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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.

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.

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)_I was then applied to estimate DRBE. Target median DRBE ratios between MC+LEM_I and NIRS plans determined correction factors for the conversion of prescription doses. Plans were re-optimized in a LEM_I-based commercial system, prescribing the NIRS uncorrected and corrected DRBE., Results: The MC+LEM_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.)

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.

The authors attempt to establish the relative biological effectiveness (RBE) calculation for designing therapeutic proton beams on the basis of microdosimetry. The tissue-equivalent proportional counter (TEPC) was used to measure microdosimetric lineal energy spectra for proton beams at various depths in a water phantom. An RBE-weighted absorbed dose is defined as an absorbed dose multiplied by an RBE for cell death of human salivary gland (HSG) tumor cells in this study. The RBE values were calculated by a modified microdosimetric kinetic model using the biological parameters for HSG tumor cells. The calculated RBE distributions showed a gradual increase to about 1cm short of a beam range and a steep increase around the beam range for both the mono-energetic and spread-out Bragg peak (SOBP) proton beams. The calculated RBE values were partially compared with a biological experiment in which the HSG tumor cells were irradiated by the SOBP beam except around the distal end. The RBE-weighted absorbed dose distribution for the SOBP beam was derived from the measured spectra for the mono-energetic beam by a mixing calculation, and it was confirmed that it agreed well with that directly derived from the microdosimetric spectra measured in the SOBP beam. The absorbed dose distributions to planarize the RBE-weighted absorbed dose were calculated in consideration of the RBE dependence on the prescribed absorbed dose and cellular radio-sensitivity. The results show that the microdosimetric measurement for the mono-energetic proton beam is also useful for designing RBE-weighted absorbed dose distributions for range-modulated proton beams.

In carbon ion radiotherapy there is an urgent clinical need to develop objective tools for the conversion of relative biological effectiveness (RBE)-weighted doses based on different models. In this work we introduce a clinically oriented method to compare NIRS-based and LEM-based GyE systems, minimizing differences in physical dose distributions between treatment plans. Carbon ion plans were optimized on target volumes of cubic and spherical shapes, for RBE-weighted dose prescription levels ranging from 3.6 to 4.4 GyE. Plans were calculated for target sizes from 4 to 12 cm defining three beam geometries: single beam, opposed beam and orthogonal beam configurations. The two treatment planning systems currently employed in clinical practice were used, providing the NIRS-based and LEM-based GyE calculations. Physical dose distributions of NIRS-based and LEM-based treatment plans were compared. LEM-based prescription doses that minimize differences in physical dose distributions between the two systems were found. These doses were compared with the mean RBE-weighted dose obtained with a Monte Carlo code (FLUKA) interfaced with LEM I. In the investigated dose range, LEM-based RBE-weighted prescription doses, that minimize differences with NIRS plans, should be higher than NIRS reported prescription doses. The optimal dose depends on target size, shape and position, number of beams and dose level. The opposed beam configuration resulted in the smallest average prescription dose difference (0.45 ± 0.09 GyE). The second approach of recalculating NIRS RBE-weighted dose with a Monte Carlo code interfaced with LEM resulted in no significant difference with the results obtained from the planning study. The delivery of a voxel by voxel iso-effective plan, if different RBE models are employed, is not feasible; it is however possible to minimize differences in a treatment plan with the simple approach presented here. Dose prescription ultimately represents a clinical task under the responsibility of the radiation oncologist, the presented analysis intends to be a quantitative and objective way to assist the clinical decision.

Purpose: Recent radiotherapy technologies including carbon-ion radiotherapy can improve the dose concentration in the target volume, thereby not only reducing side effects in organs at risk but also the secondary cancer risk within or near the irradiation field. However, secondary cancer risk in the low-dose region is considered to be non-negligible, especially for younger patients. To achieve a dose estimation of the whole body of each patient receiving carbon-ion radiotherapy, which is essential for risk assessment and epidemiological studies, Monte Carlo simulation plays an important role because the treatment planning system can provide dose distribution only in∕near the irradiation field and the measured data are limited. However, validation of Monte Carlo simulations is necessary. The primary purpose of this study was to establish a calculation method using the Monte Carlo code to estimate the dose and quality factor in the body and to validate the proposed method by comparison with experimental data. Furthermore, we show the distributions of dose equivalent in a phantom and identify the partial contribution of each radiation type., Methods: We proposed a calculation method based on a Monte Carlo simulation using the PHITS code to estimate absorbed dose, dose equivalent, and dose-averaged quality factor by using the Q(L)-L relationship based on the ICRP 60 recommendation. The values obtained by this method in modeling the passive beam line at the Heavy-Ion Medical Accelerator in Chiba were compared with our previously measured data., Results: It was shown that our calculation model can estimate the measured value within a factor of 2, which included not only the uncertainty of this calculation method but also those regarding the assumptions of the geometrical modeling and the PHITS code. Also, we showed the differences in the doses and the partial contributions of each radiation type between passive and active carbon-ion beams using this calculation method. These results indicated that it is essentially important to include the dose by secondary neutrons in the assessment of the secondary cancer risk of patients receiving carbon-ion radiotherapy with active as well as passive beams., Conclusions: We established a calculation method with a Monte Carlo simulation to estimate the distribution of dose equivalent in the body as a first step toward routine risk assessment and an epidemiological study of carbon-ion radiotherapy at NIRS. This method has the advantage of being verifiable by the measurement.

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.

We describe a method to calculate the relative biological effectiveness in mixed radiation fields of therapeutic ion beams based on the modified microdosimetric kinetic model (modified MKM). In addition, we show the procedure for integrating the modified MKM into a treatment planning system for a scanned carbon beam. With this procedure, the model is fully integrated into our research version of the treatment planning system. To account for the change in radiosensitivity of a cell line, we measured one of the three MKM parameters from a single survival curve of the current cells and used the parameter in biological optimization. Irradiation of human salivary gland tumor cells was performed with a scanned carbon beam in the Heavy Ion Medical Accelerator in Chiba (HIMAC), and we then compared the measured depth-survival curve with the modified MKM predicted survival curve. Good agreement between the two curves proves that the proposed method is a candidate for calculating the biological effects in treatment planning for ion irradiation.

Background: To evaluate the safety of focal dose escalation to regions with standardized uptake value (SUV) >2.0 using intensity-modulated radiation therapy (IMRT) by comparison of radiotherapy plans using dose-volume histograms (DVHs) and normal tissue complication probability (NTCP) for postoperative local recurrent rectal cancer, Methods: First, we performed conventional radiotherapy with 40 Gy/20 fr. (CRT 40 Gy) for 12 patients with postoperative local recurrent rectal cancer, and then we performed FDG-PET/CT radiotherapy planning for those patients. We defined the regions with SUV > 2.0 as biological target volume (BTV) and made three boost plans for each patient: 1) CRT boost plan, 2) IMRT without dose-painting boost plan, and 3) IMRT with dose-painting boost plan. The total boost dose was 20 Gy. In IMRT with dose-painting boost plan, we increased the dose for BTV+5 mm by 30% of the prescribed dose. We added CRT boost plan to CRT 40 Gy (summed plan 1), IMRT without dose-painting boost plan to CRT 40 Gy (summed plan 2) and IMRT with dose-painting boost plan to CRT 40 Gy (summed plan 3), and we compared those plans using DVHs and NTCP., Results: D(mean) of PTV-PET and that of PTV-CT were 26.5 Gy and 21.3 Gy, respectively. V50 of small bowel PRV in summed plan 1 was significantly higher than those in other plans ((summed plan 1 vs. summed plan 2 vs. summed plan 3: 47.11 +/- 45.33 cm3 vs. 40.63 +/- 39.13 cm3 vs. 41.25 +/- 39.96 cm3 (p < 0.01, respectively)). There were no significant differences in V30, V40, V60, D(mean) or NTCP of small bowel PRV., Conclusions: FDG-PET-guided IMRT can facilitate focal dose-escalation to regions with SUV above 2.0 for postoperative local recurrent rectal cancer.

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.

Treatment planning of heavy-ion radiotherapy involves predictive calculation of not only the physical dose but also the biological dose in a patient body. The biological dose is defined as the product of the physical dose and the relative biological effectiveness (RBE). In carbon-ion radiotherapy at National Institute of Radiological Sciences, the RBE value has been defined as the ratio of the 10% survival dose of 200 kVp x-rays to that of the radiation of interest for in vitro human salivary gland tumour cells. In this note, the physical and biological dose distributions of a typical therapeutic carbon-ion beam are calculated using the GEANT4 Monte Carlo simulation toolkit in comparison with those with the biological dose estimate system based on the one-dimensional beam model currently used in treatment planning. The results differed between the GEANT4 simulation and the one-dimensional beam model, indicating the physical limitations in the beam model. This study demonstrates that the Monte Carlo physics simulation technique can be applied to improve the accuracy of the biological dose distribution in treatment planning of heavy-ion radiotherapy.

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.

The latest heavy ion therapy tends to require information about the spatial distribution of the quality of radiation in a patient's body in order to make the best use of any potential advantage of swift heavy ions for the therapeutic treatment of a tumour. The deflection of incident particles is described well by Molière's multiple-scattering theory of primary particles; however, the deflection of projectile fragments is not yet thoroughly understood. This paper reports on our investigation of the spatial distribution of fragments produced from a therapeutic carbon beam through nuclear reactions in thick water. A DeltaE-E counter telescope system, composed of a plastic scintillator, a gas-flow proportional counter and a BGO scintillator, was rotated around a water target in order to measure the spatial distribution of the radiation quality. The results revealed that the observed deflection of fragment particles exceeded the multiple scattering effect estimated by Molière's theory. However, the difference can be sufficiently accounted for by considering one term involved in the multiple-scattering formula; this term corresponds to a lateral 'kick' at the point of production of the fragment. This kick is successfully explained as a transfer of the intra-nucleus Fermi momentum of a projectile to the fragment; the extent of the kick obeys the expectation derived from the Goldhaber model.

A method to establish the relationship between CT number and effective density for therapeutic radiations is proposed. We approximated body tissues to mixtures of muscle, air, fat and bone. Consequently, the relationship can be calibrated only with a CT scan of their substitutes, for which we chose water, air, ethanol and potassium phosphate solution, respectively. With simple and specific corrections for non-equivalencies of the substitutes, a calibration accuracy of 1% will be achieved. We tested the calibration method with some biological materials to verify that the proposed method would offer the accuracy, simplicity and specificity required for a standard in radiotherapy treatment planning, in particular with heavy charged particles.

The precise conversion of CT numbers to their electron densities is essential in treatment planning for hadron therapy. Although some conversion methods have already been proposed, it is hard to check the conversion accuracy during practical therapy. We have estimated the CT numbers of real tissues by a calculational method established by Mustafa and Jackson. The relationship between the CT numbers and the electron densities was investigated for various body tissues as well as some tissue-equivalent materials used for a conversion to check the accuracy of the current conversion methods. The result indicates a slight disagreement at the high-CT-number region. A precise estimation of the multiple scattering, nuclear reaction and range straggling of incident particles has been considered as being important to realize higher-level conformal therapy in the future. The relationship between these parameters and the CT numbers was also investigated for tissues and water. The result shows that it is sufficiently practical to replace these parameters for real tissues with those for water by adjusting the density.