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Background/aim: In vivo dosimetry can prevent dose delivery errors by directly measuring the dose of radiation administered to a patient. However, a method for in vivo dosimetry during carbon ion radiotherapy (CIRT) has not been established. Therefore, we investigated data from in vivo dosimetry of the urethra during CIRT for prostate cancer using small spherical diode dosimeters (SSDDs)., Patients and Methods: This study included five patients enrolled in a clinical trial (jRCT identifier: jRCTs032190180) on which the use of four-fraction CIRT for prostate cancer was examined. The urethral dose during CIRT for prostate cancer was measured using the SSDDs inserted into the ureteral catheter. The relative error between the in vivo and calculated doses obtained using the Xio-N treatment planning system was determined. Additionally, a dose-response stability test for the in vivo dosimeter was performed under clinical conditions., Results: The relative error between the in vivo and calculated urethral doses ranged from 6 to 12%. The dose-response stability under clinical conditions of the measured dose was ≤1%. Therefore, an error >1% would be due to an interfractional patient setup error in the large dose gradient in the urethra., Conclusion: The usefulness of in vivo dosimetry using SSDDs in CIRT and SSDDs' potential for detecting dose delivery errors during CIRT is herein highlighted., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The local control rate of chondrosarcomas treated with carbon-ion radiotherapy (CIRT) worsens as tumour size increases, possibly because of the intra-tumoural linear energy transfer (LET) distribution. This study aimed to evaluate the relationship between local recurrence and intra-tumoural LET distribution in chondrosarcomas treated with CIRT., Patients and Methods: Thirty patients treated with CIRT for grade 2 chondrosarcoma were included. Dose-averaged LET (LET d ) distribution was calculated by the treatment planning system, and the relationship between LET d distribution in the planning tumour volume (PTV) and local control was evaluated., Results: The mean LET d value in PTV was similar between cases with and without recurrence. Recurrence was not observed in cases where the effective minimum LET d value exceeded 40 keV/μm., Conclusion: LET d distribution in PTV is associated with local control in chondrosarcomas and patients treated with ion beams of higher LET d may have an improved local control rate for unresectable chondrosarcomas., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Microdosimetry is a particularly powerful method to estimate the relative biological effectiveness (RBE) of any mixed radiation field. This is particularly convenient for therapeutic heavy ion therapy (HIT) beams, referring to ions larger than protons, where the RBE of the beam can vary significantly along the Bragg curve. Additionally, due to the sharp dose gradients at the end of the Bragg peak (BP), or spread out BP, to make accurate measurements and estimations of the biological properties of a beam a high spatial resolution is required, less than a millimetre. This requirement makes silicon microdosimetry particularly attractive due to the thicknesses of the sensitive volumes commonly being  ∼10 [Formula: see text]m or less. Monte Carlo (MC) codes are widely used to study the complex mixed HIT radiation field as well as to model the response of novel microdosimeter detectors when irradiated with HIT beams. Therefore it is essential to validate MC codes against experimental measurements. This work compares measurements performed with a silicon microdosimeter in mono-energetic [Formula: see text], [Formula: see text] and [Formula: see text] ion beams of therapeutic energies, against simulation results calculated with the Geant4 toolkit. Experimental and simulation results were compared in terms of microdosimetric spectra (dose lineal energy, [Formula: see text]), the dose mean lineal energy, y  D and the RBE 10 , as estimated by the microdosimetric kinetic model (MKM). Overall Geant4 showed reasonable agreement with experimental measurements. Before the distal edge of the BP, simulation and experiment agreed within  ∼10% for y  D and  ∼2% for RBE 10 . Downstream of the BP less agreement was observed between simulation and experiment, particularly for the [Formula: see text] and [Formula: see text] beams. Simulation results downstream of the BP had lower values of y  D and RBE 10 compared to the experiment due to a higher contribution from lighter fragments compared to heavier fragments.

Hypofractionated carbon-ion therapy has been applied to treatment of several tumours. In this case, relative biological effectiveness (RBE) at high dose region must be considered, however, the RBE calculated physically has been not verified biologically. In this study, spheroid technique was adopted to estimate RBE in wide dose range. Cells were irradiated with X-rays and heavy-ions with LET of 13, 35, 100 and 300 keV/μm with monolayer and spheroid condition. Surviving fractions in wide dose range (0-15 Gy) were obtained to combined monolayer with spheroid survival data. The linear-quadratic and multi-target single-hit equation fitted well in survival data at low dose, and high dose region, respectively. A multi-process equation showed best fitting for survival data in wide dose range. RBE values of heavy-ions could be estimated by combination of monolayer and spheroid data. The values converged at 1.1-1.4 and varied by LET values at high and low dose region, respectively., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: To investigate the suitability of the linear-quadratic (LQ) and universal survival curve (USC) models in describing the 3-year tumor control probability data of patients with stage I non-small cell lung cancer treated with carbon-ion radiation therapy. Carbon-ion radiation therapy was given at a total dose of 59.4 to 95.4 Gy (relative biological effectiveness [RBE]) in 18 fractions, at 72 Gy[RBE] in 9 fractions, at 52.8 to 60 Gy[RBE] in 4 fractions, and at 28 to 50 Gy[RBE] in a single fraction., Methods and Materials: A meta-analysis of published clinical data from 394 patients presenting with early-stage non-small cell lung cancer was conducted. Tumor control probability modeling based on the LQ and USC models was performed by simultaneously fitting the clinical data obtained from the different fractionation schedules while considering several spread-out Bragg peak (SOBP) sizes. Radiobiological parameters were derived from the fit. On the basis of the results, a novel SOBP was created for the single-fraction regimen that was optimized with respect to the USC model and aimed at achieving a 95% local control., Results: The USC model gave a better fit to the 3-year local control data than the LQ model did. The fit using various SOBP sizes yielded transition doses between 5.6 and 7.0 Gy. The results also revealed α/β ratios between 7.4 and 9.1 Gy for the LQ model and between 7.4 and 9.4 Gy for the USC model., Conclusions: The USC model provided a better estimate of the local control rate for the single-fraction course. For the schemes with a greater number of fractions, the local control rate estimates from the LQ and USC models were comparable. A USC-based SOBP design was then created for the single-fraction schedule. The updated design resulted in a flatter RBE profile compared with the conventional SOBP design. It also gave a better clinical dose prediction to optimize the tumor control rate., (Copyright © 2018 Gunma University. Published by Elsevier Inc. All rights reserved.)

Carbon ion radiotherapy (CIRT) is developing toward a versatile tool in radiotherapy; however, the increased relative biological effectiveness (RBE) of carbon ions in tumors and normal tissues with respect to photon irradiation has to be considered by mathematical models in treatment planning. As a consequence, dose prescription and definition of dose constraints are performed in terms of RBE weighted rather than absorbed dose. The RBE is a complex quantity, which depends on physical variables, such as dose and beam quality as well as on normal tissue- or tumor-specific factors. At present, three RBE models are employed in CIRT: (a) the mixed-beam model, (b) the Microdosimetric Kinetic Model (MKM), and (c) the local effect model. While the LEM is used in Europe, the other two models are employed in Japan, and unfortunately, the concepts of how the nominal RBE-weighted dose is determined and prescribed differ significantly between the European and Japanese centers complicating the comparison, transfer, and reproduction of clinical results. This has severe impact on the way treatments should be prescribed, recorded, and reported. This contribution reviews the concept of the clinical application of the different RBE models and the ongoing clinical CIRT trials in Japan and Europe. Limitations of the RBE models and the resulting radiobiological issues in clinical CIRT trials are discussed in the context of current clinical evidence and future challenges., (© 2017 American Association of Physicists in Medicine.)

Using the CMRP 'bridge' μ+ probe, microdosimetric measurements were undertaken out-of-field using a therapeutic scanning proton pencil beam and in-field using a 12C ion therapy field. These measurements were undertaken at Mayo Clinic, Rochester, USA and at HIMAC, Chiba, Japan, respectively. For a typical proton field used in the treatment of deep-seated tumors, we observed dose-equivalent values ranging from 0.62 to 0.99 mSv/Gy at locations downstream of the distal edge. Lateral measurements at depths close to the entrance and along the SOBP plateau were found to reach maximum values of 3.1 mSv/Gy and 5.3 mSv/Gy at 10 mm from the field edge, respectively, and decreased to ~0.04 mSv/Gy 120 mm from the field edge. The ability to measure the dose-equivalent with high spatial resolution is particularly relevant to healthy tissue dose calculations in hadron therapy treatments. We have also shown qualitatively and quantitively the effects critical organ motion would have in treatment using microdosimetric spectra. Large differences in spectra and RBE10 were observed for treatments where miscalculations of 12C ion range would result in critical structures being irradiated, showing the importance of motion management.

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., (Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

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.

Particle beam therapy (PBT), including proton and carbon ion therapy, is an emerging innovative treatment for cancer patients. Due to the high cost of and limited access to treatment, meticulous selection of patients who would benefit most from PBT, when compared with standard X-ray therapy (XRT), is necessary. Due to the cost and labor involved in randomized controlled trials, the model-based approach (MBA) is used as an alternative means of establishing scientific evidence in medicine, and it can be improved continuously. Good databases and reasonable models are crucial for the reliability of this approach. The tumor control probability and normal tissue complication probability models are good illustrations of the advantages of PBT, but pre-existing NTCP models have been derived from historical patient treatments from the XRT era. This highlights the necessity of prospectively analyzing specific treatment-related toxicities in order to develop PBT-compatible models. An international consensus has been reached at the Global Institution for Collaborative Research and Education (GI-CoRE) joint symposium, concluding that a systematically developed model is required for model accuracy and performance. Six important steps that need to be observed in these considerations include patient selection, treatment planning, beam delivery, dose verification, response assessment, and data analysis. Advanced technologies in radiotherapy and computer science can be integrated to improve the efficacy of a treatment. Model validation and appropriately defined thresholds in a cost-effectiveness centered manner, together with quality assurance in the treatment planning, have to be achieved prior to clinical implementation.

Variation in the relative biological effectiveness (RBE) within the irradiation field of a carbon beam makes carbon-ion radiotherapy unique and advantageous in delivering the therapeutic dose to a deep-seated tumor, while sparing surrounding normal tissues. However, it is crucial to consider the RBE, not only in designing the dose distribution during treatment planning, but also in analyzing the clinical response retrospectively. At the National Institute of Radiological Sciences, the RBE model was established based on the response of human salivary gland cells. The response was originally handled with a linear-quadratic model, and later with a microdosimetric kinetic model. Retrospective analysis with a tumor-control probability model of non-small cell cancer treatment revealed a steep dose response in the tumor, and that the RBE of the tumor was adequately estimated using the model. A commonly used normal tissue complication probability model has not yet fully been accountable for the variable RBE of carbon ions; however, analysis of rectum injury after prostate cancer treatment suggested a highly serial-organ structure for the rectum, and a steep dose response similar to that observed for tumors.

Purpose: The measurement of depth dose profiles for range and energy verification of heavy ion beams is an important aspect of quality assurance procedures for heavy ion therapy facilities. The steep dose gradients in the Bragg peak region of these profiles require the use of detectors with high spatial resolution. The aim of this work is to characterize a one dimensional monolithic silicon detector array called the "serial Dose Magnifying Glass" (sDMG) as an independent ion beam energy and range verification system used for quality assurance conducted for ion beams used in heavy ion therapy., Methods: The sDMG detector consists of two linear arrays of 128 silicon sensitive volumes each with an effective size of 2mm × 50μm × 100μm fabricated on a p-type substrate at a pitch of 200 μm along a single axis of detection. The detector was characterized for beam energy and range verification by measuring the response of the detector when irradiated with a 290 MeV/u 12 C ion broad beam incident along the single axis of the detector embedded in a PMMA phantom. The energy of the 12 C ion beam incident on the detector and the residual energy of an ion beam incident on the phantom was determined from the measured Bragg peak position in the sDMG. Ad hoc Monte Carlo simulations of the experimental setup were also performed to give further insight into the detector response., Results: The relative response profiles along the single axis measured with the sDMG detector were found to have good agreement between experiment and simulation with the position of the Bragg peak determined to fall within 0.2 mm or 1.1% of the range in the detector for the two cases. The energy of the beam incident on the detector was found to vary less than 1% between experiment and simulation. The beam energy incident on the phantom was determined to be (280.9 ± 0.8) MeV/u from the experimental and (280.9 ± 0.2) MeV/u from the simulated profiles. These values coincide with the expected energy of 281 MeV/u., Conclusions: The sDMG detector response was studied experimentally and characterized using a Monte Carlo simulation. The sDMG detector was found to accurately determine the 12 C beam energy and is suited for fast energy and range verification quality assurance. It is proposed that the sDMG is also applicable for verification of treatment planning systems that rely on particle range., (© 2017 American Association of Physicists in Medicine.)

Background: Carbon-ion radiotherapy (CIRT) is a promising treatment for locally advanced non-small-cell lung cancer, especially for patients with inoperable lung cancer. Although the incidence of CIRT-induced radiation pneumonitis (RP) ≥ grade 2 ranges from 2.5 to 9.9%, the association between CIRT-induced RP and dosimetric parameters is not clear. Herein, we identified prognostic factors associated with symptomatic RP after CIRT for patients with non-small-cell lung cancer., Methods: Clinical results of 65 patients treated with CIRT between 2000 and 2015 at the National Institute of Radiological Sciences were retrospectively analyzed. Clinical stage II B disease (TNM classification) was the most common stage among the patients (45%). The median radiation dose was 72 Gy (68-76) relative biological effectiveness (RBE) in 16 fractions. In cases involving metastatic lymph nodes, prophylactic irradiation of mediastinal lymph nodes was performed at a median dose of 49.5 Gy (RBE). The median follow-up was 22 months., Results: Grade 2 and grade 3 RP occurred in 6 and 3 patients (9 and 5%), respectively. No patients developed grade 4 or 5 RP. Using univariate analysis, vital capacity as a percentage of predicted (%VC), forced expiratory volume in 1 s (FEV1), mean lung dose (MLD), volume of lung receiving ≥5 Gy (RBE) (V 5 ), V 10 , V 20 and V 30 were determined to be the significant predictive factors for ≥ grade 2 RP. The receiver operating characteristic (ROC) analysis revealed the cutoff values for %VC, FEV1, MLD, V 5 , V 10 , V 20 and V 30 for ≥ grade 2 RP, which were 86.9%, 1.16 L, 12.5 Gy (RBE), 28.8, 29.9, 20.1 and 15.0%, respectively. In addition, the multivariate analysis revealed that %VC <86.9% (odds ratio = 13.7; p = 0.0041) and V 30  ≥ 15% (odds ratio = 6.1; p = 0.0221) were significant risk factors., Conclusions: Our study demonstrated the risk factors for ≥ grade 2 RP after carbon-ion radiotherapy for patients with locally advanced lung cancer.

Particle therapy facilities often require Monte Carlo (MC) simulations to overcome intrinsic limitations of analytical treatment planning systems (TPS) related to the description of the mixed radiation field and beam interaction with tissue inhomogeneities. Some of these uncertainties may affect the computation of effective dose distributions; therefore, particle therapy dedicated MC codes should provide both absorbed and biological doses. Two biophysical models are currently applied clinically in particle therapy: the local effect model (LEM) and the microdosimetric kinetic model (MKM). In this paper, we describe the coupling of the NIRS (National Institute for Radiological Sciences, Japan) clinical dose to the FLUKA MC code. We moved from the implementation of the model itself to its application in clinical cases, according to the NIRS approach, where a scaling factor is introduced to rescale the (carbon-equivalent) biological dose to a clinical dose level. A high level of agreement was found with published data by exploring a range of values for the MKM input parameters, while some differences were registered in forward recalculations of NIRS patient plans, mainly attributable to differences with the analytical TPS dose engine (taken as reference) in describing the mixed radiation field (lateral spread and fragmentation). We presented a tool which is being used at the Italian National Center for Oncological Hadrontherapy to support the comparison study between the NIRS clinical dose level and the LEM dose specification.

Silicon microdosimetry is a promising technology for heavy ion therapy (HIT) quality assurance, because of its sub-mm spatial resolution and capability to determine radiation effects at a cellular level in a mixed radiation field. A drawback of silicon is not being tissue-equivalent, thus the need to convert the detector response obtained in silicon to tissue. This paper presents a method for converting silicon microdosimetric spectra to tissue for a therapeutic 12 C beam, based on Monte Carlo simulations. The energy deposition spectra in a 10 μm sized silicon cylindrical sensitive volume (SV) were found to be equivalent to those measured in a tissue SV, with the same shape, but with dimensions scaled by a factor κ equal to 0.57 and 0.54 for muscle and water, respectively. A low energy correction factor was determined to account for the enhanced response in silicon at low energy depositions, produced by electrons. The concept of the mean path length [Formula: see text] to calculate the lineal energy was introduced as an alternative to the mean chord length [Formula: see text] because it was found that adopting Cauchy's formula for the [Formula: see text] was not appropriate for the radiation field typical of HIT as it is very directional. [Formula: see text] can be determined based on the peak of the lineal energy distribution produced by the incident carbon beam. Furthermore it was demonstrated that the thickness of the SV along the direction of the incident 12 C ion beam can be adopted as [Formula: see text]. The tissue equivalence conversion method and [Formula: see text] were adopted to determine the RBE 10 , calculated using a modified microdosimetric kinetic model, applied to the microdosimetric spectra resulting from the simulation study. Comparison of the RBE 10 along the Bragg peak to experimental TEPC measurements at HIMAC, NIRS, showed good agreement. Such agreement demonstrates the validity of the developed tissue equivalence correction factors and of the determination of [Formula: see text].

Background and Purpose: In carbon ion radiotherapy (CIRT), the use of different relative biological effectiveness (RBE) models in the RBE-weighted dose (DRBE) calculation can lead to deviations in the physical dose (Dphy) delivered to the patient. Our aim is to reduce target Dphy deviations by converting prescription dose values., Material and Methods: Planning data of patients treated at the National Institute of Radiological Sciences (NIRS) were collected, with prescribed doses per fraction ranging from 3.6Gy (RBE) to 4.6Gy (RBE), according to the Japanese semi-empirical model. The Dphy was Monte Carlo (MC) re-calculated simulating the NIRS beamline. The local effect model (LEM)&#95;I was then applied to estimate DRBE. Target median DRBE ratios between MC+LEM&#95;I and NIRS plans determined correction factors for the conversion of prescription doses. Plans were re-optimized in a LEM&#95;I-based commercial system, prescribing the NIRS uncorrected and corrected DRBE., Results: The MC+LEM&#95;I target median DRBE was respectively 15% and 5% higher than the NIRS reference, for the lowest and highest dose levels. Uncorrected DRBE prescription resulted in significantly lower target Dphy in re-optimized plans, with respect to NIRS plans., Conclusions: Prescription dose conversion factors could minimize target physical dose variations due to the use of different radiobiological models in the calculation of CIRT RBE-weighted dose., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The aim of this study was to estimate normal tissue complication probability (NTCP) parameters for late rectal complications after carbon ion radiotherapy (C-ion RT) for prostate cancer., Methods and Materials: A total of 163 patients were used to derive NTCP parameters. These patients were treated with relative biological effectiveness (RBE)-weighted dose ranging from 57.6 Gy (RBE) up to 72 Gy (RBE) and included in dose escalation trials. The Lyman-Kutcher-Burman (LKB) model was used and the model parameters were fit to the relation between dose and complication observed after C-ion RT., Results: The resulting NTCP parameters were the volume effect parameter; n=0.035 (95% CI: 0.024-0.047), the steepness of the NTCP curve; m=0.10 (0.084-0.13), the tolerance dose associated with 50% probability of complication; TD50=63.6 Gy (RBE) (61.8-65.4 Gy (RBE)) for Grade⩾1, n=0.012 (0.0050-0.023), m=0.046 (0.033-0.062), TD50=69.1 Gy (RBE) (67.6-70.9 Gy (RBE)) for Grade⩾2., Conclusion: A new set of rectal NTCP parameters in C-ion RT was determined. The rather small n values suggest that the rectum was consistent with being strictly serial organ. The new derived parameter values facilitate estimation of rectal NTCP in C-ion RT., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Skin toxicity caused by radiotherapy has been visually classified into discrete grades. The present study proposes an objective and continuous assessment method of skin erythema in digital images taken under arbitrary lighting conditions, which is the case for most clinical environments. The purpose of this paper is to show the feasibility of the proposed method., Methods: Clinical data were gathered from six patients who received carbon beam therapy for lung cancer. Skin condition was recorded using an ordinary compact digital camera under unfixed lighting conditions; a laser Doppler flowmeter was used to measure blood flow in the skin. The photos and measurements were taken at 3 h, 30, and 90 days after irradiation. Images were decomposed into hemoglobin and melanin colors using independent component analysis. Pixel values in hemoglobin color images were compared with skin dose and skin blood flow. The uncertainty of the practical photographic method was also studied in nonclinical experiments., Results: The clinical data showed good linearity between skin dose, skin blood flow, and pixel value in the hemoglobin color images; their correlation coefficients were larger than 0.7. It was deduced from the nonclinical that the uncertainty due to the proposed method with photography was 15%; such an uncertainty was not critical for assessment of skin erythema in practical use., Conclusions: Feasibility of the proposed method for assessment of skin erythema using digital images was demonstrated. The numerical relationship obtained helped to predict skin erythema by artificial processing of skin images. Although the proposed method using photographs taken under unfixed lighting conditions increased the uncertainty of skin information in the images, it was shown to be powerful for the assessment of skin conditions because of its flexibility and adaptability.

Background and Purpose: Carbon-ion radiotherapy uses spread-out Bragg peaks (SOBP) to produce uniform biological effects within a target volume. The relative biological effectiveness is determined by the in vitro cell kill after a single dose is employed to design the SOBP. A question remains as to whether biological effects for in vivo tissues after fractionated doses are also uniform within the SOBP., Material and Methods: Mouse foot skin was irradiated with fractionated doses of carbon ions at various linear energy transfer (LET) values. A new ridge filter was designed based on alpha and beta values for each LET to cause moderate skin reaction, and was studied concerning its uniformity., Results: The reciprocal total doses of intermediate-LET carbon ions and of reference gamma rays linearly increased with an increase of a dose per fraction in Fe-plots. As the single total dose of higher LET run off linearity, data obtained from 2 to 6 fractions were used to design a new ridge filter. The physical dose distribution of the new ridge filter was almost identical to, and indistinguishable from, the ridge filter designed based on the in vitro cell kill., Conclusions: The LET dependence of alpha is a principle of the biological factor to be used for designing spread-out Bragg peaks of carbon-ion radiotherapy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

At the National Institute of Radiological Sciences (NIRS), more than 8,000 patients have been treated for various tumors with carbon-ion (C-ion) radiotherapy in the past 20 years based on a radiobiologically defined clinical-dose system. Through clinical experience, including extensive dose escalation studies, optimum dose-fractionation protocols have been established for respective tumors, which may be considered as the standards in C-ion radiotherapy. Although the therapeutic appropriateness of the clinical-dose system has been widely demonstrated by clinical results, the system incorporates several oversimplifications such as dose-independent relative biological effectiveness (RBE), empirical nuclear fragmentation model, and use of dose-averaged linear energy transfer to represent the spectrum of particles. We took the opportunity to update the clinical-dose system at the time we started clinical treatment with pencil beam scanning, a new beam delivery method, in 2011. The requirements for the updated system were to correct the oversimplifications made in the original system, while harmonizing with the original system to maintain the established dose-fractionation protocols. In the updated system, the radiation quality of the therapeutic C-ion beam was derived with Monte Carlo simulations, and its biological effectiveness was predicted with a theoretical model. We selected the most used C-ion beam with αr = 0.764 Gy(-1) and β = 0.0615 Gy(-2) as reference radiation for RBE. The C-equivalent biological dose distribution is designed to allow the prescribed survival of tumor cells of the human salivary gland (HSG) in entire spread-out Bragg peak (SOBP) region, with consideration to the dose dependence of the RBE. This C-equivalent biological dose distribution is scaled to a clinical dose distribution to harmonize with our clinical experiences with C-ion radiotherapy. Treatment plans were made with the original and the updated clinical-dose systems, and both physical and clinical dose distributions were compared with regard to the prescribed dose level, beam energy, and SOBP width. Both systems provided uniform clinical dose distributions within the targets consistent with the prescriptions. The mean physical doses delivered to targets by the updated system agreed with the doses by the original system within ± 1.5% for all tested conditions. The updated system reflects the physical and biological characteristics of the therapeutic C-ion beam more accurately than the original system, while at the same time allowing the continued use of the dose-fractionation protocols established with the original system at NIRS.

To understand the biological response of normal cells to fractionated carbon beam irradiation, the effects of potentially lethal damage repair (PLDR) and sublethal damage repair (SLDR) were both taken into account in a linear-quadratic (LQ) model. The model was verified by the results of a fractionated cell survival experiment with normal human fibroblast cells. Cells were irradiated with 200-kV X-rays and monoenergetic carbon ion beams (290 MeV/u) at two irradiation depths, corresponding to linear energy transfers (LETs) of approximately 13 keV/μm and 75 keV/μm, respectively, at the Heavy Ion Medical Accelerator in Chiba of the National Institute of Radiological Sciences. When we only took into account the repair factor of PLDR, γ, which was derived from the delayed assay, the cell survival response to fractionated carbon ion irradiation was not fully explained in some cases. When both the effects of SLDR and PLDR were taken into account in the LQ model, the cell survival response was well reproduced. The model analysis suggested that PLDR occurs in any type of radiation. The γ factors ranged from 0.36-0.93. In addition, SLD was perfectly repaired during the fraction interval for the lower LET irradiations but remained at about 30% for the high-LET irradiation.

We have developed a novel design method of ridge filters for carbon-ion therapy using a broad-beam delivery system to improve the flatness of a biologically effective dose in the spread-out Bragg peak (SOBP). So far, the flatness of the SOBP is limited to about ±5% for carbon beams since the weight control of component Bragg curves composing the SOBP is difficult. This difficulty arises from using a large number of ridge-bar steps (e.g. about 100 for a SOBP width of 60 mm) required to form the SOBP for the pristine Bragg curve with an extremely sharp distal falloff. Instead of using a single ridge filter, we introduce a ripple filter to broaden the Bragg peak so that the number of ridge-bar steps can be reduced to about 30 for SOBP with of 60 mm for the ridge filter designed for the broadened Bragg peak. Thus we can manufacture the ridge filter more accurately and then attain a better flatness of the SOBP due to well-controlled weights of the component Bragg curves. We placed the ripple filter on the same frame of the ridge filter and arranged the direction of the ripple-filter-bar array perpendicular to that of the ridge-filter-bar array. We applied this method to a 290 MeV u(-1) carbon-ion beam in Heavy Ion Medical Accelerator in Chiba and verified the effectiveness by measurements., (© 2012 Institute of Physics and Engineering in Medicine)

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.

Purpose: Recent successful results in passive carbon-ion radiotherapy allow the patient to live for a longer time and allow younger patients to receive the radiotherapy. Undesired radiation exposure in normal tissues far from the target volume is considerably lower than that close to the treatment target, but it is considered to be non-negligible in the estimation of the secondary cancer risk. Therefore, it is very important to reduce the undesired secondary neutron exposure in passive carbon-ion radiotherapy without influencing the clinical beam. In this study, the source components in which the secondary neutrons are produced during passive carbon-ion radiotherapy were identified and the method to reduce the secondary neutron dose effectively based on the identification of the main sources without influencing the clinical beam was investigated., Methods: A Monte Carlo study with the PHITS code was performed by assuming the beamline at the Heavy-Ion Medical Accelerator in Chiba (HIMAC). At first, the authors investigated the main sources of secondary neutrons in passive carbon-ion radiotherapy. Next, they investigated the reduction in the neutron dose with various modifications of the beamline device that is the most dominant in the neutron production. Finally, they investigated the use of an additional shield for the patient., Results: It was shown that the main source is the secondary neutrons produced in the four-leaf collimator (FLC) used as a precollimator at HIAMC, of which contribution in the total neutron ambient dose equivalent is more than 70%. The investigations showed that the modification of the FLC can reduce the neutron dose at positions close to the beam axis by 70% and the FLC is very useful not only for the collimation of the primary beam but also the reduction in the secondary neutrons. Also, an additional shield for the patient is very effective to reduce the neutron dose at positions farther than 50 cm from the beam axis. Finally, they showed that the neutron dose can be reduced by approximately 70% at any position without influencing the primary beam used in treatment., Conclusions: This study was performed by assuming the HIMAC beamline; however, this study provides important information for reoptimizing the arrangement and the materials of beamline devices and designing a new facility for passive carbon-ion radiotherapy and probably passive proton radiotherapy.

We developed a calculation technique to evaluate the biological dose distribution of heavy ion beams, and verified its reliability by comparison with experimental results. The calculation technique was developed by connecting two general-purpose Monte Carlo codes. In order to evaluate the radiation quality and biological effect, the microdosimetric kinetic model was adopted. We estimated the distribution of physical dose and radiation quality for the carbon broad beam with experiments and with Monte Carlo calculations. Relative biological effectiveness (RBE) was estimated from radiation quality, and biological dose could be calculated as the product of the physical dose and the RBE. Our calculations showed good agreement with experiments, not only for the physical dose, but also for the dose-averaged lineal energy as an expression of radiation quality and therefore biological dose. This finding indicates that our calculation tool will be useful to estimate biological dose distribution in the design of heavy ion radiation facilities or for quality assurance in treatment planning.

Both the microdosimetric kinetic model (MKM) and the local effect model (LEM) can be used to calculate the surviving fraction of cells irradiated by high-energy ion beams. In this study, amorphous track structure models instead of the stochastic energy deposition are used for the MKM calculation, and it is found that the MKM calculation is useful for predicting the survival curves of the mammalian cells in vitro for (3)He-, (12)C- and (20)Ne-ion beams. The survival curves are also calculated by two different implementations of the LEM, which inherently used an amorphous track structure model. The results calculated in this manner show good agreement with the experimental results especially for the modified LEM. These results are compared to those calculated by the MKM. Comparison of the two models reveals that both models require three basic constituents: target geometry, photon survival curve and track structure, although the implementation of each model is significantly different. In the context of the amorphous track structure model, the difference between the MKM and LEM is primarily the result of different approaches calculating the biological effects of the extremely high local dose in the center of the ion track.

Purpose: A retrospective analysis was made to examine appropriateness in the estimation of the biologic effectiveness of carbon-ion radiotherapy using resultant data from clinical trials at the heavy-ion medical accelerator complex (HIMAC) at the National Institute of Radiological Sciences in Chiba, Japan., Methods and Materials: At HIMAC, relative biologic effectiveness (RBE) values of therapeutic carbon beams were determined based on experimental results of cell responses, on values expected with the linear-quadratic model, and based on experiences with neutron therapy. We use fixed RBE values independent of dose levels, although this apparently contradicts radiobiologic observations. Our RBE system depends only on LET of the heavy-ion radiation fields. With this RBE system, over 2,000 patients have been treated by carbon beams. With data from these patients, the local control rate of non-small-cell lung cancer was analyzed to verify the clinical RBE of the carbon beam. The local control rate was compared with rates published by groups from Gunma University and Massachusetts General Hospital. Using a simplified tumor control probability (TCP) model, clinical RBE values were obtained for different levels of TCP., Results: For the 50% level of the clinical TCP, the RBE values nearly coincide with those for in vitro human salivary gland cell survival at 10%. For the higher levels of clinical TCP, the RBE values approach closer to those adapted in clinical trials at HIMAC.

The treatment planning approach used within the heavy ion tumour therapy project at GSI Darmstadt includes a biological optimisation, which is based on a biophysical model, the Local Effect Model (LEM). Here we show that the predictions of the LEM are in good agreement with clinical data obtained at the HIMAC in Chiba for the treatment of non-small-cell lung cancer, and the steep dose response for carbon ions is reproduced correctly. This steeper increase corresponds to an increasing RBE with increasing dose, which apparently is in contradiction to the systematics observed in general for in vitro measurements. A possible explanation of this discrepancy is based on the interindividual variation of photon sensitivity.

In heavy-ion radiotherapy, an accelerated beam is modified to realize a desired dose distribution in patients. The setup of the beam-modifying devices in the irradiation system is changed according to the patient, and it is important to check the depth dose distributions in the patient. In order to measure dose distributions realized by an irradiation system for heavy-ion radiotherapy, a multi-layer ionization chamber(MLIC) was developed. The MLIC consists of 64 ionization chambers, which are stacked mutually. The interval between each ionization chamber is about 4.1 mm water. There are signal and high voltage plates in the MILC, which are used as electrodes of the ionization chambers and phantom. Depth dose distribution from 5.09 mm to 261.92 mm water can be measured in about 30 seconds using this MLIC. Thus, it is possible to check beam quality in a short amount of time.

Purpose: The irradiation system and biophysical characteristics of carbon beams are examined regarding radiation therapy., Methods and Materials: An irradiation system was developed for heavy-ion radiotherapy. Wobbler magnets and a scatterer were used for flattening the radiation field. A patient-positioning system using X ray and image intensifiers was also installed in the irradiation system. The depth-dose distributions of the carbon beams were modified to make a spread-out Bragg peak, which was designed based on the biophysical characteristics of monoenergetic beams. A dosimetry system for heavy-ion radiotherapy was established to deliver heavy-ion doses safely to the patients according to the treatment planning. A carbon beam of 80 keV/microm in the spread-out Bragg peak was found to be equivalent in biological responses to the neutron beam that is produced at cyclotron facility in National Institute Radiological Sciences (NIRS) by bombarding 30-MeV deuteron beam on beryllium target. The fractionation schedule of the NIRS neutron therapy was adapted for the first clinical trials using carbon beams., Results: Carbon beams, 290, 350, and 400 MeV/u, were used for a clinical trial from June of 1994. Over 300 patients have already been treated by this irradiation system by the end of 1997.

Clinical trials for tumor treatment using highly energetic heavy ions are now in progress at the HIMAC. In order to achieve the radiotherapy more precisely, it is important to know the distribution of the electron density in a human body. For this purpose, we have developed a broad beam heavy ion CT system. The performance, especially the electron density resolution, of this system is estimated in this work. Some kinds of the solution targets with the known electron densities were used as samples. The projection data were obtained using 12C of 290 MeV/u, 20Ne of 400 MeV/u and 4He of 150 MeV/u. The experimental values were in good agreement with the calculated values. [Copyright &y& Elsevier]