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Charged particle therapy is generally regarded as cutting-edge technology in oncology. Many proton therapy centres are active in the USA, Europe, and Asia, but only a few centres use heavy ions, even though these ions are much more effective than x-rays owing to the special radiobiological properties of densely ionising radiation. The National Institute of Radiological Sciences (NIRS) Chiba, Japan, has been treating cancer with high-energy carbon ions since 1994. So far, more than 8000 patients have had this treatment at NIRS, and the centre thus has by far the greatest experience in carbon ion treatment worldwide. A panel of radiation oncologists, radiobiologists, and medical physicists from the USA and Europe recently completed peer review of the carbon ion therapy at NIRS. The review panel had access to the latest developments in treatment planning and beam delivery and to all updated clinical data produced at NIRS. A detailed comparison with the most advanced results obtained with x-rays or protons in Europe and the USA was then possible. In addition to those tumours for which carbon ions are known to produce excellent results, such as bone and soft-tissue sarcoma of the skull base, head and neck, and pelvis, promising data were obtained for other tumours, such as locally recurrent rectal cancer and pancreatic cancer. The most serious impediment to the worldwide spread of heavy ion therapy centres is the high initial capital cost. The 20 years of clinical experience at NIRS can help guide strategic decisions on the design and construction of new heavy ion therapy centres.

Charged particles can achieve better dose distribution and higher biological effectiveness compared to photon radiotherapy. Carbon ions are considered an optimal candidate for cancer treatment using particles. The National Institute of Radiological Sciences (NIRS) in Chiba, Japan was the first radiotherapy hospital dedicated for carbon ion treatments in the world. Since its establishment in 1994, the NIRS has pioneered this therapy with more than 69 clinical trials so far, and hundreds of ancillary projects in physics and radiobiology. In this review, we will discuss the evolution of carbon ion radiotherapy at the NIRS and some of the current and future projects in the field.

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.

Carbon-ion radiotherapy (CIRT) has been associated with favorable clinical outcomes in patients with prostate cancer. At our facility, all patients are treated using scanning CIRT (sCIRT). We retrospectively analyzed five-year clinical outcomes of prostate cancer treated with sCIRT to investigate treatment efficacy and toxicity. In this study, we included 253 consecutive prostate cancer patients treated with sCIRT at the Kanagawa Cancer Center from December 2015 to December 2017. The total dose of sCIRT was set at 51.6 Gy (relative biological effect) in 12 fractions over three weeks. We employed the Phoenix definition for biochemical relapse. The overall survival (OS), biochemical relapse-free (bRF) rate, and cumulative incidence of late toxicity were estimated using the Kaplan-Meier method. Toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0. The median age of the patients was 70 years (range: 47-86 years). The median follow-up duration was 61.1 months (range: 4.1-80.3 months). Eight (3.2%), 88 (34.8%), and 157 (62.1%) patients were in the low-risk, intermediate-risk, and high-risk groups, respectively, according to the D'Amico classification system. The five-year OS and bRF were 97.5% and 93.3%, respectively. The five-year bRF rates for the low-risk, intermediate-risk, and high-risk groups were 87.5%, 93.7%, and 93.4%, respectively (p = 0.7215). The five-year cumulative incidence of Grade 2 or more late genitourinary and gastrointestinal toxicity was 7.4% and 1.2%, respectively. The results of this study show that sCIRT has a favorable therapeutic effect and low toxicity in the treatment of prostate cancer.

Anti-tumor immunity modulates the local effects of radiation therapy. High mobility group box 1 (HMGB1) plays a pivotal role in activating antigen-specific T-cell responses. Here, we examined the relationship between linear energy transfer (LET) and HMGB1 release. We assessed the proportions of KYSE-70, HeLa and SiHa cells surviving after carbon-ion (C-ion) beam irradiation with different LET values, using a clonogenic assay. The D10, the dose at which 10% of cells survived, was calculated using a linear-quadratic model. HMGB1 levels in the culture supernatants of C-ion beam-irradiated tumor cells were assessed by enzyme-linked immunosorbent assay. The D10 doses for 13 keV/μm of C-ion irradiation in KYSE-70, HeLa and SiHa cells were 2.8, 3.9 and 4.1 Gy, respectively, whereas those for 70 keV/μm C-ion irradiation were 1.4, 1.9 and 2.3 Gy, respectively. We found that 70 keV/μm of C-ion irradiation significantly increased HMGB1 levels in the culture supernatants of all cell lines 72 h after irradiation compared with non-irradiated controls. Furthermore, 70 keV/μm of C-ion irradiation significantly increased HMGB1 levels in the culture supernatants of all cell lines 72 h after irradiation compared with 13 keV/μm. The results suggest that HMGB1 release from several cancer cell lines increases with increased LET.

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.

Carbon ion radiotherapy (CIRT) is unique as it possesses well-localized and superior-depth dose distribution in addition to less repairable radiobiological effects. The use of CIRT for various diseases has been explored as clinical trials at the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. Since 1994, when the first clinical study of cancer therapy with carbon ion beams was started, about 50 clinical studies have been completed safely and effectively. These studies revealed that intractable cancers such as inoperable bone and soft-tissue sarcomas can be cured safely in a shorter overall treatment time, as can cancers in the head, neck, lung, liver, prostate, and postoperative pelvic recurrence of rectal cancer. The number of patients receiving CIRT has reached 6,000, and the therapy was approved as a highly advanced medical technology in 2003. Based on these experiences, we embarked on the research and development of new-generation beam delivery facilities such as a 3D scanning method with a pencil beam and a compact rotating gantry. Clinical research using pencil-beam scanning has been in operation since May 2011.

Peritoneal metastasis of gastric cancer (PMGC) is incurable and thus has an extremely poor prognosis. We have found, however, that locoregionally administered trastuzumab armed with astatine‐211 (211At‐trastuzumab) is effective against human epidermal growth factor receptor 2 (HER2)‐positive PMGC in a xenograft mouse model. We first observed that 211At‐trastuzumab can specifically bind and effectively kill NCI‐N87 (N87) cells, which are HER2‐positive human metastatic GC cells, both in vitro and in s.c. tumors. We established a PMGC mouse model using N87 xenografts stably expressing luciferase to test α‐particle radioimmunotherapy with 211At‐trastuzumab against PMGC. Biodistribution analysis in this PMGC mouse model revealed that the i.p. administration of 211At‐trastuzumab (1 MBq) was a more efficient means of delivery of 211At into metastatic tumors than i.v. injection; the maximum tumor uptake with i.p. administration was over 60% injected dose per gram of tissue (%ID/g) compared to approximately 18%ID/g with i.v. injection. Surprisingly, a single i.p. injection of 211At‐trastuzumab (1 MBq) was sufficient to completely eradicate intraperitoneally disseminated HER2‐positive GC xenografts in two of six treated mice by inducing DNA double‐strand breaks, and to drastically reduce the tumor burden in another three mice. No bodyweight loss, leukocytopenia, or significant biochemical changes in liver or kidney function were observed in the treatment group. Accordingly, locoregionally administered 211At‐trastuzumab significantly prolonged the survival time of HER2‐positive PMGC mice compared with control treatments. Our results provide a proof‐of‐concept demonstration that locoregional therapy with 211At‐trastuzumab may offer a new treatment option for HER2‐positive PMGC. Oue data provided a proof‐of‐concept demonstration that locoregional α‐radioimmunotherapy is a highly effective therapy for peritoneal metastasis of gastric cancer (PMGC), suggesting that α‐radioimmunotherapy may offer a new therapeutic option for HER2‐positive PMGC.

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. Kaplan‐Meier curves of (a) local control and (b) overall survival following re‐irradiation

Prognosis is usually grim for those with liver metastasis from colorectal cancer (CRC) who cannot receive resection. Radiation therapy can be an option for those unsuitable for resection, with carbon ion radiotherapy (CIRT) being more effective and less toxic than X‐ray due to its physio‐biological characteristics. The objective of this study is to identify the optimal dose of single fraction CIRT for colorectal cancer liver metastasis. Thirty‐one patients with liver metastasis from CRC were enrolled in the present study. Twenty‐nine patients received a single‐fraction CIRT, escalating the dose from 36 Gy (RBE) in 5% to 10% increments until unacceptable incidence of dose‐limiting toxicity was observed. Dose‐limiting toxicity was defined as grade ≥3 acute toxicity attributed to radiotherapy. The prescribed doses were as follows: 36 Gy (RBE) (3 cases), 40 Gy (2 cases), 44 Gy (4 cases), 46 Gy (6 cases), 48 Gy (3 cases), 53 Gy (8 cases) and 58 Gy (3 cases). Dose‐limiting toxicity was not observed, but late grade 3 liver toxicity due to biliary obstruction was observed in 2 patients at 53 Gy (RBE). Both cases had lesions close to the hepatic portal region, and, therefore, the dose was escalated to 58 Gy (RBE), limited to peripheral lesions. The 3‐year actuarial overall survival rate of all 29 patients was 78%, and the median survival time was 65 months. Local control improved significantly at ≥53 Gy (RBE), with a 3‐year actuarial local control rate of 82%, compared to 28% in lower doses. Treatment for CRC liver metastasis with single‐fraction CIRT appeared to be safe up to 58 Gy (RBE) as long as the central hepatic portal region was avoided. This is a dose escalation study for single fraction carbon ion radiotherapy. Treatment for CRC liver metastasis with single‐fraction CIRT appeared to be safe up to 58 Gy (RBE) as long as the central hepatic portal region was avoided.