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.

Proton beam electron return effect: Monte Carlo simulations and experimental verification.

Proton therapy (PT) is expected to benefit from integration with magnetic resonance (MR) imaging. However, the magnetic field distorts the dose distribution and enhances the dose at tissue-air interfaces by the electron return effect (ERE). The objectives were (a) to provide experimental evidence for the ERE in proton beams and (b) to systematically characterise the dependence of the dose enhancement ratio (DER) on magnetic field strength, orientation, proton energy and voxel size by computer simulations. EBT3 films were irradiated with 200 MeV protons with and without a 0.92 T transverse field of a permanent magnet to determine the DER at effective measurement depths of 0.156 and 0.467 mm from an air interface. High-resolution Monte Carlo simulations were performed to reproduce the irradiation experiments and to calculate the DER for proton energies between 50-200 MeV and magnetic field strengths between 0.35-3 T as function of distance from the air interface. Voxel sizes of 0.05, 0.5 and 1 mm were analysed. DERs of (2.2 ± 0.4)% and (0.5 ± 0.6)% were measured at 0.156 and 0.467 mm from the air interface, respectively. Measurements and simulations agreed within 0.15%. For a 200 MeV proton beam, the maximum DER in 0.05 mm voxels increased with magnetic field strength from 2.6% to 8.2% between 0.35 and 1.5 T, respectively. For a 1.0 T magnetic field, maximum DER increased from 3.2% to 7.6% between 50 and 200 MeV, respectively. Voxel sizes of 0.5 and 1 mm resulted in maximum DER values of 2.6% and 1.4%, respectively. The ERE for proton beams in transverse magnetic fields is measurable. The local dose enhancement is significant, well predictable, decreases rapidly with distance from the air interface, and is negligible beyond 1 mm depth. Its impact on air-filled ionisation chambers and porous tissues (e.g. lung) needs to be considered.

Fluence correction factors for graphite calorimetry in a low-energy clinical proton beam: I. Analytical and Monte Carlo simulations.

The conversion of absorbed dose-to-graphite in a graphite phantom to absorbed dose-to-water in a water phantom is performed by water to graphite stopping power ratios. If, however, the charged particle fluence is not equal at equivalent depths in graphite and water, a fluence correction factor, kfl, is required as well. This is particularly relevant to the derivation of absorbed dose-to-water, the quantity of interest in radiotherapy, from a measurement of absorbed dose-to-graphite obtained with a graphite calorimeter. In this work, fluence correction factors for the conversion from dose-to-graphite in a graphite phantom to dose-to-water in a water phantom for 60 MeV mono-energetic protons were calculated using an analytical model and five different Monte Carlo codes (Geant4, FLUKA, MCNPX, SHIELD-HIT and McPTRAN.MEDIA). In general the fluence correction factors are found to be close to unity and the analytical and Monte Carlo codes give consistent values when considering the differences in secondary particle transport. When considering only protons the fluence correction factors are unity at the surface and increase with depth by 0.5% to 1.5% depending on the code. When the fluence of all charged particles is considered, the fluence correction factor is about 0.5% lower than unity at shallow depths predominantly due to the contributions from alpha particles and increases to values above unity near the Bragg peak. Fluence correction factors directly derived from the fluence distributions differential in energy at equivalent depths in water and graphite can be described by kfl = 0.9964 + 0.0024·zw-eq with a relative standard uncertainty of 0.2%. Fluence correction factors derived from a ratio of calculated doses at equivalent depths in water and graphite can be described by kfl = 0.9947 + 0.0024·zw-eq with a relative standard uncertainty of 0.3%. These results are of direct relevance to graphite calorimetry in low-energy protons but given that the fluence correction factor is almost solely influenced by non-elastic nuclear interactions the results are also relevant for plastic phantoms that consist of carbon, oxygen and hydrogen atoms as well as for soft tissues.

Lack of effect of propranolol on the steady-state plasma levels of ketanserin.

The effect of propranolol treatment on the steady-state plasma levels of ketanserin was evaluated in 6 patients suffering from borderline hypertension and in 2 healthy volunteers. All subjects received ketanserin 40 mg b.i.d. for 21 days. From day 8 to 14 of the study propranolol was given additionally in a dose of 80 mg bid. This dose of propranolol had to be reduced in 3 subjects because of side effects. Steady-state plasma concentrations (measured 4-6 h after the dose) of ketanserin varied from 51.0 +/- 13.6 to 67.8 +/- 13.8 ng/ml (mean +/- SEM) during the entire study period. Treatment with propranolol (plasma concentrations ranged from 45.7 +/- 15.8 to 65.7 +/- 11.4 ng/ml) did not significantly alter the plasma concentrations of ketanserin. The same was true for the minimal plasma concentrations of ketanserin measured at the end of each treatment period. Blood pressure decreased during the 21 days treatment period with ketanserin (mean systolic blood pressure decreased from 144 +/- 5 to 123 +/- 7 and diastolic from 81 +/- 3 to 72 +/- 5 mmHg). Propranolol had a slight additional hypotensive effect. Heart rate decreased during treatment with propranolol. It is concluded that simultaneous oral treatment with propranolol in doses up to 160 mg/day does not alter the first-pass metabolism and the elimination kinetics of ketanserin.