Clinical consequences of relative biological effectiveness variations in proton radiotherapy of the prostate, brain and liver

Proton relative biological effectiveness (RBE) is known to depend on the (alpha/beta)(x) of irradiated tissues, with evidence of similar to 60% variation over (alpha/beta)(x) values from 1-10 Gy. The range of (alpha/beta)(x) values reported for prostate tumors (1.2-5.0 Gy), brain tumors (10-15 Gy) and liver tumors (13-17 Gy) imply that the proton RBE for these tissues could vary significantly compared to the commonly used generic value of 1.1. Our aim is to evaluate the impact of this uncertainty on the proton dose in Gy(RBE) absorbed in normal and tumor tissues. This evaluation was performed for standard and hypofractionated regimens. RBE-weighted total dose (RWTD) distributions for 15 patients (five prostate tumors, five brain tumors and five liver tumors) were calculated using an in-house developed RBE model as a function of dose, dose-averaged linear energy transfer (LETd) and (alpha/beta)(x). Variations of the dose-volume histograms (DVHs) for the gross tumor volume (GTV) and the organs at risk due to changes of (alpha/beta)(x) and fractionation regimen were calculated and the RWTD received by 10% and 90% of the organ volume reported. The goodness of the plan, bearing the uncertainties, was then evaluated compared to the delivered plan, which considers a constant RBE of 1.1. For standard fractionated regimens, the prostate tumors, liver tumors and all critical structures in the brain showed typically larger RBE values than 1.1. However, in hypofractionated regimens lower values of RBE than 1.1 were observed in most cases. Based on DVH analysis we found that the RBE variations were clinically significant in particular for the prostate GTV and the critical structures in the brain. Despite the uncertainties in the biological input parameters when estimating RBE values, the results show that the use of a variable RBE with dose, LETd and (alpha/beta)(x) could help to further optimize the target dose in proton treatment planning. Most importantly, this study shows that the consideration of RBE variations could influence the comparison of proton and photon treatments in clinical trials, in particular in the case of the prostate

Radiobiological studies with monoenergetic neutrons

The Radiological Research Accelerator Facility (RARAF) has the capability of producing essentially monoenergetic neutron beams, ranging in energy from 16.4 MeV down to 220 keV. In addition, two lower energy neutron beams are available which consist of a wide spectrum of energies and are described as the 110 keV and 60 keV spectra. Seedlings of Vicia faba have been used to measure the oxygen enhancement ratio (OER) and the relative biological effectiveness (RBE) of each of these neutron beams. The OER decreases as the neutron energy is reduced between 15.4 MeV and 220 keV, but does not appear to decrease further for lower energy neutrons. RBE increases as the neutron energy is reduced from 15.4 AleV to 440 keV; the curve then goes through a maximum at around 350 keV, and for lower energies the RBE falls again

Inter-patient variations in relative biological efectiveness for craniospinal irradiation with protons

Cranio-spinal irradiation (CSI) using protons has dosimetric advantages compared to photons and is expected to reduce risk of adverse effects. The proton relative biological effectiveness (RBE) varies with linear energy transfer (LET), tissue type and dose, but a variable RBE has not replaced the constant RBE of 1.1 in clinical treatment planning. We examined inter-patient variations in RBE for ten proton CSI patients. Variable RBE models were used to obtain RBE and RBE-weighted doses. RBE was quantified in terms of dose weighted organ-mean RBE (RBEd = mean RBE-weighted dose/mean physical dose) and effective RBE of the near maximum dose (D2%), i.e. RBED2% = D2%,RBE/D2%,phys, where subscripts RBE and phys indicate that the D2% is calculated based on an RBE model and the physical dose, respectively. Compared to the median RBEd of the patient population, differences up to 15% were observed for the individual RBEd values found for the thyroid, while more modest variations were seen for the heart (6%), lungs (2%) and brainstem (<1%). Large inter-patient variation in RBE could be correlated to large spread in LET and dose for these organs at risk (OARs). For OARs with small inter-patient variations, the results show that applying a population based RBE in treatment planning may be a step forward compared to using RBE of 1.1. OARs with large inter-patient RBE variations should ideally be selected for patient-specific biological or RBE robustness analysis if the physical doses are close to known dose thresholds.publishedVersio

Chemical structure matching using correlation matrix memories

This paper describes the application of the Relaxation By Elimination (RBE) method to matching the 3D structure of molecules in chemical databases within the frame work of binary correlation matrix memories. The paper illustrates that, when combined with distributed representations, the method maps well onto these networks, allowing high performance implementation in parallel systems. It outlines the motivation, the neural architecture, the RBE method and presents some results of matching small molecules against a database of 100,000 models

Evaluation of Relative Biological Effectiveness for Proton Therapy

Proton therapy for treating cancer patients has been evolved to become a highly desired choice of radiation therapy due to the physical characteristic of protons. Currently, the biologic effectiveness of protons relative to photons is considered to be a constant ratio of 1.1. However, experiments show that the RBE is higher in different portions in proton ranges. Since the usage of a constant RBE is justified based on experiments conducted using older methods of dose delivery, the re-evaluation of using a constant RBE and proposing models for determining RBE values is necessary now that recent experimental results, using new actively scanned beam delivery method, are available and suggest deviations from conventional data. To suggest a method for calculating RBE values, an experiment by Guan et al. is chosen to derive biologic response results with respect to proton beams. A widely used phenomenological RBE model by Wilkens and Oeflke is chosen for comparison purposes. The proposed RBE model is based on Wilkens and Oeflke model with revisions on tissue parameters behavior vs. LET based on Guan et al results. Three RBE models including the constant RBE, Wilkens' model and the suggested model based on Guan’s experiment are compared for three brain cancer patient cases. The comparisons are demonstrated using cumulative RBE weighted dose volume histograms. The sensitivity of models to tissue parameter changes are also analyzed. The suggested model shows escalated variable RBE weighted dose compared to constant RBE weighted dose, and it is sensitive to RBE model parameters in all three patient studies.Industrial Engineering, Department o

The Organ Sparing Potential of Different Biological Optimization Strategies in Proton Therapy

Purpose Variable relative biological effectiveness (RBE) models allow for differences in linear energy transfer (LET), physical dose, and tissue type to be accounted for when quantifying and optimizing the biological damage of protons. These models are complex and fraught with uncertainties, and therefore, simpler RBE optimization strategies have also been suggested. Our aim was to compare several biological optimization strategies for proton therapy by evaluating their performance in different clinical cases. Methods and Materials Two different optimization strategies were compared: full variable RBE optimization and differential RBE optimization, which involve applying fixed RBE for the planning target volume (PTV) and variable RBE in organs at risk (OARs). The optimization strategies were coupled to 2 variable RBE models and 1 LET-weighted dose model, with performance demonstrated on 3 different clinical cases: brain, head and neck, and prostate tumors. Results In cases with low in the tumor, the full RBE optimization strategies had a large effect, with up to 10% reduction in RBE-weighted dose to the PTV and OARs compared with the reference plan, whereas smaller variations (<5%) were obtained with differential optimization. For tumors with high the differential RBE optimization strategy showed a greater reduction in RBE-weighted dose to the OARs compared with the reference plan and the full RBE optimization strategy. Conclusions Differences between the optimization strategies varied across the studied cases, influenced by both biological and physical parameters. Whereas full RBE optimization showed greater OAR sparing, awareness of underdosage to the target must be carefully considered.publishedVersio