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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.)

Background: The aim of this study was to measure the microdosimetric distributions of a carbon pencil beam scanning (PBS) and passive scattering system as well as to evaluate the relative biological effectiveness (RBE) of different ions, namely 12 C, 14 N, and 16 O, using a silicon-on-insulator (SOI) microdosimeter with well-defined 3D-sensitive volumes (SV). Geant4 simulations were performed with the same experimental setup and results were compared to the experimental results for benchmarking., Method: Two different silicon microdosimeters with rectangular parallelepiped and cylindrical shaped SVs, both 10 μm in thickness were used in this study. The microdosimeters were connected to low noise electronics which allowed for the detection of lineal energies as low as 0.15 keV/μm in tissue. The silicon microdosimeters provide extremely high spatial resolution and can be used for in-field and out-of-field measurements in both passive scattering and PBS deliveries. The response of the microdosimeters was studied in 290 MeV/u 12 C, 180 MeV/u 14 N, 400 MeV/u 16 O passive ion beams, and 290 MeV/u 12 C scanning carbon therapy beam at heavy ion medical accelerator in Chiba (HIMAC) and Gunma University Heavy Ion Medical Center (GHMC), Japan, respectively. The microdosimeters were placed at various depths in a water phantom along the central axis of the ion beam, and at the distal part of the Spread Out Bragg Peak (SOBP) in 0.5 mm increments. The RBE values of the pristine Bragg peak (BP) and SOBP were derived using the microdosimetric lineal energy spectra and the modified microdosimetric kinetic model (MKM), using MKM input parameters corresponding to human salivary gland (HSG) tumor cells. Geant4 simulations were performed in order to verify the calculated depth-dose distribution from the treatment planning system (TPS) and to compare the simulated dose-mean lineal energy to the experimental results., Results: For a 180 MeV/u 14 N pristine BP, the dose-mean lineal energy yD¯ obtained with two types of silicon microdosimeters started from approximately 29 keV/μm at the entrance to 92 keV/μm at the BP, with a maximum value in the range of 412 to 438 keV/μm at the distal edge. For 400 MeV/u 16 O ions, the dose-mean lineal energy yD¯ started from about 24 keV/μm at the entrance to 106 keV/μm at the BP, with a maximum value of approximately 381 keV/μm at the distal edge. The maximum derived RBE 10 values for 14 N and 16 O ions were found to be 3.10 ± 0.47 and 2.93 ± 0.45, respectively. Silicon microdosimetry measurements using pencilbeam scanning 12 C ions were also compared to the passive scattering beam., Conclusions: These SOI microdosimeters with well-defined three-dimensional (3D) SVs have applicability in characterizing heavy ion radiation fields and measuring lineal energy deposition with sub-millimeter spatial resolution. It has been shown that the dose-mean lineal energy increased significantly at the distal part of the BP and SOBP due to very high LET particles. Good agreement was observed for the experimental and simulation results obtained with silicon microdosimeters in 14 N and 16 O ion beams, confirming the potential application of SOI microdosimeter with 3D SV for quality assurance in charged particle therapy., (© 2018 American Association of Physicists in Medicine.)

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.)

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.

Purpose: Successful results in carbon-ion and proton radiotherapies can extend patients' lives and thus present a treatment option for younger patients; however, the undesired exposure to normal tissues outside the treatment volume is a concern. Organ-specific information on the absorbed dose and the biological effectiveness in the patient is essential for assessing the risk, but experimental dose assessment has seldom been done. In this study, absorbed doses, quality factors, and dose equivalents in water phantom outside of the irradiation field were determined based on lineal energy distributions measured with a commercial tissue equivalent proportional counter (TEPC) at passive carbon-ion and proton radiotherapy facilities., Methods: Measurements at eight positions in the water phantom were carried out at the Heavy-Ion Medical Accelerator in Chiba of the National Institute of Radiological Sciences for 400 and 290 MeV/u carbon beams and at the National Cancer Center Hospital East for a 235 MeV proton beam., Results: The dose equivalent per treatment absorbed dose at the center of the range-modulated region H/Dt, decreased as the position became farther from the beam axis and farther from the phantom surface. The values of H/Dt ranged from 6.7 to 0.16 mSv/Gy for the 400 MeV/u carbon beam, from 1.3 to 0.055 mSv/Gy for the 290 MeV/u carbon beam, and from 4.7 to 0.24 mSv/GV for the 235 MeV proton beam. The values of the dose-averaged quality factor QD ranged from 2.4 to 4.6 for the 400 MeV/u beam, from 2.8 to 5.3 for the 290 MeV/u beam, and from 5.1 to 8.2 for the proton beam. The authors also observed differences in the distributions of H/Dt and QD between the carbon and proton beams., Conclusions: The authors experimentally obtained absorbed doses, dose-averaged quality factors, and dose equivalents in water phantom outside of the irradiation field in passive carbon-ion and proton radiotherapies with TEPC. These data are very useful for estimating the risk of secondary cancer after receiving passive radiotherapies and for verifying Monte Carlo calculations.

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.

Secondary neutron ambient dose equivalents per the treatment absorbed dose in passive carbon-ion and proton radiotherapies were measured using a rem meter, WENDI-II at two carbon-ion radiotherapy facilities and four proton radiotherapy facilities in Japan. Our measured results showed that (1) neutron ambient dose equivalent in carbon-ion radiotherapy is lower than that in proton radiotherapy, and (2) the difference to the measured neutron ambient dose equivalents among the facilities is within a factor of 3 depending on the operational beam setting used at the facility and the arrangement of the beam line, regardless of the method for making a laterally uniform irradiation field: the double scattering method or the single-ring wobbling method. The reoptimization of the beam line in passive particle radiotherapy is an effective way to reduce the risk of secondary cancer because installing an adjustable precollimator and designing the beam line devices with consideration of their material, thickness and location, etc., can significantly reduce the neutron exposure. It was also found that the neutron ambient dose equivalent in passive particle radiotherapy is equal to or less than that in the photon radiotherapy. This result means that not only scanning particle radiotherapy but also passive particle radiotherapy can provide reduced exposure to normal tissues around the target volume without an accompanied increase in total body dose.

In carbon therapy, doses at center of spread-out Bragg peaks depend on field size. For a small field of 5 x 5 cm2, the central dose reduces to 96% of the central dose for the open field in case of 400 MeV/n carbon beam. Assuming the broad beam injected to the water phantom is made up of many pencil beams, the transverse dose distribution can be reconstructed by summing the dose distribution of the pencil beams. We estimated dose profiles of this pencil beam through measurements of dose distributions of broad uniform beams blocked half of the irradiation fields. The dose at a distance of a few cm from the edge of the irradiation field reaches up to a few percent of the central dose. From radiation quality measurements of this penumbra, the large-angle scattered particles were found to be secondary fragments which have lower LET than primary carbon beams. Carbon ions break up in beam modifying devices or in water phantom through nuclear interaction with target nuclei. The angular distributions of these fragmented nuclei are much broader than those of primary carbon particles. The transverse dose distribution of the pencil beam can be approximated by a function of the three-Gaussian form. For a simplest case of mono-energetic beam, contributions of the Gaussian components which have large mean deviations become larger as the depth in the water phantom increases.