Clinical Relative Biological Effectiveness Research Articles

A systematic analysis of the particle irradiation data ensemble in the key of the microdosimetric kinetic model: Should clonogenic data be used for clinical relative biological effectiveness?

PurposeTo perform a systematic analysis of the Particle Irradiation Data Ensemble (PIDE) database for clonogenic survival assays in the context of the Microdosimetric Kinetic Model (MKM). Methods and materialOur study used data from the PIDE database containing data on various cell lines and radiation types. Two main parameters of the MKM were determined experiment-wise: the domain radius, which accounts for the increase of the linear parameter as a function of LET or lineal energy, and the nucleus radius, which accounts for the overkilling effect at LET high enough. We used experiments with LET less and more than 75 keV/μm to determine domain and nucleus radius, respectively. Experiments with cells in asynchronous phase of the cell cycle and monoenergetic beams were considered, and data from 294 out of 461 available experiments with protons, alpha, and carbon beams were used. ResultsDomain and nucleus radii were determined for 32 cell lines as the median among cell-specific experiments after filtering experiments using protons, α-particles, and carbon ions, including 28 human cells and 12 rodent cells. The median values found for domain radii were 380 nm for normal human cells, 390 nm for tumor human cells, 295 nm for normal rodent cells, and 525 nm for tumor rodent cells (only one experiment with rodent tumor cells) with large variability across cell lines and across experiments on each cell line. ConclusionsLarge inter-experiment variabilities were found for the same cell lines, based on enormous experimental uncertainties and different experimental conditions. Our analysis raises questions about how convenient is to use clonogenic data to feed RBE models to be utilized in the clinical practice in particle therapy.

Data-driven ion-independent relative biological effectiveness modeling using the beam quality Q

Beam quality Q = Z2/E (Z = ion charge, E = energy), an alternative to the conventionally used linear energy transfer (LET), enables ion-independent modeling of the relative biological effectiveness (RBE) of ions. Therefore, the Q concept, i.e. different ions with similar Q have similar RBE values, could help to transfer clinical RBE knowledge from better-studied ion types (e.g. carbon) to other ions. However, the validity of the Q concept has so far only been demonstrated for low LET values. In this work, the Q concept was explored in a broad LET range, including the so-called overkilling region. The particle irradiation data ensemble (PIDE) was used as experimental in vitro dataset. Data-driven models, i.e. neural network (NN) models with low complexity, were built to predict RBE values for H, He, C and Ne ions at different in vitro endpoints taking different combinations of clinically available candidate inputs: LET, Q and linear-quadratic photon parameter α x/β x. Models were compared in terms of prediction power and ion dependence. The optimal model was compared to published model data using the local effect model (LEM IV). The NN models performed best for the prediction of RBE at reference photon doses between 2 and 4 Gy or RBE near 10% cell survival, using only α x/β x and Q instead of LET as input. The Q model was not significantly ion dependent (p > 0.5) and its prediction power was comparable to that of LEM IV. In conclusion, the validity of the Q concept was demonstrated in a clinically relevant LET range including overkilling. A data-driven Q model was proposed and observed to have an RBE prediction power comparable to a mechanistic model regardless of particle type. The Q concept provides the possibility of reducing RBE uncertainty in treatment planning for protons and ions in the future by transferring clinical RBE knowledge between ions.

Creation, evolution, and future challenges of ion beam therapy from a medical physicist’s viewpoint (Part 2). Chapter 2. Biophysical model, treatment planning system and image guided radiotherapy

When an ion beam penetrates deeply into the body, its kinetic energy decreases, and its biological effect increases due to the change of the beam quality. To give a uniform biological effect to the target, it is necessary to reduce the absorbed dose with the depth. A bio-physical model estimating the relationship between ion beam quality and biological effect is necessary to determine the relative biological effectiveness (RBE) of the ion beam that changes with depth. For this reason, Lawrence Berkeley Laboratory, National Institute of Radiological Sciences (NIRS) and GSI have each developed their own model at the starting of the ion beam therapy. Also, NIRS developed a new model at the starting of the scanning irradiation. Although the Local Effect Model (LEM) at the GSI and the modified Microdosimetric Kinetic Model (MKM) at the NIRS, the both are currently used, can similarly predict radiation quality-induced changes in surviving fraction of cultured cell, the clinical RBE-weighted doses for the same absorbed dose are different. This is because the LEM uses X-rays as a reference for clinical RBE, whereas the modified MKM uses carbon ion beam as a reference and multiplies it by a clinical factor of 2.41. Therefore, both are converted through the absorbed dose. In PART 2, I will describe the development of such a bio-physical model, as well as the birth and evolution of a treatment planning system and image guided radiotherapy.

The clinical relative biological effectiveness and prostate-specific antigen kinetics of carbon-ion radiotherapy in low-risk prostate cancer.

To evaluate the clinical relative biological effectiveness (RBE) of carbon-ion radiotherapy (C-ion RT) for prostate cancer. The records of 262 patients with low-risk prostate cancer (median age, 65 [47-80] years) treated with C-ion RT at QST Hospital, National Institutes for Quantum Science and Technology in Japan during 2000-2018 were reviewed retrospectively. Four different protocol outcomes and prostate-specific antigen (PSA) responses were evaluated. The median follow-up was 8.4 years. The Kaplan-Meier method was used to estimate the biochemical or clinical failure-free rate (BCFFR). Clinical RBE was calculated using the tumor control probability model. The 5-, 7-, and 10-year BCFFRs were 91.7%, 83.8%, and 73.2%, respectively. The 10-year BCFFRs of patients who received C-ion RT at 66 Gy (RBE) in 20 fractions, 63 Gy (RBE) in 20 fractions, and 57.6Gy (RBE) in 16 fractions were 81.4%, 70.9%, and 68.9%, respectively. The PSA level and density during follow-up were better in the patients treated with the lower fraction size. A higher PSA nadir and shorter time to PSA nadir were risk factors for biochemical or clinical failure by multivariate Cox regression. The tumor control probability analysis showed that the estimated clinical RBE values to achieve an 80% BCFFR at 10 years for 20, 16, and 12 fractions were 2.19 (2.18-2.24), 2.16 (2.14-2.23), and 2.12 (2.09-2.21), respectively. Using clinical data from low-risk prostate cancer patients, we showed the clinical RBE of C-ion RT decreased with increasing dose per fraction.

An ion-independent phenomenological relative biological effectiveness (RBE) model for proton therapy

BackgroundA relative biological effectiveness (RBE) of 1.1 is used for proton therapy though clinical evidence of varying RBE was raised. Clinical studies on RBE variability have been conducted for decades for carbon radiation, which could advance the understanding of the clinical proton RBE given an ion-independent RBE model. In this work, such a model, linear and simple, using the beam quantity Q = Z2/E (Z = ion charge, E = kinetic energy per nucleon) was tested and compared to the commonly used, proton-specific and linear energy transfer (LET) based Wedenberg RBE model. Material and methodsThe Wedenberg and Q models, both predicting RBEmax and RBEmin (i.e., RBE at vanishing and very high dose, respectively), are compared in terms of ion-dependence and prediction power. An experimental in-vitro data ensemble covering 115 publications for various ions was used as dataset. ResultsThe model parameter of the Q model was observed to be similar for different ions (in contrast to LET). The Q model was trained without any prior knowledge of proton data. For proton RBE, the differences between experimental data and corresponding predictions of the Wedenberg or the Q model were highly comparable. ConclusionsA simple linear RBE model using Q instead of LET was proposed and tested to be able to predict proton RBE using model parameter trained based on only RBE data of other particles in a clinical proton energy range for a large in-vitro dataset. Adding (pre)clinical knowledge from carbon ion therapy may, therefore, reduce the dominating biological uncertainty in proton RBE modelling. This would translate in reduced RBE related uncertainty in proton therapy treatment planning.

The RBE in ion beam radiotherapy: In vivo studies and clinical application

Ion beams used for radiotherapy exhibit an increased relative biological effectiveness (RBE), which depends on several physical treatment parameters as well as on biological factors of the irradiated tissues. While the RBE is an experimentally well-defined quantity, translation to patients is complex and requires radiobiological studies, dedicated models to calculate the RBE in treatment planning as well as strategies for dose prescription. Preclinical in vivo studies and analysis of clinical outcome are important to validate and refine RBE-models. This review describes the concept of the experimental and clinical RBE and explains the fundamental dependencies of the RBE based on in vitro experiments. The available preclinical in vivo studies on normal tissue and tumor RBE for ions heavier than protons are reviewed in the context of the historical and present development of ion beam radiotherapy. In addition, the role of in vivo RBE-values in the development and benchmarking of RBE-models as well as the transition of these models to clinical application are described. Finally, limitations in the translation of experimental RBE-values into clinical application and the direction of future research are discussed.

RBE variation in prostate carcinoma cells in active scanning proton beams: In-vitro measurements in comparison with phenomenological models.

In-vitro radiobiological studies are essential for modelling the relative biological effectiveness (RBE) in proton therapy. The purpose of this study was to experimentally determine the RBE values in proton beams along the beam path for human prostate carcinoma cells (Du-145). RBE-dose and RBE-LETd (dose-averaged linear energy transfer) dependencies were investigated and three phenomenological RBE models, i.e. McNamara, Rørvik and Wilkens were benchmarked for this cell line. Cells were placed at multiple positions along the beam path, employing an in-house developed solid phantom. The experimental setup reflected the clinical prostate treatment scenario in terms of field size, depth, and required proton energies (127.2-180.1MeV) and the physical doses from 0.5 to 6Gy were delivered. The reference irradiation was performed with 200kV X-ray beams. Respective (α/β) values were determined using the linear quadratic model and LETd was derived from the treatment planning system at the exact location of cells. Independent of the cell survival level, all experimental RBE values were consistently higher in the target than the generic clinical RBE value of 1.1; with the lowest RBE value of 1.28 obtained at the beginning of the SOBP. A systematic RBE decrease with increasing dose was observed for the investigated dose range. The RBE values from all three applied models were considerably smaller than the experimental values. A clear increase of experimental RBE values with LETd parameter suggests that proton LET must be taken into consideration for this low (α/β) tissue.

A Monte Carlo based radiation response modelling framework to assess variability of clinical RBE in proton therapy

The clinical implementation of a variable relative biological effectiveness (RBE) in proton therapy is currently controversially discussed. Initial clinical evidence indicates a variable proton RBE, which needs to be verified. In this study, a radiation response modelling framework for assessing clinical RBE variability is established. It was applied to four selected glioma patients (grade III) treated with adjuvant radio(chemo)therapy and who developed late morphological image changes on T1-weighted contrast-enhanced (T1w-CE) magnetic resonance (MR) images within approximately two years of recurrence-free follow-up. The image changes were correlated voxelwise with dose and linear energy transfer (LET) values using univariable and multivariable logistic regression analysis. The regression models were evaluated by the area-under-the-curve (AUC) method performing a leave-one-out cross validation. The tolerance dose TD50 at which 50% of patient voxels experienced toxicity was interpolated from the models. A Monte Carlo (MC) model was developed to simulate dose and LET distributions, which includes variance reduction (VR) techniques to decrease computation time. Its reliability and accuracy were evaluated based on dose calculations of the clinical treatment planning system (TPS) as well as absolute dose measurements performed in the patient specific quality assurance.Morphological image changes were related to a combination of dose and LET. The multivariable models revealed cross-validated AUC values of up to 0.88. The interpolated TD50 curves decreased with increasing LET indicating an increase in biological effectiveness. The MC model reliably predicted average TPS dose within the clinical target volume as well as absolute water phantom dose measurements within 2% accuracy using dedicated VR settings.The observed correlation of dose and LET with late brain tissue damage suggests considering RBE variability for predicting chronic radiation-induced brain toxicities. The MC model simulates radiation fields in patients precisely and time-efficiently. Hence, this study encourages and enables in-depth patient evaluation to assess the variability of clinical proton RBE.

Report of the AAPM TG-256 on the relative biological effectiveness of proton beams in radiation therapy.

The biological effectiveness of proton beams relative to photon beams in radiation therapy has been taken to be 1.1 throughout the history of proton therapy. While potentially appropriate as an average value, actual relative biological effectiveness (RBE) values may differ. This Task Group report outlines the basic concepts of RBE as well as the biophysical interpretation and mathematical concepts. The current knowledge on RBE variations is reviewed and discussed in the context of the current clinical use of RBE and the clinical relevance of RBE variations (with respect to physical as well as biological parameters). The following task group aims were designed to guide the current clinical practice: Assess whether the current clinical practice of using a constant RBE for protons should be revised or maintained. Identifying sites and treatment strategies where variable RBE might be utilized for a clinical benefit. Assess the potential clinical consequences of delivering biologically weighted proton doses based on variable RBE and/or LET models implemented in treatment planning systems. Recommend experiments needed to improve our current understanding of the relationships among invitro, invivo, and clinical RBE, and the research required to develop models. Develop recommendations to minimize the effects of uncertainties associated with proton RBE for well-defined tumor types and critical structures.

Modeling in vivo relative biological effectiveness in particle therapy for clinically relevant endpoints

Background: The relative biological effectiveness (RBE) of particle therapy compared to photon radiotherapy is known to be variable but the exact dependencies are still subject to debate. In vitro data suggested that RBE is to a large extend independent of ion type if parametrized by the beam quality Q. This study analyzed the RBE dependence of pre-clinical data on late toxicity with an emphasis on the beam quality.Material and methods: Published pre-clinical RBE dose-response data of the spinal cord following one and two fractions of photon and carbon ion irradiation were compiled. The beam quality for each treatment condition was obtained from Monte Carlo simulations. The αp and βp parameters of the linear-quadratic (LQ) model for particle irradiation were determined from the pre-clinical data and was provided as a function of Q. An introduced model proposed αp to increase linearly with Q and βp to remain constant. RBE values predicted by the model were compared to the published data.Results: The αp parameter was highly correlated with Q (R2 = 0.96) with a linear slope of 0.019 Gy−1. No significant variation of βp with Q was found. RBE and Q were also highly correlated (R2 = 0.98) for one and two fractions. The (extrapolated) RBE at Q = 0 (theoretical photon limit) for one and two fractions was 1.22 and significantly larger than 1 (p = .004). The model reproduced the dependence of RBE on fractionation well.Conclusions: Fraction dose and beam quality Q were sufficient to describe the RBE variability for a late toxicity model within a carbon ion treatment field. Assuming the independence of the identified RBE parameters on the ion type might suggest the translation of variable (pre-) clinical RBE data from carbon ion to proton therapy.

Modelling the radiobiological effect of intraoperative X-ray brachytherapy for breast cancer using an air-filled spherical applicator.

PurposeWe present a framework, in which we compare a conventional standard dose of 50 Gy in 25 fractions with accelerated partial breast irradiation (APBI) using electronic brachytherapy (eBT). We discuss how radiobiological modelling enables us to establish a framework, within which we can compare external beam radiotherapy (EBRT). This leads to a determination of the shell of isoeffect in breast tissue, at which very low kV eBT can be considered to be clinically equivalent to standard EBRT.Material and methodsTo estimate relative biological effectiveness (RBE) values as a function of dose and irradiation time, we used a modified linear quadratic (LQ) approach, taking into account the ability of this new device, to deliver 20 Gy at the surface of a 40 mm diameter rigid, hollow spherical applicator in less than 2 minutes. In this study, we considered the radiobiological effectiveness of the Papillon +™ X-ray brachytherapy device operating at 30 kV, 0.3 mA producing dose rates in excess of 14 Gy/min.ResultsCalculated clinical RBEs ranged from 1.154 at the surface of a 40 mm diameter applicator to 1.100 at 35 mm from the applicator surface for the Papillon+ device. The absolute physical dose D (abs) 30 kV ranged from 20.00 Gy at the applicator surface to 1.20 at 35 mm distant. The product of the isoeffective single dose of 60Co reference radiation – (RBE)60Co, and the RBE corrected standard 2 Gy equivalent dose fractions (EQD2) doses, EQD2(30 kV) * (RBE)60Co ranged from 98.62 Gy at the applicator surface to 1.13 at 35 mm. The ‘shell of isoeffect’, the value on the X-axis where the EQD2(30 kV) * (RBE)60Co line crosses the 50 Gy mark on the Y-axis, was found to be approximately 3.5 mm beyond the applicator surface.ConclusionsThe ‘shell of isoeffect’ can serve as a useful metric with which to compare the radiobiological effectiveness of low kV eBT with various regimes of conventional EBRT.

Fifteen symposia on microdosimetry: implications for modern particle-beam cancer radiotherapy.

The objective of microdosimetry was, and still is, to identify physical descriptions of the initial physical processes of ionising radiation interacting with biological matter which correlate with observed radiobiological effects with a view to improve the understanding of radiobiological mechanisms and effects. The introduction of therapy with particles starting with fast neutrons followed by negative pions, protons and light ions necessitated the application of biological weighting factors for absorbed dose in order to account for differences of the relative biological effectiveness (RBE). Dedicated radiobiological experiments in therapy beams with mammalian cells and with laboratory animals provided sets of RBE values which are used to evaluate empirical 'clinical RBE values'. The combination of such experiments with microdosimetric measurements in identical conditions offered the possibility to establish semi-empirical relationships between microdosimetric parameters and results of RBE studies.

Radiobiological intercomparison of the 160 MeV and 230 MeV proton therapy beams at the Harvard Cyclotron Laboratory and at Massachusetts General Hospital.

The purpose of this study was to determine the relative biological effectiveness (RBE) along the axis of two range-modulated proton beams (160 and 230 MeV). Both the depth and the dose dependence of RBE were investigated. Chinese hamster V79-WNRE cells, suspended in medium containing gelatin and cooled to 2 °C, were used to obtain complete survival curves at multiple positions throughout the entrance and 10 cm spread-out Bragg peak (SOBP). Simultaneous measurements of the survival response to (60)Co gamma rays served as the reference data for the proton RBE determinations. For both beams the RBE increased significantly with depth in the 10 cm SOBP, particularly in the distal half of the SOBP, then rose even more sharply at the distal edge, the most distal position measured. At a 4 Gy dose of gamma radiation (S = 0.34) the average RBE values for the entrance, proximal half, distal half and distal edge were 1.07 ± 0.01, 1.10 ± 0.01, 1.17 ± 0.01 and 1.21 ± 0.01, respectively, and essentially the same for both beams. At a 2 Gy dose of gamma radiation (S = 0.71) the average RBE values rose to 1.13 ± 0.03, 1.15 ± 0.02, 1.26 ± 0.02 and 1.30 ± 0.02, respectively, for the same four regions of the SOBP. The difference between the 4 Gy and 2 Gy RBE values reflects the dose dependence of RBE as measured in these V79-WNRE cells, which have a low α/β value, as do other widely used cell lines that also show dose-dependent RBE values. Late-responding tissues are also characterized by low α/β values, so it is possible that these cell lines may be predictive for the response of such tissues (e.g., spinal cord, optic nerve, kidney, liver, lung). However, in the very small number of studies of late-responding tissues performed to date there appears to be no evidence of an increased RBE for protons at low doses. Similarly, RBE measurements using early responding in vivo systems (mostly mouse jejunum, an early-responding tissue which has a large α/β ∼ 10 Gy) have generally shown little or no detectable dose dependence. It is useful to compare the RBE values reported here to the commonly used generic clinical RBE of 1.1, which assumes no dependence on depth or on dose. Our proximal RBEs obviously avoid the depth-related increase in RBE and for doses of 4 Gy or more, the low-dose increase in RBE is also minimized, as shown in this article. Thus the proximal RBE at a 4 Gy dose of 1.10 ± 0.01, quoted above, represents an interesting point of congruence with the clinical RBE for conditions where it could reasonably be expected in the measurements reported here. The depth dependence of RBE reported here is consistent with the majority of measurements, both in vitro and in vivo, by other investigators. The dose dependence of RBE, on the other hand, is tissue specific but has not yet been demonstrated for protons by RBE values in late-responding normal tissue systems. This indicates a need for additional RBE determination as function of dose, especially in late-responding tissues.

TU‐A‐BRE‐01: The Relative Biological Effectiveness of Proton Beams Relative to Photon Beams

Proton therapy patients receive a 10% lower physical dose than the dose administered using photons, i.e. the proton relative biological effectiveness (RBE) is 1.1 in comparison to high‐energy photons. The use of a generic, spatially invariant RBE within tumor targets and normal tissue structures disregards a large body of evidence indicating that proton RBE tends to increase with increasing linear energy transfer (LET). Because the doseaveraged proton LET in the distal edge of a spread out Bragg peak (SOBP) is larger than the LET in the plateau region or proximal edge of a SOBP, the use of a spatially invariant RBE is not well justified from a mechanistic point of view. On the other hand, the available clinical data on local tumor control rates and early or late side effects do not provide strong evidence against the continued use of a constant and spatially invariant clinical RBE. The only potential downside to the ongoing use of a constant RBE of 1.1 seems to be that we are missing a potential opportunity to enhance the therapeutic ratio, i.e., design proton therapy treatments in ways that exploit, rather than mitigate, spatial variations in proton RBE. Speakers in this symposium will:1‐review the laboratory and clinical evidence for and against the continued use of a spatially invariant RBE of 1.1,2‐examine some of the putative mechanisms connecting spatial variations in particle LET to estimates of the proton RBE at the molecular, cellular and tissue levels3‐assess the possible clinical significance of incorporating models for spatial variations in proton RBE into treatment planning systems.4‐discuss treatment planning and delivery techniques that will exploit the spatial variations of RBE within proton beams.Learning Objectives: To review laboratory and clinical evidence for and against the continued use of a constant RBE of 1.1 To understand major mechanisms connecting proton LET to RBE at the molecular, cellular and tissue levels. To quantify the potential opportunities and potential pitfalls of neglecting spatial variations in proton RBE in treatment plans To understand the minimum requirements required to design proton treatment plans that benefit from a spatially changing RBE and discuss some of the technological challenges they may require.

Lineal energy and radiation quality in radiation therapy: model calculations and comparison with experiment

Microdosimetry is a recommended method for characterizing radiation quality in situations when the biological effectiveness under test is not well known. In such situations, the radiation beams are described by their lineal energy probability distributions. Results from radiobiological investigations in the beams are then used to establish response functions that relate the lineal energy to the relative biological effectiveness (RBE). In this paper we present the influence of the size of the simulated volume on the relation to the clinical RBE values (or weighting factors). A single event probability distribution of the lineal energy is approximated by its dose average lineal energy () which can be measured or calculated for volumes from a few micrometres down to a few nanometres. The clinical RBE values were approximated as the ratio of the α-values derived from the LQ-relation. Model calculations are presented and discussed for the SOBP of a 12C ion (290 MeV u−1) and the reference 60Co γ therapy beam. Results were compared with those for a conventional x-ray therapy beam, a 290 MeV proton beam and a neutron therapy beam. It is concluded that for a simulated volume of about 10 nm, the α-ratio increases approximately linearly with the -ratio for all the investigated beams. The correlation between y and α provides the evidence to characterize a radiation therapy beam by the lineal energy when, for instance, weighting factors are to be estimated.

Fractionation effects in particle radiotherapy: implications for hypo-fractionation regimes

The aim is to demonstrate the potential impact of changes in the value of the β parameter in the linear quadratic (LQ) model on the calculation of clinical relative biological effectiveness (RBE) values used for high linear energy transfer (LET) radiotherapy. The parameter RBEmin is introduced into the LQ formulation to account for possible changes in the β radiosensitivity coefficient with changing LET. The model is used to fit fractionated data under two conditions, where RBEmin = 1 and RBEmin ≠ 1. Nonlinear regression and analysis of variance are used to test the hypothesis that the inclusion of a non-unity value of RBEmin better predicts the total iso-effective dose required at low number of fractions for fast neutrons, carbon ions, π-meson and proton fractionation data obtained for various tissues from previous publications. For neutrons the assumption of RBEmin ≠ 1 provided a better fit in 89% of the cases, whereas for carbon ions RBEmin ≠ 1 provided a better fit only for normal tissue at the spread-out Bragg peak. The results provide evidence of the impact that variations in the β parameter may have when calculating clinically relevant RBE values, especially when using high doses per fraction (i.e. hypofractionation) of high-LET radiations.

The relative biological effectiveness of proton and ion beams

The understanding of the biological effectiveness of proton and ion beams plays an important role in two very different scientific fields: radiotherapy and space research. Due to the many similarities of both types of radiation, the question is addressed, if the experience gained in radiotherapy with proton and ion beams is of relevance for the assessment of risks due to galactic radiation in manned space flight. The basic characteristics of the relative biological effectiveness (RBE) of proton and ion beams is reviewed, including the dependence on particle type, LET and dose as well as on biological systems and end points. The relevance of these factors for risk assessment in space flight is outlined. The concept of clinical RBE is reviewed and the RBE database gained in vivo is briefly outlined. Emphasis is put here on the most important endpoint for radiation protection, which is carcinogenesis. The database for risk assessment due to galactic cosmic rays is nearly completely based on animal experiments conducted at ion beam therapy facilities. The data especially for carcinogenesis due to heavy ions are very scarce and the estimation of risk factors is connected to large uncertainties. The database gained by the clinical application of ion beams is still too limited to draw any direct conclusion for space research. This may change in the next decade due to the increasing patient numbers that will be treated in the new ion beam facilities. Until relevant data for late effects (esp. carcinogenesis) become available from an analysis of patients treated at ion beam facilities, animal experiments seem to be the only reasonable way to obtain more accurate and systematic data which are needed for a reduction of the uncertainties in the assessment of risks due to galactic cosmic rays in space flight.

Specification of Carbon Ion Dose at the National Institute of Radiological Sciences (NIRS)

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

A simple track structure model of ion beam radiotherapy

A simple radiotherapy ion beam calculation based on the cellular track structure model, using in vitro cell survival parameters fitted from recent experimental data, is presented. The calculation represents a single-fraction ion exposure (roughly corresponding to a 2 Gy fraction of megavolt X rays) and exploits concepts used in clinical radiotherapy, such as entrance, or 'skin' ion dose. The depth distribution of cells surviving their irradiation by a beam of 385 MeV amu(-1) carbon ions is calculated over the range of the stopping ions, as a sequence of track-segments, in the continuous slowing-down approximation. An interpretation of the 'clinical relative biological effectiveness' concept is suggested.

Proton RBE for early intestinal tolerance in mice after fractionated irradiation

Background and purpose: To determine the influence of the number of fractions (or the dose per fraction) on the proton relative biological effectiveness (RBE). Materials and methods: Intestinal crypt regeneration in mice was used as the biological endpoint. RBE was determined relative to cobalt-60 gamma rays for irradiations in one, three and ten fractions separated by a time interval of 3.5 h. Proton irradiations were performed at the middle of a 7-cm Spread Out Bragg Peak (SOBP). Results: Proton RBEs (and corresponding gamma dose per fraction) at the level of 20 regenerated crypts per circumference were found equal to 1.15±0.04 (10.0 Gy), 1.15±0.05 (4.8 Gy) and 1.14±0.07 (1.7 Gy) for irradiations in one, three and ten fractions, respectively. Alpha/beta ratios as derived from direct analysis of the ‘quantal radiation response data’ were found to be 7.6 Gy for gamma rays and 8.2 Gy for protons. Additional proton irradiations in ten fractions at the end of the SOBP were found to be more effective than at the middle of the SOBP by a factor of 1.14 (1.05–1.23). Conclusion: Proton RBE for crypt regeneration was found to be independent of fractionation up to ten fractions. One can expect that it remains unchanged for higher number of fractions as the lethalities for doses smaller than 3 Gy are exclusively due to direct lethal events. As a tendency for increased effectiveness at the end of the SOBP is reported in the majority of the studies, for clinical applications it would be advisable to allow for by arranging a sloping depth dose curve in the deeper part of the target volume. Finally, it must be noticed that most of in vitro and in vivo RBE values for protons are larger than the current clinical RBE (RBE=1.10).