Relative biological effectiveness of single and split helium ion doses in the rat spinal cord increases strongly with linear energy transfer.

BACKGROUND AND PURPOSE: Determination of the relative biological effectiveness (RBE) of helium ions as a function of linear energy transfer (LET) for single and split doses using the rat cervical spinal cord as model system for late-responding normal tissue. MATERIAL AND METHODS: The rat cervical spinal cord was irradiated at four different positions within a 6 cm spread-out Bragg-peak (SOBP) (LET 2.9, 9.4, 14.4 and 20.7 keV/µm) using increasing levels of single or split doses of helium ions. Dose-response curves were determined and based on TD50-values (dose at 50% effect probability using paresis II as endpoint), RBE-values were derived for the endpoint of radiation-induced myelopathy. RESULTS: With increasing LET, RBE-values increased from 1.13 ± 0.04 to 1.42 ± 0.05 (single dose) and 1.12 ± 0.03 to 1.50 ± 0.04 (split doses) as TD50-values decreased from 21.7 ± 0.3 Gy to 17.3 ± 0.3 Gy (single dose) and 30.6 ± 0.3 Gy to 22.9 ± 0.3 Gy (split doses), respectively. RBE-models (LEM I and IV, mMKM) deviated differently for single and split doses but described the RBE variation in the high-LET region sufficiently accurate. CONCLUSION: This study established the LET-dependence of the RBE for late effects in the central nervous system after single and split doses of helium ions. The results extend the existing database for protons and carbon ions and allow systematic testing of RBE-models. While the RBE-values of helium were generally lower than for carbon ions, the increase at the distal edge of the Bragg-peak was larger than for protons, making detailed RBE-modeling necessary.

Fractionated carbon ion irradiations of the rat spinal cord: comparison of the relative biological effectiveness with predictions of the local effect model.

BACKGROUND: To determine the relative biological effectiveness (RBE) and α/ß-values after fractionated carbon ion irradiations of the rat spinal cord with varying linear energy transfer (LET) to benchmark RBE-model calculations. MATERIAL AND METHODS: The rat spinal cord was irradiated with 6 fractions of carbon ions at 6 positions within a 6 cm spread-out Bragg-peak (SOBP, LET: 16-99 keV/µm). TD50-values (dose at 50% complication probability) were determined from dose-response curves for the endpoint radiation induced myelopathy (paresis grade II) within 300 days after irradiation. Based on TD50-values of 15 MV photons, RBE-values were calculated and adding previously published data, the LET and fractional dose-dependence of the RBE was used to benchmark the local effect model (LEM I and IV). RESULTS: At six fractions, TD50-values decreased from 39.1 ± 0.4 Gy at 16 keV/µm to 17.5 ± 0.3 Gy at 99 keV/µm and the RBE increased accordingly from 1.46 ± 0.05 to 3.26 ± 0.13. Experimental α/ß-ratios ranged from 6.9 ± 1.1 Gy to 44.3 ± 7.2 Gy and increased strongly with LET. Including all available data, comparison with model-predictions revealed that (i) LEM IV agrees better in the SOBP, while LEM I fits better in the entrance region, (ii) LEM IV describes the slope of the RBE within the SOBP better than LEM I, and (iii) in contrast to the strong LET-dependence, the RBE-deviations depend only weakly on fractionation within the measured range. CONCLUSIONS: This study extends the available RBE data base to significantly lower fractional doses and performes detailed tests of the RBE-models LEM I and IV. In this comparison, LEM IV agrees better with the experimental data in the SOBP than LEM I. While this could support a model replacement in treatment planning, careful dosimetric analysis is required for the individual patient to evaluate potential clinical consequences.

Is the dose-averaged LET a reliable predictor for the relative biological effectiveness?

PURPOSE: The dose-averaged linear energy transfer (LETD ) is frequently used as representative quantity for the biological effectiveness of a radiation field. Moreover, relative biological effectiveness (RBE) values measured or calculated in mixed radiation fields are typically plotted vs the LETD . In this study, we will investigate whether the LETD is an appropriate quantity to describe the RBE of any mixed radiation field of protons and heavier ions and discuss potential limitations. METHODS: To study the reliability of LETD , we investigate model predictions of RBE in monoenergetic beams under track segment conditions and pristine Bragg peaks as well as spread out Bragg peaks (SOBP) in water. Both, the pristine Bragg peaks and the SOBPs are regarded as mixed radiation fields in this analysis, that is, they are characterized by a certain width of the energy spectrum of the projectile, although the underlying energy distribution is much broader in the case of an SOBP as compared to a pristine peak. For both cases, the corresponding RBE values are compared to those of strictly monoenergetic particles under track segment conditions, characterized by a single LET value. For the planning we use the treatment planning software TRiP98 together with the Local Effect Model to predict the RBE of protons, helium, and carbon ions. We further compare our model predictions for protons with a simplistic linear RBE-LET relationship representative for the phenomenological models in literature. RESULTS: Regarding pristine Bragg peaks in water, the deviations in RBE compared to monoenergetic particles under track segment conditions for the same LET value are low (mostly 0-5%), except for the distal fall-off region. The situation changes in SOBPs for which we found deviations in the order of up to 25% for the lighter particles and even more pronounced deviations for heavier particles like carbon ions. CONCLUSIONS: The analysis showed that LETD is a sufficiently accurate predictor for RBE only in regions with comparably narrow, but not in regions with broad, LET distribution as in a single SOBP or in multiple overlapping fields. The deviations are caused by the nonlinearity of the RBE(LET) relationship in the case of track segment conditions. Thus, independent of the underlying RBE model and the particle type regarded, as long as the RBE(LET) relationship deviates from being purely linear, LETD is not a good predictor for RBE, and especially for heavier particles like carbon ions knowledge of the underlying LET distribution is mandatory to describe the RBE in mixed radiation fields.

Late normal tissue response in the rat spinal cord after carbon ion irradiation.

BACKGROUND: The present work summarizes the research activities on radiation-induced late effects in the rat spinal cord carried out within the "clinical research group ion beam therapy" funded by the German Research Foundation (DFG, KFO 214). METHODS AND MATERIALS: Dose-response curves for the endpoint radiation-induced myelopathy were determined at 6 different positions (LET 16-99 keV/µm) within a 6 cm spread-out Bragg peak using either 1, 2 or 6 fractions of carbon ions. Based on the tolerance dose TD50 of carbon ions and photons, the relative biological effectiveness (RBE) was determined and compared with predictions of the local effect model (LEM I and IV). Within a longitudinal magnetic resonance imaging (MRI)-based study the temporal development of radiation-induced changes in the spinal cord was characterized. To test the protective potential of the ACE (angiotensin converting enzyme)-inhibitor ramipril™, an additional dose-response experiment was performed. RESULTS: The RBE-values increased with LET and the increase was found to be larger for smaller fractional doses. Benchmarking the RBE-values as predicted by LEM I and LEM IV with the measured data revealed that LEM IV is more accurate in the high-LET, while LEM I is more accurate in the low-LET region. Characterization of the temporal development of radiation-induced changes with MRI demonstrated a shorter latency time for carbon ions, reflected on the histological level by an increased vessel perforation after carbon ion as compared to photon irradiations. For the ACE-inhibitor ramipril™, a mitigative rather than protective effect was found. CONCLUSIONS: This comprehensive study established a large and consistent RBE data base for late effects in the rat spinal cord after carbon ion irradiation which will be further extended in ongoing studies. Using MRI, an extensive characterization of the temporal development of radiation-induced alterations was obtained. The reduced latency time for carbon ions is expected to originate from a dynamic interaction of various complex pathological processes. A dominant observation after carbon ion irradiation was an increase in vessel perforation preferentially in the white matter. To enable a targeted pharmacological intervention more details of the molecular pathways, responsible for the development of radiation-induced myelopathy are required.

Systematics of relative biological effectiveness measurements for proton radiation along the spread out Bragg peak: experimental validation of the local effect model.

The purpose of this study is to compare the predictions of the local effect model (LEM) in an extensive analysis to proton relative biological effectiveness (RBE) experiments found in the literature, and demonstrate the capabilities of the model as well as to discuss potential limitations. 19 publications with in vitro experiments and 10 publications with in vivo experiments focusing on proton RBE along the spread out Bragg peak (SOBP) were considered. In total the RBE values of over 100 depth positions were compared to LEM predictions. The treatment planning software TRiP98 was used to reconstruct the proton depth dose profile, and, together with the physical dose distribution, the RBE prediction was conducted based on the LEM. Only parameters from photon dose response curves are used as input for the LEM, and no free parameters are introduced, thus allowing us to demonstrate the predictive power of the LEM for protons. The LEM describes the RBE adequately well within the SOBP region with a relative deviation of typically less than 10% up to 10 keV µm-1. In accordance with previous publications a clear dependence of RBE on the dose-averaged linear energy transfer (LETD) was observed. The RBE in the experiments tends to increase above 1.1 for LETD values above 2 keV µm-1 and above 1.5 for LETD values higher than 10 keV µm-1 (distal part of the SOBP). The dose dependence is most pronounced for doses lower than 3 Gy (RBE). However, both the LEM predictions and experimental data show only a weak dependence of RBE on the tissue type, as characterized by the α/ß ratio, which is considered insignificant with regard to the general uncertainties of RBE. The RBE predicted by the LEM shows overall very good agreement with the experimental data within the SOBP region and is in better agreement with the experimental data than the constant RBE of 1.1 that is currently applied in the clinics. All RBE trends deduced from the experiments were also reflected by the LEM predictions, which are purely based on input parameters derived from low-LET photon radiation.

Split dose carbon ion irradiation of the rat spinal cord: Dependence of the relative biological effectiveness on dose and linear energy transfer.

PURPOSE: To measure the relative biological effectiveness (RBE) of carbon ions relative to 15 MeV photons in the rat spinal cord for different linear energy transfers (LET) to validate model calculations. METHODS AND MATERIALS: The cervical spinal cord of rats was irradiated with 2 fractions of carbon ions at six positions of a 6 cm spread-out Bragg-peak (SOBP, 16-99 keV/µm). TD50-values (dose at 50% complication probability) were determined from dose-response curves for the endpoint radiation induced myelopathy (paresis grade II) within 300 days after irradiation. Using previously published TD50-values for photons (Karger et al., 2006; Debus et al., 2003), RBE-values were determined and compared with predictions of two versions of the local effect model (LEM I and IV). RESULTS: TD50-values for paresis grade II were 26.7 ± 0.4 Gy (16 keV/µm), 24.0 ± 0.3 Gy (21 keV/µm), 22.5 ± 0.3 Gy (36 keV/µm), 20.1 ± 1.2 Gy (45 keV/µm), 17.7 ± 0.3 Gy (66 keV/µm), and 14.9 ± 0.3 Gy (99 keV/µm). RBE-values increased from 1.28 ± 0.03 (16 keV/µm) up to 2.30 ± 0.06 at 99 keV/µm. At the applied high fractional doses, LEM I fits best at 16 keV/µm and deviates progressively toward higher LETs while LEM IV agrees best at 99 keV/µm and shows increasing deviations, especially below 66 keV/µm. CONCLUSIONS: The measured data improve the knowledge on the accuracy of RBE-calculations for carbon ions.

Assessment of potential advantages of relevant ions for particle therapy: a model based study.

PURPOSE: Different ion types offer different physical and biological advantages for therapeutic applications. The purpose of this work is to assess the advantages of the most commonly used ions in particle therapy, i.e., carbon ((12)C), helium ((4)He), and protons ((1)H) for different treatment scenarios. METHODS: A treatment planning analysis based on idealized target geometries was performed using the treatment planning software TRiP98. For the prediction of the relative biological effectiveness (RBE) that is required for biological optimization in treatment planning the local effect model (LEM IV) was used. To compare the three ion types, the peak-to-entrance ratio (PER) was determined for the physical dose (PERPHY S), the RBE (PERRBE), and the RBE-weighted dose (PERBIO) resulting for different dose-levels, field configurations, and tissue types. Further, the dose contribution to artificial organs at risk (OAR) was assessed and a comparison of the dose distribution for the different ion types was performed for a patient with chordoma of the skull base. RESULTS: The study showed that the advantages of the ions depend on the physical and biological properties and the interplay of both. In the case of protons, the consideration of a variable RBE instead of the clinically applied generic RBE of 1.1 indicates an advantage in terms of an increased PERRBE for the analyzed configurations. Due to the fact that protons show a somewhat better PERPHY S compared to helium and carbon ions whereas helium shows a higher PERRBE compared to protons, both protons and helium ions show a similar RBE-weighted dose distribution. Carbon ions show the largest variation of the PERRBE with tissue type and a benefit for radioresistant tumor types due to their higher LET. Furthermore, in the case of a two-field irradiation, an additional gain in terms of PERBIO is observed when using an orthogonal field configuration for carbon ions as compared to opposing fields. In contrast, for protons, the PERBIO is almost independent on the field configuration. Concerning the artificial lateral OAR, the volume receiving 20% of the prescribed RBE-weighted dose (V20) was reduced by over 35% using helium ions and by over 40% using carbon ions compared to protons. The analysis of the patient plan showed that protons, helium, and carbon ions are similar in terms of target coverage whereas the dose to the surrounding tissue is increasing from carbon ions toward protons. The mean dose to the brain stem can be reduced by more than 55% when using helium ions and by further 25% when using carbon ions instead of protons. CONCLUSIONS: The comparison of the PERRBE and PERPHY S of the three ion types suggests a strong dependence of the advantages of the three ions on the dose-level, tissue type, and field configuration. In terms of conformity, i.e., dose to the normal tissue, a clear gain is expected using carbon or helium ions compared to protons.

Physical and biological factors determining the effective proton range.

PURPOSE: Proton radiotherapy is rapidly becoming a standard treatment option for cancer. However, even though experimental data show an increase of the relative biological effectiveness (RBE) with depth, particularly at the distal end of the treatment field, a generic RBE of 1.1 is currently used in proton radiotherapy. This discrepancy might affect the effective penetration depth of the proton beam and thus the dose to the surrounding tissue and organs at risk. The purpose of this study was thus to analyze the impact of a tissue and dose dependent RBE of protons on the effective range of the proton beam in comparison to the range based on a generic RBE of 1.1. METHODS: Factors influencing the biologically effective proton range were systematically analyzed by means of treatment planning studies using the Local Effect Model (LEM IV) and the treatment planning software TRiP98. Special emphasis was put on the comparison of passive and active range modulation techniques. RESULTS: Beam energy, tissue type, and dose level significantly affected the biological extension of the treatment field at the distal edge. Up to 4 mm increased penetration depth as compared to the depth based on a constant RBE of 1.1. The extension of the biologically effective range strongly depends on the initial proton energy used for the most distal layer of the field and correlates with the width of the distal penumbra. Thus, the range extension, in general, was more pronounced for passive as compared to active range modulation systems, whereas the maximum RBE was higher for active systems. CONCLUSIONS: The analysis showed that the physical characteristics of the proton beam in terms of the width of the distal penumbra have a great impact on the RBE gradient and thus also the biologically effective penetration depth of the beam.

Mapping of RBE-weighted doses between HIMAC- and LEM-Based treatment planning systems for carbon ion therapy.

PURPOSE: A method was developed to convert clinically prescribed RBE (Relative Biological Effectiveness)-weighted doses from the approach used at the Heavy-Ion Medical Accelerator (HIMAC) at the National Institute of Radiological Science, Chiba, Japan, to the LEM (Local Effect Model)-based TReatment planning for Particles (TRiP98) approach used in the pilot project at the GSI Helmholtzzentrum, Darmstadt, and the Heidelberg Ion-Beam Therapy Center (HIT). METHODS AND MATERIALS: The proposed conversion method is based on a simulation of the fixed spread-out Bragg peak (SOBP) depth dose profiles as used for the irradiation at HIMAC by LEM/TRiP98 and a recalculation of the resulting RBE-weighted dose distribution. We present data according to the clinical studies conducted at GSI in the past decade (LEM I), as well as data used in current studies (refined LEM version: LEM IV). RESULTS: We found conversion factors (RBE-weighted dose LEM/RBE-weighted dose HIMAC) reaching from 0.4 to 2.0 for prescribed carbon ion doses from 1 to 60 Gy (RBE) for SOBP extensions ranging from 20 to 120 mm according to the HIMAC approach. A conversion factor of 1.0 was found for approximately 5 Gy (RBE). The conversion factor decreases with increasing prescribed dose. Slightly smaller values for the LEM IV-based data set compared with LEM I were found. A significant dependence of the conversion factor from the SOBP width could be observed in particular for LEM IV, whereas the depth dependence was found to be small. CONCLUSIONS: For the interpretation and comparison of clinical trials performed at HIMAC and GSI/HIT, it is of extreme importance to consider these conversion factors because according to the various methods to determine the RBE-weighted dose, similar dose values might not necessarily be related to similar clinical outcomes.