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Background and Purpose: Radiation-induced cancer is a serious late effect that may follow radiotherapy. A considerable uncertainty is associated with carcinogenesis from photon-based treatment, and even less established when including relative biological effectiveness (RBE) for particle therapy. The aim of this work was therefore to estimate and in particular explore relative risks (RR) of secondary cancer (SC) following particle therapy as applied in treatment of prostate cancer., Material and Methods: RRs of radiation-induced SC in the bladder and rectum were estimated using a bell-shaped dose-response model incorporating RBE and fractionation effects. The risks from volumetric modulated arc therapy (VMAT) were compared to intensity-modulated proton therapy (IMPT) and scanning carbon ions for ten patients., Results: The mean estimated RR (95% CI) of SC for VMAT/C-ion was 1.31 (0.65-2.18) for the bladder and 0.58 (0.41-0.80) for the rectum. Corresponding values for VMAT/IMPT were 1.72 (1.06-2.37) and 1.10 (0.78-1.43). The radio-sensitivity parameter α had the strongest influence on the results with decreasing RR for increasing values of α., Conclusion: Based on the wide spread in RR between patients and variations across the included parameter values, the risk profiles of the rectum and bladder were not dramatically different for the investigated radiotherapy techniques., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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.

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.

We investigated the applicability of the repairable-conditionally repairable (RCR) model and the multi-target (MT) model to dose conversion in high-dose-per-fraction radiotherapy in comparison with the linear-quadratic (LQ) model. Cell survival data of V79 and EMT6 single cells receiving single doses of 2-12 Gy or 2 or 3 fractions of 4 or 5 Gy each, and that of V79 spheroids receiving single doses of 5-26 Gy or 2-5 fractions of 5-12 Gy, were analyzed. Single and fractionated doses to actually reduce cell survival to the same level were determined by a colony assay. Single doses used in the experiments and surviving fractions at the doses were substituted into equations of the RCR, MT and LQ models in the calculation software Mathematica, and each parameter coefficient was computed. Thereafter, using the coefficients and the three models, equivalent single doses for the hypofractionated doses were calculated. They were then compared with actually-determined equivalent single doses for the hypofractionated doses. The equivalent single doses calculated using the RCR, MT and LQ models tended to be lower than the actually determined equivalent single doses. The LQ model seemed to fit relatively well at doses of 5 Gy or less. At 6 Gy or higher doses, the RCR and MT models seemed to be more reliable than the LQ model. In hypofractionated stereotactic radiotherapy, the LQ model should not be used, and conversion models incorporating the concept of the RCR or MT models, such as the generalized linear-quadratic models, appear to be more suitable.

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.

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.

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.

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.