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According to guidelines, carbon-ion beam therapy is considered to carry a high safety risk for patients with cardiac implantable electronic devices (CIEDs), although the actual impacts remain unclear. In this study, we investigated the safety of carbon-ion beam therapy in patients with CIEDs. Patients with CIEDs who underwent carbon-ion therapy at Gunma University Heavy Ion Medical Center between June 2010 and December 2019 were identified and investigated for abnormalities in the operation of their CIEDs, such as oversensing and resetting during irradiation, and abnormalities in operation after treatment. In addition, the risk of irradiation from carbon-ion beam therapy was evaluated by model simulations. Twenty patients (22 sites) with CIEDs were identified, 19 with pacemakers and one with an implantable cardioverter-defibrillator (ICD). Treatments were completed without any problems, except for one case in which the treatment was discontinued because of worsening of the primary disease. Monte Carlo simulation indicated that the carbon beam irradiation produced neutrons at a constant and high level in the irradiation field. Nevertheless, with the distances between the CIEDs and the irradiation fields in the analyzed cases, the quantity of neutrons at the CIEDs was lower than that within the irradiation. Although carbon-ion beam therapy can be safely administered to patients with CIEDs, it is advisable to perform the therapy with sufficient preparation and backup devices because of the risks involved.

We propose a two-step method to converse human tissue materials from patient computed tomography (CT) images, which is required in dose reconstructions for a retrospective study of carbon-ion radiotherapy (CIRT) using Monte Carlo (MC) simulation. The first step was to assign the standard tissues of the International Commission on Radiological Protection reference phantoms according to the CT-number. The second step was to determine the mass density of each material based on the relationship between CT-number and stopping power ratio (Hounsfield unit [HU]-SPR) registered in treatment planning system (TPS). Direct implementation of the well-calibrated HU-SPR curve allows the reproduction of previous clinical treatments recorded in TPS without uncertainty due to a mismatch of the CT scanner or scanning conditions, whereas MC simulation with realistic human tissue materials can fulfill the out-of-field dose, which was missing in the record. To validate our proposed method, depth-dose distributions in the homogenous and heterogeneous phantoms irradiated by a 400 MeV/u carbon beam with an 8 cm spread-out Bragg peak (SOBP) were computed by the MC simulation in combination with the proposed methods and compared with those of TPS. Good agreement of the depth-dose distributions between the TPS and MC simulation (within a 1% discrepancy in range) was obtained for different materials. In contrast, fluence distributions of secondary particles revealed the necessity of MC simulation using realistic human tissue. The proposed material assignment method will be used for a retrospective study using previous clinical data of CIRT at the National Institute of Radiological Sciences (NIRS).

This study aimed to determine the maximum tolerance dose (MTD) and to estimate the recommended dose (RD) of concomitant S-1 with carbon-ion radiotherapy (RT) for sinonasal squamous cell carcinoma (SCC). Nine patients with sinonasal SCC received carbon-ion RT with escalating doses of S-1 according to phase I methods. Doses of 40, 60 and 80 mg/m2/day were administered twice daily in dose levels 1, 2 and 3, respectively, from days 1 to 14 and 22 to 35. Carbon-ion RT was administered at a dose of 70.4 Gy (relative biological effectiveness) in 32 fractions, 5 days a week. Two patients developed grade 3 acute dermatitis. However, none developed dose-limiting toxicities. Therefore, the MTD of S-1 could not be determined; the RD was estimated to be 80 mg/m2/day with concurrent carbon-ion RT. Partial response and stable disease were noted in 5 and 4 patients, respectively. The 2-year overall survival and local control rates were 56 and 74%, respectively. Overall, 2 patients developed ≥grade 3 late toxicities; among them, 1 patient developed grade 3 cataract and the other developed grade 4 cataract, optic nerve disorder and hearing impairment. To the best of our knowledge, this phase I study is the first clinical trial to evaluate concomitant S-1 with carbon-ion RT for sinonasal SCC. The MTD of S-1 could not be determined, and the RD was estimated to be 80 mg/m2/day. This study demonstrated a manageable safety profile for this combination. The observed outcomes may facilitate further evaluation of this novel therapy.

Even with its high RBE and >20 years history, there had been no breast cancer clinical trial using carbon-ion radiotherapy. We started a Phase I trial of carbon ion radiotherapy for Stage I breast cancer in 2013. This article describes the clinical and pathological evaluation of this study. Patients with low-risk Stage I breast cancer were eligible. A dose escalation study was designed, with dose levels of 48.0, 52.8 or 60.0 Gy relative biological effectiveness (RBE) administered in four fractions within 1 week. Three months after radiotherapy, the patients underwent tumor excision for pathological evaluation. Between April 2013 and December 2014, three cases receiving 48 Gy (RBE), three cases receiving 52.8 Gy (RBE) and one case receiving 60 Gy (RBE) underwent this protocol. No adverse effects were observed except for Grade 1 acute skin reaction in four cases. Pathological evaluation revealed that all four cases with doses of 52.8 Gy (RBE) and 60.0 Gy (RBE) achieved Grade 2b or more, but only two cases reached Grade 3. At the end of 2017, all cases were alive without recurrence or late had not caused any late adverse reaction. Carbon ion radiotherapy for Stage I breast cancer seems to be safe, and we found that it did not reach enough treatment effect 3 months after the treatment.

It is difficult to treat patients with an inoperable sarcoma adjacent to the gastrointestinal (GI) tract using carbon ion radiotherapy (C-ion RT), owing to the possible development of serious GI toxicities. In such cases, spacer placement may be useful in physically separating the tumor and the GI tract. We aimed to evaluate the usefulness of spacer placement by conducting a simulation study of dosimetric comparison in a patient with sacral chordoma adjacent to the rectum treated with C-ion RT. The sacral chordoma was located in the third to fourth sacral spinal segments, in extensive contact with and compressing the rectum. Conventional C-ion RT was not indicated because the rectal dose would exceed the tolerance dose. Because we chose spacer placement surgery to physically separate the tumor and the rectum before C-ion RT, bioabsorbable spacer sheets were inserted by open surgery. After spacer placement, 67.2 Gy [relative biological effectiveness (RBE)] of C-ion RT was administered. The thickness of the spacer was stable at 13–14 mm during C-ion RT. Comparing the dose–volume histogram (DVH) parameters, Dmax for the rectum was reduced from 67 Gy (RBE) in the no spacer plan (simulation plan) to 45 Gy (RBE) in the spacer placement plan (actual plan) when a prescribed dose was administered to the tumor. Spacer placement was advantageous for irradiating the tumor and the rectum, demonstrated using the DVH parameter analysis.

The dose distribution of passive and scanning irradiation for carbon-ion radiotherapy for breast cancer was compared in order to determine the preferred treatment method. Eleven Japanese patients who received carbon-ion radiotherapy for breast cancer were retrospectively analyzed. The original clinical plans were used for the passive irradiation method, while the plans for the scanning irradiation method were more recently made. Statistical analysis suggested that there was no significant difference in superiority in terms of dose distribution between the passive and scanning irradiation methods. The present study found that the scanning irradiation method was not always superior to the passive method, despite a previous study having reported the superiority of scanning irradiation. The present result is considered to arise from characteristics of breast cancer treatment, such as the simplicity of the organ at risk and the shallow depth point of the target from the skin. It is noteworthy that the present study suggests that the passive irradiation method can provide better dose distribution, depending on the case.

This is a pooled analysis to evaluate the toxicity and efficacy of carbon-ion radiotherapy (C-ion RT) for inoperable endometrial carcinoma. Eligible patients had previously untreated Stage I–III endometrial carcinoma without para-aortic lymph node metastasis. Total dose to the tumor was 62.4–74.4 Gy [relative biological effectiveness (RBE)] in 20 fractions, and the dose to the gastrointestinal tract was limited to

Carbon-ion radiotherapy (CIRT) is an advanced radiotherapy and has achieved good local control, even in tumors that are resistant to conventional photon beam radiotherapy (PBRT). However, distant metastasis control is an important issue. Recently, the combination of radiotherapy and immunotherapy has attracted the attention. In immunotherapy, dendritic cells (DCs) play a pivotal role in the anti-tumor immune system. However, the mechanisms underlying the combination therapy of DCs and radiotherapy have been unclear. In the present study, we evaluated anti-metastatic effects of this combination therapy, focused on the irradiation type and the route of DC administration, using a mouse model. C3H/He mice bearing NR-S1 cells were treated with CIRT or PBRT, using biologically equivalent doses. Subsequently, DCs were administered intratumorally (IT) or intravenously (IV). IV and IT DC administrations combined with CIRT to the local tumor, but not alone, significantly suppressed pulmonary metastasis, whereas the combination of DCs with PBRT suppressed metastasis at a relatively higher dose. Additionally, the anti-metastatic effect was greater in IV DC administration compared with in IT DC administration in both CIRT and PBRT. The expression levels of CD40 and IL-12 in DCs were significantly increased after co-culturing with CIRT-treated NR-S1 cells. In addition, IV administration of those co-cultured DCs significantly suppressed pulmonary metastasis. Furthermore, ecto-calreticulin levels from CIRT-treated NR-S1 cells significantly increased compared with those of a PBRT-treated tumor. Taken together, these results suggest that local CIRT combined with IV DCs augments an immunogenicity of the tumor cells by ecto-calreticulin expression and the maturation of DCs to stimulate anti-tumor immunity to decrease lung metastases.

Oral mucosal malignant melanoma (OMM) is extremely rare and has a poor prognosis. Owing to its rarity, it has not yet been possible to establish an optimal treatment modality. The objective of this study was to evaluate the long-term efficacy of carbon-ion radiotherapy (C-ion RT) for OMM. Between 1997 and 2013, 19 patients with OMM were treated with C-ion RT alone. Patient ages ranged from 44 to 84 years (median, 69 years). Nine men and 10 women were included. OMMs were restaged in accordance with the seventh edition of the tumour/node/metastasis (TNM) Staging System of the International Union Against Cancer. Before treatment, 14 patients had T3 disease and 5 had T4a disease. Three patients were classified as having N1 disease. All patients were classified as having M0. The hard palate was the most frequently involved oral subsite. All patients were treated with 57.6 Gy (relative biological effectiveness) in 16 fractions. The median follow-up period was 61 months (range, 8–190 months). The 5-year local control, overall survival and progression-free survival rates were 89.5%, 57.4% and 51.6%, respectively. For local control and overall survival, T classification was found to be a significant prognostic factor. Grade 2 and 3 osteoradionecrosis was observed in three and four patients, respectively. The presence of teeth within the planning target volume was a significant risk factor for developing osteoradionecrosis. C-ion RT was an effective treatment option with acceptable toxicity for OMM.

Comparison of the efficiency of photon and carbon ion radiotherapy (RT) administered with the same number of fractions might be of limited clinical interest, since a wide range of fractionation patterns are used clinically today. Due to advanced photon treatment techniques, hypofractionation is becoming increasingly accepted for prostate and lung tumours, whereas patients with head and neck tumours still benefit from hyperfractionated treatments. In general, the number of fractions is considerably lower in carbon ion RT. A clinically relevant comparison would be between fractionation schedules that are optimal within each treatment modality category. In this in silico study, the relative clinical effectiveness (RCE) of carbon ions was investigated for human salivary gland tumours, assuming various radiation sensitivities related to their oxygenation. The results indicate that, for hypoxic tumours in the absence of reoxygenation, the RCE (defined as the ratio of D(50) for photons to carbon ions) ranges from 3.5 to 5.7, corresponding to carbon ion treatments given in 36 and 3 fractions, respectively, and 30 fractions for photons. Assuming that interfraction local oxygenation changes take place, results for RCE are lower than that for an oxic tumour if only a few fractions of carbon ions are used. If the carbon ion treatment is given in more than 12 fractions, the RCE is larger for the hypoxic than for the well-oxygenated tumour. In conclusion, this study showed that in silico modelling enables the study of a wide range of factors in the clinical considerations and could be an important step towards individualisation of RT treatments.

The Korea Heavy Ion Medical Accelerator project focuses on the development of medical accelerator facilities for delivering carbon-ion beams to cancer patients. The purpose of the present study was to estimate the clinical need for carbon-ion therapy in Korea. Seven tumor sites, namely head and neck, liver, lung, colon and rectum, prostate, bone and soft tissue, and pancreas were selected as eligible sites for receiving carbon-ion radiotherapy (RT) by radiation oncologists of the Korea Institute of Radiological and Medical Sciences. Cancer incidence data for the selected tumor sites were obtained from the Korea National Cancer Incidence Database in order to estimate the potential medical need for carbon-ion RT. The carbon-ion RT adaption rate was assessed based on the clinical experience of other carbon-ion therapy facilities. An estimation model was constructed for estimating the medical need for carbon-ion RT, and from this, 25 606 patients were deemed to be potential candidates for carbon-ion RT. This estimated potential need corresponded to 10% of newly diagnosed cancer patients in Korea. The realistic estimation was calculated as ranging between 4000 and 6300 patients, depending on the carbon-ion RT adaptation rate. This estimated medical need corresponded to 2-3% of newly diagnosed cancer patients in Korea. Taken together, our findings suggest that there is a clear medical need for carbon-ion RT in Korea, with at least 4000 potential patients per year.

The effect of carbon ion radiotherapy on hypoxic tumors has recently been questioned because of low linear energy transfer (LET) values in the spread-out Bragg peak (SOBP). The aim of this study was to investigate the role of hypoxia and local oxygenation changes (LOCs) in fractionated carbon ion radiotherapy. Three-dimensional tumors with hypoxic subvolumes were simulated assuming interfraction LOCs. Different fractionations were applied using a clinically relevant treatment plan with a known LET distribution. The surviving fraction was calculated, taking oxygen tension, dose and LET into account, using the repairable–conditionally repairable (RCR) damage model with parameters for human salivary gland tumor cells. The clinical oxygen enhancement ratio (OER) was defined as the ratio of doses required for a tumor control probability of 50% for hypoxic and well-oxygenated tumors. The resulting OER was well above unity for all fractionations. For the hypoxic tumor, the tumor control probability was considerably higher if LOCs were assumed, rather than static oxygenation. The beneficial effect of LOCs increased with the number of fractions. However, for very low fraction doses, the improvement related to LOCs did not compensate for the increase in total dose required for tumor control. In conclusion, our results suggest that hypoxia can influence the outcome of carbon ion radiotherapy because of the non-negligible oxygen effect at the low LETs in the SOBP. However, if LOCs occur, a relatively high level of tumor control probability is achievable with a large range of fractionation schedules for tumors with hypoxic subvolumes, but both hyperfractionation and hypofractionation should be pursued with caution.

Carbon ion radiotherapy (C-ion RT) is an advanced modality for treating malignant melanoma. After we treated our first case of gynecological melanoma using C-ion RT in November 2004, we decided to conduct a clinical trial to evaluate its usefulness for the treatment of gynecological melanoma. The eligibility criteria for enrollment in this study were histologically proven malignant melanoma of the gynecological regions with lymph node metastasis remaining in the inguinal and pelvic regions. The small pelvic space, including the GTV and the metastatic lymph node, was irradiated with up to a total dose of 36 GyE followed by a GTV boost of up to a total dose of 57.6 GyE or 64 GyE in 16 fractions. A series of 23 patients were treated between November 2004 and October 2012. Patient age ranged from 51–80 with a median of 71. Of the tumor sites, 14 were located in the vagina, 6 in the vulva, and 3 in the cervix uteri. Of the 23 patients, 22 were irradiated with up to a total dose of 57.6 GyE, and 1 patient was irradiated with up to a total dose of 64 GyE. Chemotherapy and interferon-β were also used to treat 11 of the patients. Acute and late toxicities of Grade 3 or higher were observed in 1 patient treated with concurrent interferon-β. The median follow-up time was 17 months (range, 6–53 months). There was recurrence in 14 patients, and the 3-year local control and overall survival rates were 49.9% and 53.0%, respectively. C-ion RT may become a non-invasive treatment option for gynecological melanoma.

On-line verification of the delivered dose during proton and carbon ion radiotherapy is currently a very desirable goal for quality assurance of hadron therapy treatment plans. In-beam positron emission tomography (ibPET), which can provide an image of the β+ activity induced in the patient during irradiation, which in turn is correlated to the range of the ion beam, is one of the modalities for achieving this goal. Application to hadron therapy requires that the scanner geometry be modified from that which is used in nuclear medicine. In particular, PET detectors that allow a sub-nanosecond time-of-flight (TOF) registration of the collinear photons have been proposed. Inclusion of the TOF information in PET data leads to more effective PET sensitivity. Considering the challenges inherent in the ibPET technique, namely limited β+ activity and the effect of biological washout due to blood flow, TOF-PET technologies are very attractive. In this context, the TERA Foundation is investigating the use of resistive plate chambers (RPC) for an ibPET application because of their excellent timing properties and low cost. In this paper we present a novel compact multi-gap RPC (MRPC) module design and construction method, which considering the large number of modules that would be needed to practically implement a high-sensitivity RPC-PET scanner, could be advantageous. Moreover, we give an overview of the efficiency and timing measurements that have been obtained in the laboratory using such single-gap and multi-gap RPC modules.

The aim of this study was to prospectively assess 5-year health-related quality of life (HRQOL) of patients treated with carbon ion radiotherapy (C-ion RT) for clinically localized prostate cancer. A total of 417 patients received carbon ion radiotherapy at a total dose of 63–66 Gray-equivalents (GyE) in 20 fractions over 5 weeks, and neoadjuvant and adjuvant androgen deprivation therapy (ADT) were administered for intermediate and high-risk patients. A HRQOL assessment was performed at five time points (immediately before the initiation of C-ion RT, immediately after, and at 12, 36 and 60 months after completion of C-ion RT) using Functional Assessment of Cancer Therapy (FACT) questionnaires. FACT-G and FACT-P scores were significantly decreased; however, the absolute change after 60 months was minimal. The transient decreases in the Trial Outcome Index (TOI) score returned to their baseline levels. Use of ADT, presence of adverse events, and biochemical failure were related to lower scores. Scores of subdomains of FACT instruments indicated characteristic changes. The pattern of HRQOL change after C-ion RT was similar to that of other modalities. Further controlled studies focusing on a HRQOL in patients with prostate cancer are warranted.

Microdosimetry/Carbon-ion radiotherapy/TEPC/RBE. The RBE-weighted absorbed dose, called “biological dose,” has been routinely used for carbon-ion treatment planning in Japan to formulate dose prescriptions for treatment protocols. This paper presents a microdosimetric approach to measuring the biological dose, which was redefined to be derived from microdosimetric quantities measured by a tissue-equivalent proportional counter (TEPC). The TEPC was calibrated in 60 Co gamma rays to assure a traceability of the TEPC measurement to Japanese standards and to eliminate the discrepancies among matching counters. The absorbed doses measured by the TEPC were reasonably coincident with those measured by a reference ionization chamber. The RBE value was calculated from the microdosimetric spectrum on the basis of the microdosimetric kinetic model. The biological doses obtained by the TEPC were compared with those prescribed in the carbon-ion treatment planning system. We found that it was reasonable for the measured biological doses to decrease with depth around the rear SOBP region because of beam divergence, scattering effect, and fragmentation reaction. These results demonstrate that the TEPC can be an effective tool to assure the radiation quality in carbon-ion radiotherapy.

In the last few years, hospital-based facilities for carbon-ion radiotherapy are being constructed and proposed in Europe and Asia. During the next few years, several new facilities will be opened for carbon-ion radiotherapy in the world. These facilities in operation or under construction are categorized in two types by the beam shaping method used. One is the passive beam shaping method that is mainly improved and systematized for routine clinical use at HIMAC, Japan. The other method is active beam shaping which is also known as beam scanning adopted at GSI/HIT, Germany. In this paper an overview of some technical aspects for beam shaping is reported. The technique of passive beam shaping is established for stable clinical application and has clinical result of over 4000 patients in HIMAC. In contrast, clinical experience of active beam shaping is about 400 patients, and there is no clinical experience to respiratory moving target. A great advantage of the active beam shaping method is patient-specific collimator-less and compensator-less treatment. This may be an interesting potential for adaptive radiotherapy.

Carbon ions/Charged particles/Dose distribution/RBE/Clinical study. In 1994 a Phase I/II clinical study on carbon ion radiotherapy was begun at NIRS using HIMAC, which was then the world’s only heavy ion accelerator complex dedicated to medical use in a hospital environment. Among several types of ion species, we have chosen carbon ions for cancer therapy because they had the most optimal properties in terms of possessing, both physically and biologically, the most effective dose-localization in the body. The purpose of the clinical study was to investigate the efficacy of carbon ion radiotherapy against a variety of tumors as well as to develop effective techniques for delivering an efficient dose to the tumor. The RBE of carbon ions was estimated to be 2.0 to 3.0 along the SOBP for acute skin reactions. As of August 2006, a total of 2,867 patients had been entered into Phase I/II or Phase II studies and analyzed for toxicity and local tumor response. The results have shown that carbon ion radiotherapy has the potential ability to provide a sufficient dose to the tumor with acceptable morbidity in the surrounding normal tissues. Tumors that appear to respond favorably to carbon ions include locally advanced tumors and those with histologically non-squamous cell type of tumors such as adenocarcinoma, adenoid cystic carcinoma, malignant melanoma, hepatoma, and bone/soft tissue sarcoma. By taking advantage of the biological and physical properties of high-LET radiation, the efficacy of treatment regimens with small fractions in short treatment times has been confirmed for almost all types of tumors in carbon ion radiotherapy.

LET/Intra-track damage/Inter-track damage/Repair. The biological effectiveness of carbon ions relative to γ rays (RBE) was compared between the tumor growth delay and an early skin reaction of syngeneic mice. The RBE was larger for a tumor than skin when irradiated with large doses of high-LET (linear energy transfer) carbon ions. The intra-track damage ( α term of a linear quadratic model) of a tumor and skin increased equally with an increase of the LET, while the inter-track damage ( β term) of skin alone increased with the LET. These data provide evidence that high-LET radiotherapy could achieve therapeutic gain by minimizing the difference in response to fractionated irradiation between the tumor and normal tissue.

Cerebral radionecrosis is a significant side effect in radiotherapy for brain cancer. The purpose of this study is to calculate the relative biological effectiveness (RBE) of carbon-ion beams on brain cells and to show RBE-weighted dose distributions for cerebral radionecrosis speculation in a carbon-ion treatment planning system. The RBE value of the radionecrosis for the carbon-ion beam is calculated by the modified microdosimetric kinetic model on the assumption of a typical clinical α/β ratio of 2 Gy for cerebral radionecrosis in X-rays. This calculation method for the RBE-weighted dose is built into the treatment planning system for the carbon-ion radiotherapy. The RBE-weighted dose distributions are calculated on computed tomography (CT) images of four patients who had been treated by carbon-ion radiotherapy for astrocytoma (WHO grade 2) and who suffered from necrosis around the target areas. The necrotic areas were detected by brain scans via magnetic resonance imaging (MRI) after the treatment irradiation. The detected necrotic areas are easily found near high RBE-weighted dose regions. The visual comparison between the RBE-weighted dose distribution and the necrosis region indicates that the RBE-weighted dose distribution will be helpful information for the prediction of radionecrosis areas after carbon-ion radiotherapy.

Medical physics is very important in carbon ion radiotherapy, as it is in conventional radiotherapy using X-rays and in estimation of exposed dose in the space environment. High-energy ion beams such as carbon beams have physical characteristics such as the Bragg curve, high LET, and nuclear reactions producing fragmentations. Therefore, understanding these properties well is essential for further development of carbon radiotherapy and manned space activity. We invited, therefore, the following six presentations relevant to issues ranging from the measurement of fragmentations, lineal energy distributions using the microdosimetric approach, and neutron dose with active beam delivery of carbon-ion therapy, to the depth–dose distribution of various ions inside a human head phantom.

Introduction: In 1994, we started carbon-ion radiotherapy (CIRT) for peripheral stage I non-small-cell lung cancer (NSCLC). First, two phase I/II clinical trials demonstrated the optimal doses of 90.0 GyE in 18 fractions over 6 weeks (Protocol 9303) and 72.0 GyE in 9 fractions over 3 weeks (Protocol 9701) for achieving more than 95% local control with minimal pulmonary toxicity. As a next step, we conducted two successive phase II trials. The first trial (Protocol 9802) used a regimen of 72 GyE per 9 fractions over 3 weeks and the second trial (Protocol 0001) used a regimen of 4 fractions over 1 week, at a fixed dose of 52.8 GyE for stage IA and 60 GyE for IB. In these Phase II trials, the local control rate (LCR) for all patients was 91.5%, and those for T1 and T2 tumors were 96.3 and 84.7%, respectively. The 5-year cause-specific survival rate (CSS) was 67.0% (IA: 84.4, IB: 43.7), and overall survival (OS) was 45.3% (IA: 53.9, IB: 34.2). No adverse events greater than grade 2 occurred in the lung. In 2003, we also started a phase I/II clinical trial (Protocol 0201) as a dose escalation study using single fraction. The initial total dose was 28.0 GyE administered and escalated in increments of 2.0 GyE each, up to 50.0 GyE. This clinical trial ended in February 2012 and is still followed up. In this article, we investigated the preliminary results of this phase I/II trial. Materials and methods: In this prospective study, 151 primary stage I NSCLC were treated by CIRT monotherapy using a total dose of 36.0 GyE (n = 18), 38.0 GyE (n = 14), 40.0 GyE (n = 20), 42.0 GyE (n = 15), 44.0 GyE (n = 44), 46.0 GyE (n = 20), 48.0 GyE (n = 10) and 50.0 GyE (n = 10) using single fractionation. Mean age was 73.9 years, and size of tumor included T1 (n = 91) and T2 (n = 60). By type (cancer type was determined by biopsy), there were 104 adenocarcinomas, 46 squamous cell carcinomas and 1 large cell carcinoma. Medical inoperability was 55.6%. The patient is fixed on the rotational couch by using a custom-made immobilization device. Under free breathing conditions, planning CT images were acquired for treatment planning. The clinical target volume (CTV) was determined by adding >10-mm margin to the gross tumor volume (GTV). The planning target volume (PTV) was created by adding an internal margin to CTV as 5 mm in craniocaudal direction. The prescribed dose was delivered to PTV with different coplanar four beam angles. A respiratory-gated irradiation system was used in all irradiation sessions. Results: The median follow-up time was 45.6 months (range, 1.6–88.4 months). For 151 patients, the 5-year overall LCR was 79.2%, and those for T1 (n = 91) and T2 (n = 60) tumors were 83.6 and 72.2%, respectively. Also, local control in T1a, T1b, T2a and T2b were 96.8, 84.4, 80.2 and 20.0%, respectively. The OS was 55.1% and the CSS was 73.1%. No toxicity greater than grade 2 was observed in the lung and the skin. Conclusions: In patients with stage I NSCLC, CIRT using single fraction is considered as a promising curative modality. Especially for elderly and inoperable cases, CIRT could be a minimally invasive therapeutic option as a valid alternative to surgical resection (Fig. 1).Fig 1.Overall survival and local control in 151 patients with stage I non-small-cell lung cancer.

In June 1994, the world's first clinical center offering carbon ion radiotherapy opened at the National Institute of Radiological Science (NIRS), Japan. Among several types of ion species, carbon ions were chosen for cancer therapy because they were judged to have the most optimal properties in terms of superior physical and biological characteristics. As of March 2010, 5,196 patients have been registered for carbon ion radiotherapy. Clinical results have shown that carbon ion radiotherapy has the potential to provide a sufficient radiation dose to the tumor, while having acceptable morbidity in the surrounding normal tissues. Tumors that appear to respond favorably to carbon ions include locally advanced tumors as well as histologically non-squamous cell tumor types such as adenocarcinoma, adenoid cystic carcinoma, malignant melanoma, hepatoma, and bone/soft tissue sarcoma. By taking advantage of the unique properties of carbon ions, treatment with small fractions within a short treatment period has been successfully carried out for a variety of tumors. This means that carbon ion radiotherapy can offer treatment for larger numbers of patients than is possible with other modalities over the same time period.

We aimed to determine the effect of carbon ion irradiation on the uptake of N-benzyl-N-11C-methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([(11)C]DAC), a positron emission tomography (PET) ligand for the peripheral-type benzodiazepine receptor (PBR), in tumor cells and tumor-bearing mice. Spontaneous murine fibrosarcoma (NFSa) cells were implanted into the right hind legs of syngeneic C3H male mice. Conditioning irradiation with 290 MeV/u carbon ions was delivered to the 7- to 8-mm tumors In vitro uptake of [(11)C]DAC was measured in single NFSa cells isolated from NFSa-bearing mice after irradiation. In vivo biodistribution of [(11)C]DAC in NFSa-bearing mice was determined by small animal PET scanning and dissection. In vitro autoradiography was performed using tumor sections prepared from mice after PET scanning. In vitro and in vivo uptake of [(11)C]DAC in single NFSa cells and NFSa-bearing mice was significantly reduced by carbon ion irradiation. The decrease in [(11)C]DAC uptake in the tumor sections was mainly due to the change in PBR expression. In conclusion, [(11)C]DAC PET responded to the change in PBR expression in tumors caused by carbon ion irradiation in this study. Thus, [(11)C]DAC is a promising predictor for evaluating the effect of carbon ion radiotherapy.

To investigate the influence of fractionation on cell survival and radiation induced premature differentiation as markers for early and late effects after X-rays and carbon irradiation. Normal human fibroblasts NHDF, AG1522B and WI-38 were irradiated with 250 kV X-rays, or 266 MeV/u, 195 MeV/u and 11 MeV/u carbon ions. Cytotoxicity was measured by a clonogenic survival assay or by determination of the differentiation pattern. Experiments with high-energy carbon ions show that fractionation induced repair effects are similar to photon irradiation. The RBE(10) values for clonogenic survival are 1.3 and 1.6 for irradiation in one or two fractions for NHDF cells and around 1.2 for AG1522B cells regardless of the fractionation scheme. The RBE for a doubling of post mitotic fibroblasts (PMF) in the population is 1 for both single and two fractionated irradiation of NHDF cells. Using 11 MeV/u carbon ions, no repair effect can be seen in WI-38 cells. The RBE(10) for clonogenic survival is 3.2 for single irradiation and 4.9 for two fractionated irradiations. The RBE for a doubling of PMF is 3.1 and 5.0 for single and two fractionated irradiations, respectively. For both cell lines the effects of high-energy carbon ions representing the irradiation of the skin and the normal tissue in the entrance channel are similar to the effects of X-rays. The fractionation effects are maintained. For the lower energy, which is representative for the irradiation of the tumor region, RBE is enhanced for clonogenic survival as well as for premature terminal differentiation. Fractionation effects are not detectable. Consequently, the therapeutic ratio is significantly enhanced by fractionated irradiation with carbon ions.

HIMAC/RBE/Carbon ion radiotherapy. The clinical dose distributions of therapeutic carbon beams, currently used at NIRS HIMAC, are bas ed on in-vitro Human Salivary Gland (HSG) cell survival response and clinical experience from fast neutron radiotherapy. Moderate radiosensitivity of HSG cells is expected to be a typical response of tumours to carbon beams. At first, the biological dose distribution is designed so as to cause a flat biological effect on HSG cells in the spread-out Bragg peak (SOBP) region. Then, the entire biological dose distribution is evenly raised in order to attain a RBE (rel ative biological effectiveness) = 3.0 at a depth where dose-averaged LET (linear energy transfer) is 80 keV/μm. At that point, biological experiments have shown that carbon ions can be expected to have a biological effect identical to fast neutrons, which showed a clinical RBE of 3.0 for fast neutron radiotherapy at NIRS. The resulting clinical dose distribution in this approximation is not dependent on dose level, tumour t ype or fractionation scheme and thus reduces the unknown parameters in the analysis of the clinical results. The width SOBP and the clinical / physical dose at the center of SOBP specify the dose distribution. The clinical results analysed in terms of TCP were f ound to show good agreement with the expected RBE value at higher TCP levels. The TCP analysis method was applied for the prospective dose estimation of hypofractionation.

Carbon ion radiotherapy at HIMAC started in 1994 using two horizontal and two vertical beam ports with broad beam method. The maximum beam energy extracted from accelerators was 400 MeV/n for the horizontal beam port, and 350 MeV/n for the vertical one. In recent years, the scope of diseases that can be treated by the carbon ion radiotherapy has widened and their tumor targets have varied in dimension and location. So, situations of shortage in the beam range in treatment planning have increased. In order to provide sufficient dose to the deeply seated target, we adopted higher energy beam, that is, 430 and 400 MeV/n for the horizontal port and the vertical port, respectively. For the introduction of the new energy beams, we carried out the following. (1) Adjustment of new parameter-sets of the accelerators for the high-energy beams. (2) Replacement of ridge filters with the redesigned ones for the high-energy beams. (3) Updating irradiation condition tables in the irradiation control system and registering new beam data in the treatment planning system, on the base of dose distribution measurements. As a result, the beam range for horizontal port and vertical port was extended ∼30 and 50 mm, respectively. This allows us to treat all patients without ingenuity of patient's posturing and beam weight for each direction. On the other hand, adding new operational energies leads to a decrease in whole throughput, because it takes time to switch among the beam energies. We have at the same time simplified the procedures for the dose calibration and beam adjustment in the switching of energy. The broad beam method has reached maturity as a standard irradiation method of carbon ion radiotherapy and has achieved superior clinical results. We will continue to make upgrades this system with maintenance of its performance and improve the usability of this systems.