Increase In Relative Biological Effectiveness Research Articles

Induction of Chromosomal Aberrations after Exposure to the Auger Electron Emitter Iodine-125, the β--emitter Tritium and Cesium-137 γ rays.

High-LET-type cell survival curves have been observed in cells that were allowed to incorporate 125I-UdR into their DNA. Incorporation of tritiated thymidine into the DNA of cells has also been shown to result in an increase in relative biological effectiveness in cell survival experiments, but the increase is smaller than observed after incorporation of 125I-UdR. These findings are explained in the literature by the overall complexity of the induced DNA damage resulting from energies of the ejected electron(s) during the decay of 3H and 125I. Chromosomal aberrations (CA) are defined as morphological or structural changes of one or more chromosomes, and can be induced by ionizing radiation. Whether the number of CA is associated with the linear energy transfer (LET) of the radiation and/or the actual complexity of the induced DNA double-strand breaks (DSB) remains elusive. In this study, we investigated whether DNA lesions induced at different cell cycle stages and by different radiation types [Auger-electrons (125I), β- particles (3H), or γ radiation (137Cs)] have an impact on the number of CA induced after induction of the same number of DSB as determined by the γ-H2AX foci assay. Cells were synchronized and pulse-labeled in S phase with low activities of 125I-UdR or tritiated thymidine. For decay accumulation, cells were cryopreserved either after pulse-labeling in S phase or after progression to G2/M or G1 phase. Experiments with γ irradiation (137Cs) were performed with synchronized and cryopreserved cells in S, G2/M or G1 phase. After thawing, a CA assay was performed. All experiments were performed after a similar number of DSB were induced. CA induction after 125I-UdR was incorporated was 2.9-fold and 1.7-fold greater compared to exposure to γ radiation and radiation from incorporated tritiated thymidine, respectively, when measured in G2/M cells. In addition, measurement of CA in G2/M cells after incorporation of 125I-UdR was 2.5-fold greater when compared to cells in G1 phase. In contrast, no differences were observed between the three radiation qualities with respect to exposure after cryopreservation in S or G1 phase. The data indicate that the 3D organization of replicated DNA in G2/M cells seems to be more sensitive to induction of more complex DNA lesions compared to the DNA architecture in S or G1 cells. Whether this is due to the DNA organization itself or differences in DNA repair capability remains unclear.

Biological Characterization of the Effects of Filtration on the Xoft Axxent® Electronic Brachytherapy Source for Cervical Cancer Applications.

Low-energy X-ray sources that operate in the kilovoltage energy range have been shown to induce more cellular damage when compared to their megavoltage counterparts. However, low-energy X-ray sources are more susceptible to the effects of filtration on the beam spectrum. This work sought to characterize the biological effects of the Xoft Axxent® source, a low-energy therapeutic X-ray source, both with and without the titanium vaginal applicator in place. It was hypothesized that there would be an increase in relative biological effectiveness (RBE) of the Axxent® source compared to 60Co and that the source in the titanium vaginal applicator (SIA) would have decreased biological effects compared to the bare source (BS). This hypothesis was drawn from linear energy transfer (LET) simulations performed using the TOPAS Monte Carlo user code as well a reduction in dose rate of the SIA compared to the BS. A HeLa cell line was maintained and used to evaluate these effects. Clonogenic survival assays were performed to evaluate differences in the RBE between the BS and SIA using 60Co as the reference beam quality. Neutral comet assay was used to assess induction of DNA strand damage by each beam to estimate differences in RBE. Quantification of mitotic errors was used to evaluate differences in chromosomal instability (CIN) induced by the three beam qualities. The BS was responsible for the greatest quantity of cell death due to a greater number of DNA double strand breaks (DSB) and CIN observed in the cells. The differences observed in the BS and SIA surviving fractions and RBE values were consistent with the 13% difference in LET as well as the factor of 3.5 reduction in dose rate of the SIA. Results from the comet and CIN assays were consistent with these results as well. The use of the titanium applicator results in a reduction in the biological effects observed with these sources, but still provides an advantage over megavoltage beam qualities. © 2023 by Radiation Research Society.

Microdosimetry of a therapeutic proton beam with a mini-TEPC and a MicroPlus-Bridge detector for RBE assessment

Proton beams are widely used worldwide to treat localized tumours, the lower entrance dose and no exit dose, thus sparing surrounding normal tissues, being the main advantage of this treatment modality compared to conventional photon techniques. Clinical proton beam therapy treatment planning is based on the use of a general relative biological effectiveness (RBE) of 1.1 along the whole beam penetration depth, without taking into account the documented increase in RBE at the end of the depth dose profile, in the Bragg peak and beyond. However, an inaccurate estimation of the RBE can cause both underdose or overdose, in particular it can cause the unfavourable situation of underdosing the tumour and overdosing the normal tissue just beyond the tumour, which limits the treatment success and increases the risk of complications. In view of a more precise dose delivery that takes into account the variation of RBE, experimental microdosimetry offers valuable tools for the quality assurance of LET or RBE-based treatment planning systems. The purpose of this work is to compare the response of two different microdosimetry systems: the mini-TEPC and the MicroPlus-Bridge detector. Microdosimetric spectra were measured across the 62 MeV spread out Bragg peak of CATANA with the mini-TEPC and with the Bridge microdosimeter. The frequency and dose distributions of lineal energy were compared and the different contributions to the spectra were analysed, discussing the effects of different site sizes and chord length distributions. The shape of the lineal energy distributions measured with the two detectors are markedly different, due to the different water-equivalent sizes of the sensitive volumes: 0.85 μm for the TEPC and 17.3 μm for the silicon detector. When the Loncol’s biological weighting function is applied to calculate the microdosimetric assessment of the RBE, both detectors lead to results that are consistent with biological survival data for glioma U87 cells. Both the mini-TEPC and the MicroPlus-Bridge detector can be used to assess the RBE variation of a 62 MeV modulated proton beam along its penetration depth. The microdosimetric assessment of the RBE based on the Loncol’s weighting function is in good agreement with radiobiological results when the 10% biological uncertainty is taken into account.

Clinical Radiobiology of Fast Neutron Therapy: What Was Learnt?

Neutron therapy was developed from neutron radiobiology experiments, and had identified a higher cell kill per unit dose and an accompanying reduction in oxygen dependency. But experts such as Hal Gray were sceptical about clinical applications, for good reasons. Gray knew that the increase in relative biological effectiveness (RBE) with dose fall-off could produce marked clinical limitations. After many years of research, this treatment did not produce the expected gains in tumour control relative to normal tissue toxicity, as predicted by Gray. More detailed reasons for this are discussed in this paper. Neutrons do not have Bragg peaks and so did not selectively spare many tissues from radiation exposure; the constant neutron RBE tumour prescription values did not represent the probable higher RBE values in late-reacting tissues with low α/β values; the inevitable increase in RBE as dose falls along a beam would also contribute to greater toxicity than in a similar megavoltage photon beam. Some tissues such as the central nervous system white matter had the highest RBEs partly because of the higher percentage hydrogen content in lipid-containing molecules. All the above factors contributed to disappointing clinical results found in a series of randomised controlled studies at many treatment centres, although at the time they were performed, neutron therapy was in a catch-up phase with photon-based treatments. Their findings are summarised along with their technical aspects and fractionation choices. Better understanding of fast neutron experiments and therapy has been gained through relatively simple mathematical models—using the biological effective dose concept and incorporating the RBEmax and RBEmin parameters (the limits of RBE at low and high dose, respectively—as shown in the Appendix). The RBE itself can then vary between these limits according to the dose per fraction used. These approaches provide useful insights into the problems that can occur in proton and ion beam therapy and how they may be optimised. This is because neutron ionisations in living tissues are mainly caused by recoil protons of energy proportional to the neutron energy: these are close to the proton energies that occur close to the Bragg peak region. To some extent, neutron RBE studies contain the highest RBE ranges found within proton and ion beams near Bragg peaks. In retrospect, neutrons were a useful radiobiological tool that has continued to inform the scientific and clinical community about the essential radiobiological principles of all forms of high linear energy transfer therapy. Neutron radiobiology and its implications should be taught on training courses and studied closely by clinicians, physicists, and biologists engaged in particle beam therapies.

Radiation Track Structure: How the Spatial Distribution of Energy Deposition Drives Biological Response

Ionising radiation is incredibly effective at causing biological effects. This is due to the unique way energy is deposited along highly structured tracks of ionisation and excitation events, which results in correlation with sites of DNA damage from the nanometre to the micrometre scale. Correlation of these events along the track on the nanometre scale results in clustered damage, which not only results in the formation of DNA double-strand breaks (DSB), but also more difficult to repair complex DSB, which include additional damage within a few base pairs. The track structure varies significantly with radiation quality and the increase in relative biological effectiveness observed with increasing linear energy transfer in part corresponds to an increase in the probability and complexity of clustered DNA damage produced. Likewise, correlation over larger scales, associated with packing of DNA and associated chromosomes within the cell nucleus, can also have a major impact on the biological response. The proximity of the correlated damage along the track increases the probability of miss-repair through pairwise interactions resulting in an increase in probability and complexity of DNA fragments/deletions, mutations and chromosomal rearrangements. Understanding the mechanisms underlying the biological effectiveness of ionising radiation can provide an important insight into ways of increasing the efficacy of radiotherapy, as well as the risks associated with exposure. This requires a multi-scale approach for modelling, not only considering the physics of the track structure from the millimetre scale down to the nanometre scale, but also the structural packing of the DNA within the nucleus, the resulting chemistry in the context of the highly reactive environment of the nucleus, together with the subsequent biological response.

Brain Necrosis in Adult Proton Therapy Patients. Do Necrotic Regions Have Elevated Linear Energy Transfer?

To investigate if brain necrosis induction correlates with regions of high linear energy transfer (LET) for proton radiation therapy treatments with partial brain involvement for central nervous system (CNS) and head and neck (H&N) patients. Fifty patients irradiated between 2004-2016 with CT image changes indicative of brain necrosis after irradiation were collected. For each patient, the necrotic region was contoured using MRI imaging. To obtain the LET distributions in the patients, treatment plans were recalculated using Monte Carlo simulations with TOPAS version 3.0.1. For each patient, voxels in the necrotic region were dose-matched with randomly selected voxels in the non-necrotic region of the brain and analyzed for a correlation of LET and occurrence of necrosis. In addition, a simplified relative biological effectiveness (RBE) model assuming a linear increase of RBE with LET was applied. A multilevel mixed-effects logistic regression was used to assess the impact of LET, dose, and tumor site on voxel-based necrosis. The probability of voxel necrosis was statistically significantly associated with increasing dose (p<0.0001) and tumor site (i.e., for the same dose H&N voxels are significantly more likely than CNS voxels to develop necrosis, p<0.0001). The LET was not associated with necrosis when adjusted for dose and tumor site, p=0.7. However, there are significant differences between patients (I2 statistics = 99.4%, p<0.0001) with some patients having significantly higher mean LET values in the necrotic regions (e.g., average LET 5.0 keV/μm vs 3.4 keV/μm, p<0.0001) while others having no difference or even lower LET values in the necrotic regions (e.g., 3.3 keV/μm vs 3.7 keV/μm, p<0.0001). The average difference in LET for dose-matched voxels was less than 0.2 keV/μm for the CNS and H&N cohorts as well as the average over the entire patient cohort. Selecting only high dose voxels (> 50 Gy) or the hottest 20 or 100 voxels also did not reveal any correlation between LET and onset of necrosis. The largest difference in LET was 1.8 keV/μm. The average difference in RBE over the patient cohort was less than 0.5 Gy(RBE), however, 13 patients had over 1 Gy(RBE) higher biological dose in the necrotic region and two patients showed a difference of over 4 Gy(RBE). Overall, we did not find any evidence for higher LET in necrotic voxels compared to non-necrotic voxels with the same dose (p=0.7). The LET (or RBE) variation alone cannot explain the induction of brain necrosis and there are other risk factors that need to be accounted for. Nevertheless, for some patients, high LET regions correlated with the necrotic region. These patients may benefit from LET optimization.

Investigating Dependencies of Relative Biological Effectiveness for Proton Therapy in Cancer Cells.

Relative biological effectiveness (RBE) accounts for the differences in biological effect from different radiation types. The RBE for proton therapy remains uncertain, as it has been shown to vary from the clinically used value of 1.1. In this work we investigated the RBE of protons and correlated the biological differences with the underlying physical quantities. Three cell lines were irradiated (CHO, Chinese hamster ovary; A549, human lung adenocarcinoma; and T98, human glioma) and assessed for cell survival by using clonogenic assay. Cells were irradiated with 71- and 160-MeV protons at depths along the Bragg curve and 6-MV photons to various doses. The dose-averaged lineal energy ( ) was measured under similar conditions as the cells by using a microdosimeter. Dose-averaged linear energy transfer (LETd) was also calculated by using Monte Carlo (MC) simulations. Survival data were fit by using the linear quadratic model. The RBE values were calculated by comparing the physical dose (D6MV/Dp) that results in 50% (RBE0.5) and 10% (RBE0.1) cell survival, and survival after 2 Gy (RBE2Gy). Proton RBE values ranged from 0.89 to 2.40. The RBE for all 3 cell lines increased with decreasing proton energy and was higher at 50% survival than at 10% survival. Additionally, both A549 and T98 cells generally had higher RBE values relative to the CHO cells, indicating a greater biological response to protons. An increase in RBE corresponded with an increase in and LETd. Proton RBE was found to depend on mean proton energy, survival end point, and cell type. Changes in both and LETd were also found to impact proton RBE values, but consideration of the energy spectrum may provide additional information. The RBE values in this study vary greatly, indicating the clinical value of 1.1 may not be suitable in all cases.

Relating the proton relative biological effectiveness to tumor control and normal tissue complication probabilities assuming interpatient variability in α/β

Background: Proton therapy uses a constant relative biological effectiveness (RBE) of 1.1. The use of variable RBE values has been suggested but is currently not feasible due to uncertainties. The impact of variable RBE has solely been studied using dosimetric indices. This work elucidates the impact of RBE variations on tumor control and normal tissue complication probabilities (TCP/NTCP).Methods: Models to estimate TCP and NTCP were used in combination with an empirical proton RBE model. Variations in outcome as a function of linear-quadratic model parameters for cellular radiosensitivity were determined for TCP in prostate and ependymoma. In addition, NTCP analysis was done for brainstem necrosis.Results: Considering a variable proton RBE as a dose-modifying factor for prescription doses and dose constraints is misleading, as TCP/NTCP do not simply scale with RBE. The dependency of RBE on α/β cannot be interpreted independent of TCP/NTCP because variations in radiosensitivity affect both photon and proton treatments. Assuming interpatient variability in radiosensitivity results in lower TCP for patients with low α/β. In proton therapy, the magnitude of TCP variations is reduced due to an RBE increase as α/β decreases. The TCP in proton therapy is less affected by interpatient variability in α/β. On the other hand, patients with a lower α/β would have a lower complication probability, which is counteracted by an increase in RBE as α/β decreases. Toxicities in proton therapy would be more affected by α/β variations compared to photon therapy.Conclusions: Assessment of variable RBE in proton therapy should be based on TCP and NTCP. Potential interpatient variability in radiosensitivity causes a smaller variance in TCP but a larger variance in NTCP for proton patients. The relative TCP as a function of α/β was found to be higher than the RBE, whereas the relative NTCP was lower than a calculated RBE.

Gadolinium-based nanoparticles as sensitizing agents to carbon ions in head and neck tumor cells

Hadrontherapy presents the major advantage of improving tumor sterilization while sparing surrounding healthy tissues because of the particular ballistic (Bragg peak) of carbon ions. However, its efficacy is still limited in the most resistant cancers, such as grade III-IV head and neck squamous cell carcinoma (HNSCC), in which the association of carbon ions with gadolinium-based nanoparticles (AGuIX®) could be used as a Trojan horse. We report for the first time the radioenhancing effect of AGuIX® when combined with carbon ion irradiation in human tumor cells. An increase in relative biological effectiveness (1.7) in three HNSCC cell lines (SQ20B, FaDu, and Cal33) was associated with a significant reduction in the radiation dose needed for killing cells. Radiosensitization goes through a higher number of unrepaired DNA double-strand breaks. These results underline the strong potential of AGuIX® in sensitizing aggressive tumors to hadrontherapy and, therefore, improving local control while lowering acute/late toxicity.

Relative biological effectiveness for photons: implication of complex DNA double-strand breaks as critical lesions

Current knowledge in radiobiology ascribes the adverse biological effects of ionizing radiation primarily to the induction of DNA double-strand breaks (DSBs), which is supposed to be potentially lethal and may be converted to lethal damage due to misrepair. Soft and ultrasoft x-rays have been found to bear elevated biological effectiveness for cell killing compared with conventional x-rays or 60Co γ-rays. This phenomenon is qualitatively interpreted as the increased level of DSB induction for low energy photons, however, a thorough quantitative reasoning is lacking. Here, we systematically compared the relative biological effectiveness (RBE) with relative DSB induction for photons from several hundreds of eV up to MeV. Although there is an approximate two-fold increase in the yields of DSB for low energy photons found in our calculation and a large number of experimental measurements, it is far from enough to account for the three- to four-fold increase in RBE. Further theoretical investigations show that DSB complexity (additional single-strand breaks and base damage within 10 base pairs) increases notably for low energy photons, which largely reconciles the discrepancy between RBE and DSB induction. Our theoretical results are in line with accumulating experimental evidence that complex DSBs are refractory to repair machinery and may contribute predominantly to the formation of lethal damage.

The relative biological effectiveness of antiprotons

Background and purposeAside from the enhancement of physical dose deposited by antiprotons annihilating in tissue-like material compared to protons of the same range a further increase of biological effective dose has been demonstrated. This enhancement can be expressed in an increase of the relative biological effectiveness (RBE) of antiprotons near the end of range. We have performed the first-ever direct measurement of the RBE of antiprotons both at rest and in flight. Materials and methodsExperimental data were generated on the RBE of an antiproton beam entering a tissue-like target consisting of V79 cells embedded in gelatin with an energy providing a range of approximately 10cm. ResultsThe RBE in the entrance channel (the “plateau”) is only slightly above the value for a comparable proton beam, and remains low until the proximal edge of the spread-out Bragg peak (SOBP). A steep increase of RBE is seen starting from the onset of the SOBP. ConclusionsThis paper reports the final results of the experiment AD-4/ACE at CERN on the first-ever direct measurement of RBE of antiprotons and constitutes the first step toward developing treatment plans.

SU-F-T-682: In-Vivo Simulation of the Relative Biological Effectiveness in Proton Therapy Using a Monte Carlo Method

Purpose: In proton therapy, the relative biological effectiveness (RBE) – compared with conventional photon therapy – is routinely set to 1.1. However, experimental in vitro studies indicate evidence for the variability of the RBE. To clarify the impact on patient treatment, investigation of the RBE in a preclinical case study should be performed. Methods: The Monte Carlo software TOPAS was used to simulate the radiation field of an irradiation setup at the experimental beamline of the proton therapy facility (OncoRay) in Dresden, Germany. Simulations were performed on cone beam CT-data (CBCT) of a xenogeneous mouse with an orthotopic lung carcinoma obtained by an in-house developed small animal image-guided radiotherapy device. A homogeneous physical fraction dose of 1.8Gy was prescribed for the contoured tumor volume. Simulated dose and linear energy transfer distributions were used to estimate RBE values in the mouse based on an RBE model by Wedenberg et al. To characterize radiation sensitivity of normal and tumor tissue, α/β-ratios were taken from the literature for NB1RGB (10.1Gy) and human squamous lung cancer (6.2Gy) cell lines, respectively. Results: Good dose coverage of the target volume was achieved with a spread-out Bragg peak (SOBP). The contra-lateral lung was completely spared from receiving radiation. An increase in RBE towards the distal end of the SOBP from 1.07 to 1.35 and from 1.05 to 1.3 was observed when considering normal tissue and tumor, respectively, with the highest RBE values located distal to the target volume. Conclusion: Modeled RBE values simulated on CBCT for experimental preclinical proton therapy varied with tissue type and depth in a mouse and differed therefore from a constant value of 1.1. Further translational work will include, first, conducting preclinical experiments and, second, analogous RBE studies in patients using experimentally verified simulation settings for our clinically used patient-specific beam conforming technique.

Exponential Increase in Relative Biological Effectiveness Along Distal Edge of a Proton Bragg Peak as Measured by Deoxyribonucleic Acid Double-Strand Breaks

To quantify the relative biological effectiveness (RBE) of the distal edge of the proton Bragg peak, using an in vitro assay of DNA double-strand breaks (DSBs). U2OS cells were irradiated within the plateau of a spread-out Bragg peak and at each millimeter position along the distal edge using a custom slide holder, allowing for simultaneous measurement of physical dose. A reference radiation signal was generated using photons. The DNA DSBs at 3 hours (to assess for early damage) and at 24 hours (to assess for residual damage and repair) after irradiation were measured using the γH2AX assay and quantified via flow cytometry. Results were confirmed with clonogenic survival assays. A detailed map of the RBE as a function of depth along the Bragg peak was generated using γH2AX measurements as a biological endpoint. At 3 hours after irradiation, DNA DSBs were higher with protons at every point along the distal edge compared with samples irradiated with photons to similar doses. This effect was even more pronounced after 24 hours, indicating that the impact of DNA repair is less after proton irradiation relative to photons. The RBE demonstrated an exponential increase as a function of depth and was measured to be as high as 4.0 after 3 hours and as high as 6.0 after 24 hours. When the RBE-corrected dose was plotted as a function of depth, the peak effective dose was extended 2-3 mm beyond what would be expected with physical measurement. We generated a highly comprehensive map of the RBE of the distal edge of the Bragg peak, using a direct assay of DNA DSBs in vitro. Our data show that the RBE of the distal edge increases with depth and is significantly higher than previously reported estimates.

Protons, Photons, and the Prostate - Is There Emerging Evidence in the Ongoing Discussion on Particle Therapy for the Treatment of Prostate Cancer?

Proton therapy is actively and repeatedly discussed within the framework of particle therapy for the treatment of prostate cancer (PC). The argument in favor of treating the prostate with protons is partly financial: given that small volumes are treated, treatment times are low, resulting in a hypothetical high patient throughput. However, such considerations should not form the basis of medical decision-making. There are also physical and biological arguments which further support the use of particle therapy for PC. The only relevant randomized data currently available is the study by Zietman and colleagues, comparing a high to a low proton boost, resulting in a significant increase in PSA-free survival in the experimental (high dose) arm (1). With modern photon treatments and image-guided radiotherapy (IGRT), equally high doses can be applied with photons and, thus, a randomized trial comparing high-end photons to protons is warranted. For high-linear energy transfer (LET) particles, such as carbon ions, the increase in relative biological effectiveness could potentially convert into an improvement in outcome. Additionally, through the physical differences of protons and carbon ions, the steeper dose gradient with carbon ions and the lack of beam broadening in the carbon beam lead to a superior dose distribution supporting the idea of hypofractionation. Biological and clinical data are emerging, however, has practice-changing evidence already arrived?

Variation in RBE for Survival of V79-4 Cells as a Function of Alpha-Particle (Helium Ion) Energy

High linear energy transfer (LET) α particles are important with respect to the carcinogenic risk associated with human exposure to ionizing radiation, most notably to radon and its progeny. Additionally, the potential use of alpha-particle-emitting radionuclides in radiotherapy is increasingly being explored. Within the body the emitted alpha particles slow down, traversing a number of cells with a range of energies and therefore with varying efficiencies at inducing biological response. The LET of the particle typically rises from between ~70-90 keV μm(-1) at the start of the track (depending on initial energy) to a peak of ~237 keV μm(-1) towards the end of the track, before falling again at the very end of its range. To investigate the variation in biological response with incident energy, a plutonium-238 alpha-particle irradiator was calibrated to enable studies with incident energies ranging from 4.0 MeV down to 1.1 MeV. The variation in clonogenic survival of V79-4 cells was determined as a function of incident energy, along with the relative variation in the initial yields of DNA double-strand breaks (DSB) measured using the FAR assay. The clonogenic survival data also extends previously published data obtained at the Medical Research Council (MRC), Harwell using the same cells irradiated with helium ions, with energies ranging from 34.9 MeV to 5.85 MeV. These studies were performed in conjunction with cell morphology measurements on live cells enabling the determination of absorbed dose and calculation of the average LET in the cell. The results show an increase in relative biological effectiveness (RBE) for cell inactivation with decreasing helium ion energy (increasing LET), reaching a maximum for incident energies of ~3.2 MeV and corresponding average LET of 131 keV μm(-1), above which the RBE is observed to fall at lower energies (higher LETs). The effectiveness of single alpha-particle traversals (relevant to low-dose exposure) at inducing cell inactivation was observed to increase with decreasing energy to a peak of ~68% survival probability for incident energies of ~1.8 MeV (average LET of 190 keV μm(-1)) producing ~0.39 lethal lesions per track. However, the efficiency of a single traversal will also vary significantly with cell morphology and angle of incidence, as well as cell type.

SU‐F‐BRD‐13: A Phenomenological Relative Biological Effectiveness (RBE) Model for Proton Therapy Based On All Published in Vitro Cell Survival Data

Purpose:Proton therapy treatments are currently planned and delivered using the assumption that the proton relative biological effectiveness (RBE) relative to photons is 1.1. This assumption ignores strong experimental evidence that suggests the RBE varies. A recent review study (Paganetti 2014), collected over 72 experimental reports on proton RBE, providing a comprehensive dataset for predicting proton RBE. Using this dataset we develop a model to predict RBE based on dose, linear energy transfer (LET) and the tissue specific parameter (α/β)x.Methods:The relationship of the RBE on dose, dose average LET (LETd) and (α/β)x was explored using 290 experimental data points. The RBE was calculated for each experimental point for doses ranging from 1 to 10 Gy. An RBE model, based on the linear‐quadratic model, was derived using a nonlinear regression fit to the experimental data.Results:The proposed RBE model predicts that the RBE increases with LET and decreases with (α/β)x. The model additionally predicts a decrease in RBE with increasing dose for low (α/β)x values (&lt; 3 Gy). However the model predicts an increase in RBE with increasing dose for large (α/β)x (&gt; 4 Gy). Previous phenomenological models were based on a small subset of experimental data and deviate significantly from our findings.Conclusion:The proposed RBE model is derived using the most comprehensive collection of proton RBE experimental data to date. The model agrees with previous theoretical predictions on the relationship between RBE, LETd and (α/β)x and also makes predictions on the relationship between RBE and dose. The proposed model shows a relationship between α and LETd but no significant relationship between β and LETd. Previously published phenomenological models based on a limited data set might have to be revised.

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.

Range modulation in proton therapy planning: a simple method for mitigating effects of increased relative biological effectiveness at the end-of-range of clinical proton beams

BackgroundThe increase in relative biological effectiveness (RBE) of proton beams at the distal edge of the spread out Bragg peak (SOBP) is a well-known phenomenon that is difficult to quantify accurately in vivo. For purposes of treatment planning, disallowing the distal SOBP to fall within vulnerable tissues hampers sparing to the extent possible with proton beam therapy (PBT). We propose the distal RBE uncertainty may be straightforwardly mitigated with a technique we call “range modulation”. With range modulation, the distal falloff is smeared, reducing both the dose and average RBE over the terminal few millimeters of the SOBP.MethodsOne patient plan was selected to serve as an example for direct comparison of image-guided radiotherapy plans using non-range modulation PBT (NRMPBT), and range-modulation PBT (RMPBT). An additional plan using RMPBT was created to represent a re-treatment scenario (RMPBTrt) using a vertex beam. Planning statistics regarding dose, volume of the planning targets, and color images of the plans are shown.ResultsThe three plans generated for this patient reveal that in all cases dosimetric and device manufacturing advantages are able to be achieved using RMPBT. Organ at risk (OAR) doses to critical structures such as the cochleae, optic apparatus, hypothalamus, and temporal lobes can be selectively spared using this method. Concerns about the location of the RBE that did significantly impact beam selection and treatment planning no longer have the same impact on the process, allowing these structures to be spared dose and subsequent associated issues.ConclusionsThis present study has illustrated that RMPBT can improve OAR sparing while giving equivalent coverage to target volumes relative to traditional PBT methods while avoiding the increased RBE at the end of the beam. It has proven easy to design and implement and robust in our planning process. The method underscores the need to optimize treatment plans in PBT for both traditional energy dose in gray (Gy) and biologic dose (RBE).

RBE of kV CBCT radiation determined by Monte Carlo DNA damage simulations

Due to the higher LET of kilovoltage (kV) radiation, there is potential for an increase in relative biological effectiveness (RBE) of absorbed doses of radiation from kV cone beam computed tomography (CBCT) sources in reference to megavoltage or Co-60 doses. This work develops a method for accurately coupling a Monte Carlo (MC) radiation transport code (PENELOPE) with the damage simulation (MCDS) to predict relative numbers of DNA double strand breaks (DSBs). The MCDS accounts for slowing down of electrons and delta ray production within the cell nucleus; however, determining the spectrum of electrons incident on the cell nucleus from photons interacting in a larger region of tissue is not trivial. PENELOPE simulations were conducted with a novel tally algorithm invoked where electrons incident on a detection material were tracked and both the incident energy and the final deposited dose were recorded. The DSB yield predicted by a set of MCDS runs of monoenergetic electrons was then looked up in a table and weighted by the specific energy of the incident electron. Our results indicate that the RBE for DSB induction is 1.1 for diagnostic x-rays with energies from 80 to 125 kVp. We found no significant change in RBE with depth or filtration. The predicted absolute DSB yields are about three times lower for cells irradiated under anoxic conditions than the yield in cells irradiated under normoxic (5%) or fully aerobic (100%) conditions. However, oxygen concentration has a negligible (±0.02) effect on the RBE of kV CBCT x-rays.

In vitro studies on radiosensitization effect of glucose capped gold nanoparticles in photon and ion irradiation of HeLa cells

Noble metal nanoparticles are of great interest due to their potential applications in diagnostics and therapeutics. In the present work, we synthesized glucose capped gold nanoparticle (Glu-AuNP) for internalization in the HeLa cell line (human cervix cancer cells). The capping of glucose on Au nanoparticle was confirmed by Raman spectroscopy. The Glu-AuNP did not show any toxicity to the HeLa cell. The γ-radiation and carbon ion irradiation of HeLa cell with and without Glu-AuNP were performed to evaluate radiosensitization effects. The study revealed a significant reduction in radiation dose for killing the HeLa cells with internalized Glu-AuNPs as compared to the HeLa cells without Glu-AuNP. The Glu-AuNP treatment resulted in enhancement of radiation effect as evident from increase in relative biological effectiveness (RBE) values for carbon ion irradiated HeLa cells.