 19 patients were 94.1%, 68.9%, 100%, and 89.2%, respectively. This updated retrospective analysis based on long‐term follow‐up data suggests that CIRT is a safe treatment for primary RCC patients without definitive renal comorbidities pre‐CIRT, and yield favorable treatment outcomes, even in inoperable cases. [ABSTRACT FROM AUTHOR]

Purpose The aim of this work was to estimate typical dose equivalents to out-of-field organs during carbon-ion radiotherapy (CIRT) with a passive beam for prostate cancer treatment. Additionally, sensitivity analyses of organ doses for various beam parameters and phantom sizes were performed. Methods Because the CIRT out-of-field dose depends on the beam parameters, the typical values of those parameters were determined from statistical data on the target properties of patients who received CIRT at the Heavy-Ion Medical Accelerator in Chiba (HIMAC). Using these typical beam-parameter values, out-of-field organ dose equivalents during CIRT for typical prostate treatment were estimated by Monte Carlo simulations using the Particle and Heavy-Ion Transport Code System (PHITS) and the ICRP reference phantom. Results The results showed that the dose decreased with distance from the target, ranging from 116 mSv in the testes to 7 mSv in the brain. The organ dose equivalents per treatment dose were lower than those either in 6-MV intensity-modulated radiotherapy or in brachytherapy with an Ir-192 source for organs within 40 cm of the target. Sensitivity analyses established that the differences from typical values were within ∼30% for all organs, except the sigmoid colon. Conclusions The typical out-of-field organ dose equivalents during passive-beam CIRT were shown. The low sensitivity of the dose equivalent in organs farther than 20 cm from the target indicated that individual dose assessments required for retrospective epidemiological studies may be limited to organs around the target in cases of passive-beam CIRT for prostate cancer. [ABSTRACT FROM AUTHOR]

A treatment of carbon-ion radiotherapy (CIRT) is generally evaluated using the dose weighted by relative biological effectiveness (RBE) while ignoring the radiation quality varying in the patient. In this study, we have developed a method of estimating linear energy transfer (LET) from the RBE in an archived treatment plan to represent the radiation quality of the treatment. The LET in a beam database was associated with the RBE by two fitting functions per energy, one for the spread-out Bragg peak (SOBP) and the other for shallower depths, to be differentiated by RBE per energy per modulation. The estimated LET was generally consistent with the original calculation within a few keV/μm, except for the overkill region near the distal end of SOBP. The knowledge of experimental radiobiology can thereby be associated with CIRT treatments through LET, which will potentially contribute to deeper understanding of clinical radiobiology and further optimization of CIRT. [ABSTRACT FROM AUTHOR]

Intrathoracic recurrence after carbon-ion radiotherapy for primary or metastatic lung tumors remains a major cause of cancer-related deaths. However, treatment options are limited. Herein, we report on the toxicity and efficacy of re-irradiation with carbon- ion radiotherapy for locoregionally recurrent, metastatic, or secondary lung tumors. Data of 95 patients with prior intrathoracic carbon-ion radiotherapy who were treated with re-irradiation with carbon-ion radiotherapy at our institution between 2006 and 2016 were retrospectively analyzed. Seventy-three patients (76.8%) had primary lung tumors and 22 patients (23.2%) had metastatic lung tumors. The median dose of initial carbon-ion radiotherapy was 52.8 Gy (relative biological effectiveness) and the median dose of re-irradiation was 66.0 Gy (relative biological effectiveness). None of the patients received concurrent chemotherapy. The median follow-up period after re-irradiation was 18 months. In terms of grade ≥3 toxicities, one patient experienced each of the following: grade 5 bronchopleural fistula, grade 4 radiation pneumonitis, grade 3 chest pain, and grade 3 radiation pneumonitis. The 2-year local control and overall survival rates were 54.0% and 61.9%, respectively. In conclusion, re-irradiation with carbon-ion radiotherapy was associated with relatively low toxicity and moderate efficacy. Re-irradiation with carbon-ion radiotherapy might be an effective treatment option for patients with locoregionally recurrent, metastatic, or secondary lung tumors. [ABSTRACT FROM AUTHOR]

A retrospective multicenter study was carried out to assess the clinical outcomes of carbon-ion radiotherapy for head and neck malignancies (Japan Carbon-Ion Radiation Oncology Study Group [J-CROS] study: 1402 HN). We evaluated the safety and efficacy of carbon-ion radiotherapy in patients with major salivary gland carcinoma. Sixty-nine patients treated with carbon-ion radiotherapy at four Japanese institutions were analyzed. Thirty-three patients (48%) had adenoid cystic carcinomas, 10 (14%) had mucoepidermoid carcinomas, and 26 (38%) had other disease types. Three patients (4%) had T1 disease, 8 (12%) had T2, 25 (36%) had T3, and 33 (48%) had T4. The median radiation dose was 64 Gy (relative biological effectiveness) in 16 fractions. The median gross tumor volume was 27 mL. The median follow- up period was 32.7 months. The 3-year local control rate and overall survival rate were 81% and 94%, respectively. Regarding acute toxicities, seven patients had grade 3 mucositis and seven had grade 3 dermatitis. Regarding late toxicities, one patient had grade 3 dysphagia and one had a grade 3 brain abscess. No grade 4 or worse late reactions were observed. In conclusion, definitive carbon-ion radiotherapy was effective with acceptable toxicity for major salivary gland carcinomas. [ABSTRACT FROM AUTHOR]

Radiotherapy using high-energy carbon beams from the Heavy Ion Medical Accelerator in Chiba has been carried out at theNational Institute of Radiological Sciences (NIRS) since June 1994, andmore than 10 000 patients have been treated to date. With the prospective clinical results for the first ten years, we designed a compact accelerator facility for carbon-ion radiotherapy (CIRT), and performed related Research and Development (R&D) works for widespread use of CIRT since 2004. Based on the design and the R&D works, three compact facilities for CIRT were constructed and are in treatment operation, and furthermore two facilities are being constructed in Japan. To further develop the sophisticated CIRT, we constructed a new treatment facility at NIRS. This new facility is equipped with three treatment rooms; two of them have both horizontal and vertical fixed-irradiation-ports, and the other is a rotating-gantry port. For all ports, fast three-dimensional raster-scanning irradiation technology is employed. The rotating gantry equips ten combined-function superconducting magnets, and can deliver carbon ions having the energy of between E = 430 and 50MeV/u to an isocenterwith irradiation angles of over±180°. Construction as well as installation of the superconducting gantry was completed by the end of September 2015, and treatments using the gantry began since May 2015. Presently, we are further designing a next-generation compact facility as a future project; superconducting and laser technologies are to be used for accelerator design. In this paper, we report development of carbon-ion accelerator facilities as well as the future project. [ABSTRACT FROM AUTHOR]

Radiotherapy using energetic carbon beams from the Heavy Ion Medical Accelerator in Chiba (HIMAC) has been carried out at the National Institutes of Quantum Science and Technology (QST) since June 1994. Based on positive clinical results, carbon-ion radiotherapy was authorized as an Advanced Medical Technology by Japanese government from 2003 and it was subsequently approved for inclusion in the Japanese National Health Insurance system from 2016. For the widespread use of carbon-ion radiotherapy, design studies as well as related research and development projects were conducted to develop a compact accelerator facility from 2004. Based on these studies, five compact facilities were constructed in Japan. However, since the accelerators are large in size, construction of these facilities is currently limited to university hospitals or large medical centers, and hence development of a more compact accelerator is desired. To further promote widespread proliferation of heavy-ion facilities and concurrently to maximize the potential of heavy-ion therapy, a project to develop a compact superconducting accelerator, the Quantum Scalpel project, was proposed. The compact accelerator employs superconducting technology to reduce the footprint of the entire accelerator system and the accelerator can provide various therapeutic beams of helium, carbon, oxygen, and neon ions having the energy of 56-430 MeV/ u to advanced heavy-ion therapy. In this article, we report the design of the compact superconducting accelerator for the advanced heavy-ion therapy and describe the progress of related research and development projects. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) is one of the key modalities for cancer treatment, and more than 70% of tumor patients will receive RT during the course of their disease. Particle radiotherapy, such as proton radiotherapy, carbon-ion radiotherapy (CIRT) and boron neutron capture therapy (BNCT), is currently available for the treatment of patients Immunotherapy combined with photon RT has been successfully used in the clinic. The effect of immunotherapy combined with particle RT is an area of interest. However, the molecular mechanisms underlying the effects of combined immunotherapy and particle RT remain largely unknown. In this review, we summarize the properties of different types of particle RT and the mechanisms underlying their radiobiological effects. Additionally, we compared the main molecular players in photon RT and particle RT and the mechanisms involved the RT-mediated immune response. [Display omitted] • Immunotherapy combined with photon RT is now used in clinic successfully. The effect of immunotherapy combined with particle RT are awaited with interest. • The review compared the notable effects on immune induced by photon RT and particle RT from the point of view of tumor cells and different immune cells in order to find the unconfirmed problems in the field of particle RT on immunity for reference. [ABSTRACT FROM AUTHOR]

The treatment outcomes of patients with high-risk localized prostate cancer ( PC) after carbon-ion radiotherapy ( CIRT) combined with long-term androgen deprivation therapy ( LTADT) were analyzed, and compared with those of other treatment modalities, focusing on PC-specific mortality ( PCSM). A total of 1247 patients were enrolled in three phase II clinical trials of fixed-dose CIRT between 2000 and 2013. Excluding patients with T4 disease, 608 patients with high-risk or very-high-risk PC, according to the National Comprehensive Cancer Network classification system, who received CIRT with LTADT were evaluated. The median follow-up time was 88.4 months, and the 5-/10-year PCSM rates were 1.5%/4.3%, respectively. T3b disease, Gleason score of 9-10 and percentage of positive biopsy cores >75% were associated with significantly higher PCSM on univariate and multivariate analyses. The 10-year PCSM rates of patients having all three ( n = 16), two ( n = 74) or one of these risk factors ( n = 217) were 27.1, 11.6 and 5.7%, respectively. Of the 301 patients with none of these factors, only 1 PCSM occurred over the 10-year follow-up (10-year PCSM rate, 0.3%), and significant differences were observed among the four stratified groups ( P <0.001). CIRT combined with LTADT yielded relatively favorable treatment outcomes in patients with high-risk PC and very favorable results in patients without any of the three abovementioned factors for PCSM. Because a significant difference in PCSM among the high-risk PC patient groups was observed, new categorization and treatment intensity adjustment may be required for high-risk PC patients treated with CIRT. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to evaluate the safety and efficacy of carbon-ion radiotherapy (CIRT) in patients with hepatocellular carcinoma (HCC) with stepwise dose escalation and hypofractionation in 2 combined prospective trials.Methods: Sequential phase 1/2 (protocol 9603) and phase 2 (protocol 0004) trials were conducted for patients with histologically proven HCC. The phase 1 component of protocol 9603 was a dose-escalation study; CIRT was delivered in 12, 8, or 4 fractions. After determination of the recommended dose, 2 phase 2 trials were performed in an expanded cohort, and the data were pooled to analyze toxicity, local control, and overall survival.Results: In the phase 1 component of protocol 9603, 69.6, 58.0, and 52.8 Gy (relative biological effectiveness [RBE]) in 12, 8, and 4 fractions, respectively, constituted the maximum tolerated doses, and 52.8 Gy (RBE) in 4 fractions was established as the recommended dose regimen for the 2 phase 2 studies. In 124 patients with a total of 133 lesions, few severe adverse effects occurred, and local-control and overall survival rates at 1, 3, and 5 years were 94.7% and 90.3%, 91.4% and 50.0%, and 90.0% and 25.0%, respectively; this included 1-, 3-, and 5-year local-control rates of 97.8%, 95.5%, and 91.6%, respectively, in the phase 2 study. In a multivariate analysis, Child-Pugh class B and the presence of a tumor thrombus were significant factors for mortality.Conclusions: The safety and efficacy of CIRT in 12, 8, and 4 fractions were confirmed, with 52.8 Gy (RBE) in 4 fractions established as the recommended treatment course for eligible HCC patients. Cancer 2017;123:3955-65. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. [ABSTRACT FROM AUTHOR]

Background and purpose We aimed to evaluate the relationship between brainstem necrosis and dose–volume histograms in patients with head and neck tumors after carbon-ion radiotherapy. Material and methods We evaluated 85 patients with head and neck tumors who underwent carbon-ion radiotherapy and were followed-up for ≥12 months. Brainstem necrosis was evaluated using the Common Terminology Criteria for Adverse Events (version 4.0). Results The median follow-up was 24 months, and four patients developed grade 1 brainstem necrosis, with 2-year and 3-year cumulative rates of 2.8% and 6.5%, respectively. Receiver operating characteristic curve analysis revealed the following significant cut-off values: a maximum brainstem dose of 48 Gy (relative biological effectiveness [RBE]), D1 cm 3 of 27 Gy (RBE), V40 Gy (RBE) of 0.1 cm 3 , V30 Gy (RBE) of 0.7 cm 3 , and V20 Gy (RBE) of 1.4 cm 3 . Multivariate analysis revealed that V30 Gy (RBE) was most significantly associated with brainstem necrosis. The 2-year cumulative rates were 33% and 0% for V30 Gy (RBE) of ≥0.7 cm 3 and <0.7 cm 3 , respectively ( p < 0.001). Conclusions The present study indicated that the dose constraints might help minimize brainstem necrosis after carbon-ion radiotherapy. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy and safety of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck, 35 patients were enrolled in this prospective study. The primary end-point was the 3-year local control rate, and the secondary end-points included the 3-year overall survival rate and adverse events. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time for all patients was 39 months. Thirty-two and three patients received 64.0 Gy (relative biological effectiveness) and 57.6 Gy (relative biological effectiveness) in 16 fractions, respectively. Adenoid cystic carcinoma was dominant (60%). Four patients had local recurrence and five patients died. The 3-year local control and overall survival rates were 93% and 88%, respectively. Acute grade 2-3 radiation mucositis (65%) and dermatitis (31%) was common, which improved immediately with conservative therapy. Late mucositis of grade 2, grade 3, and grade 4 were observed in 11, one, and no patients, respectively. There were no adverse events of grade 5. Carbon-ion radiotherapy achieved excellent local control and overall survival rates for non-squamous cell carcinoma. However, the late mucosal adverse events were not rare, and meticulous treatment planning is required. Trial registration no. UMIN000007886. [ABSTRACT FROM AUTHOR]

A ridge filter (RGF), a beam energy modulation device, is usually used for particle radiotherapy with a pencil beam scanning system. The conventional RGF has a one-dimensional (1D) periodic laterally stepped structure in orthogonal plane with a central beam direction. The energy of a beam passing through the different thicknesses of the stepped RGF is modulated. Although the lateral pencil beam size is required to cover the several stepped RGF units to modulate its energy as designed, the current trend is to decrease lateral beam size to improve the scanning system. As a result, the beam size becomes smaller than the size of the individual RGF unit. The aim of this study was to develop a new RGF with two-dimensional (2D) honeycomb geometry to simultaneously achieve both a decrease in lateral beam size and the desired energy modulation. The conventional 1D-RGF and the 2D-RGF with honeycomb geometry were both designed so that the Bragg peak size of a 79 MeV/u carbon ion pencil beam in water was 1 mm RMS in the beam direction. To validate the design of the 2D-RGF, we calculated depth dose distributions in water using a simplified Monte Carlo method. In the calculations, we decreased the lateral pencil beam size at the entrance of the RGF and investigated the threshold of lateral beam size with which the pencil beam can reproduce the desired Bragg peak size for each type of RGF. In addition, we calculated lateral dose distributions in air downstream from the RGF and evaluated the inhomogeneity of the lateral dose distributions. Using the 2D-RGF, the threshold of lateral beam size with which the pencil beam can reproduce the desired Bragg peak size was smaller than that using the 1D-RGF. Moreover, the distance from the RGF at which the lateral dose distribution becomes uniform was shorter using the 2D-RGF than that using the 1D-RGF. These results indicate that when the periodic length of both RGFs is the same, the 2D-RGF allows use of a pencil beam with smaller lateral beam size and a shorter distance from the RGF to the target, resulting in improvement in the conformity of dose distribution in a tumor. [ABSTRACT FROM AUTHOR]

A superconducting rotating-gantry for carbon-ion radiotherapy was developed. This isocentric rotating gantry can transport carbon ions having the maximum kinetic energy of E = 430 MeV/ u to an isocenter with irradiation angles of over ±180°, and is further capable of performing three-dimensional raster-scanning irradiation. By using combined-function superconducting magnets, we could design a compact rotating gantry for carbon-ion radiotherapy. Construction of the gantry structure began since early 2014, and the installation of the entire gantry system to the Heavy Ion Medical Accelerator in Chiba (HIMAC) complex was completed by the end of September, 2015. Beam tuning subsequently began since October, 2015, and carbon ions, as accelerated by the HIMAC upper synchrotron, having kinetic energies of between E = 430–48 MeV/ u were successfully transported with the rotating gantry to the isocenter. The size and shape of the beam spots at the isocenter is being tuned over various combinations of the beam energies and the gantry angle. We will present the recent progress as well as the current status of the superconducting rotating-gantry. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the clinical outcomes of patients with mucoepidermoid carcinomas in the head and neck treated with carbon-ion radiotherapy. Data from 26 patients who underwent carbon-ion radiotherapy in four facilities were analyzed in this multi-institutional retrospective study: the Japan Carbon-ion Radiation Oncology Study Group. The median follow-up time was 34 months. One patient experienced local recurrence, and the 3-year local control rate was 95%. One patient developed lymph node recurrence and five developed distant metastases. The 3-year progression-free survival rate was 73%. Five patients died, two of mucoepidermoid carcinoma and three of intercurrent disease. The 3-year overall survival rate was 89%. Acute mucositis and dermatitis of grade 3 or higher were experienced by 19% and 8% of patients, respectively; these improved with conservative therapy. Late mucositis and osteonecrosis of jaw were observed in 12% and 23% of patients, respectively. The 3-year cumulative rate of any late adverse event of grade 3 or higher was 14%. None of the patients died of the acute or late adverse events. Carbon-ion radiotherapy was efficacious and safe for treating mucoepidermoid carcinoma in this multi-institutional retrospective study (registration no. UMIN000024473). We are currently undertaking a prospective multicenter study. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to evaluate the effect of histological subtypes of head and neck adenoid cystic carcinoma (ACC) on the results of carbon-ion radiotherapy (CIRT). Material and methods Of the 113 patients with ACC who were treated with CIRT between December 2006 and July 2013, 100 patients with identified histological subtypes were enrolled in this study. CIRT at a total dose of 57.6 or 64.0 Gy (RBE) was administered in 16 fractions. Histological grading was defined as the presence or absence of a solid growth pattern. Results Median follow-up was 60 months. 5-Year local control (LC), overall survival (OS) and distant metastasis free survival (DMFS) of all patients were 68.6%, 74.8% and 65.7%, respectively. On multivariate analysis, the prescribed dose ( p = 0.001) and gross tumor volume ( p = 0.002) were significant independent risk factors for LC. No significant difference for local control of solid/non-solid growth patterns was found ( p = 0.093). Solid growth pattern was an independent risk factor for both OS ( p = 0.033) and DMFS ( p = 0.024). Conclusions CIRT appears able to locally control solid growth pattern ACC in the head and neck. Improved intervention is needed to extend DMFS and OS. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to present our evaluation of the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for locally advanced parotid gland carcinomas. Methods Clinicopathological features and outcomes were evaluated in 46 patients receiving C-ion RT for parotid gland carcinomas. Results Sixteen patients had adenoid cystic carcinoma; 8 had adenocarcinoma, 8 had mucoepidermoid carcinoma, and 14 had other carcinomas. T2, T3, T4a, and T4b diseases were diagnosed in 3, 18, 8, and 17 patients, respectively. C-ion RT was provided to 25 patients as the primary treatment, to 20 patients for local recurrences after surgery, and to 1 patient for residual tumor after surgery. During follow-up (median duration, 62 months), 5-year local control and overall survival (OS) rates were 74.5% and 70.1%, respectively. Of the 30 patients without facial nerve palsy before C-ion RT, 25 showed no radiation-induced facial nerve palsy. Conclusion C-ion RT is effective and has acceptable toxicity levels for locally advanced parotid gland carcinomas. © 2016 Wiley Periodicals, Inc. Head Neck 39: 724-729, 2017 [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.

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., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

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.

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., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Carbon-ion radiotherapy (CIRT) has progressed rapidly in technological delivery, indications, and efficacy. Owing to a focused dose distribution in addition to high linear energy transfer and subsequently high relative biological effect, CIRT is uniquely able to target otherwise untreatable hypoxic and radioresistant disease, while opening the door for substantially hypofractionated treatment of normal and radiosensitive disease. CIRT has increasingly garnered international attention, and is nearing the tipping point for international adoption.