Niels Bassler

Relative biological effectiveness (RBE) and distal edge effects of proton radiation on early damage in vivo

Abstract Introduction: The aim of the present study was to examine the RBE for early damage in an in vivo mouse model, and the effect of the increased linear energy transfer (LET) towards the distal edge of the spread-out Bragg peak (SOBP). Method: The lower part of the right hind limb of CDF1 mice was irradiated with single fractions of either 6u2009MV photons, 240u2009kV photons or scanning beam protons and graded doses were applied. For the proton irradiation, the leg was either placed in the middle of a 30-mm SOBP, or to assess the effect in different positions, irradiated in 4u2009mm intervals from the middle of the SOBP to behind the distal dose fall-off. Irradiations were performed with the same dose plan at all positions, corresponding to a dose of 31.25u2009Gy in the middle of the SOBP. Endpoint of the study was early skin damage of the foot, assessed by a mouse foot skin scoring system. Results: The MDD50 values with 95% confidence intervals were 36.1 (34.2–38.1) Gy for protons in the middle of the SOBP for score 3.5. For 6u2009MV photons, it was 35.9 (34.5–37.5) Gy and 32.6 (30.7–34.7) Gy for 240u2009kV photons for score 3.5. The corresponding RBE was 1.00 (0.94–1.05), relative to 6u2009MV photons and 0.9 (0.85–0.97) relative to 240u2009kV photons. In the mice group positioned at the SOBP distal dose fall-off, 25% of the mice developed early skin damage compared with 0–8% in other groups. LETd,zu2009=u20091 was 8.4u2009keV/μm at the distal dose fall-off and the physical dose delivered was 7% lower than in the central SOBP position, where LETd,z =1 was 3.3u2009keV/μm. Conclusions: Although there is a need to expand the current study to be able to calculate an exact enhancement ratio, an enhanced biological effect in vivo for early skin damage in the distal edge was demonstrated.

Differential gene expression in primary fibroblasts induced by proton and cobalt-60 beam irradiation

Abstract Introduction: Proton beam therapy delivers a more conformal dose distribution than conventional radiotherapy, thus improving normal tissue sparring. Increasing linear energy transfer (LET) along the proton track increases the relative biological effectiveness (RBE) near the distal edge of the Spread-out Bragg peak (SOBP). The severity of normal tissue side effects following photon beam radiotherapy vary considerably between patients. Aim: The dual study aim was to identify gene expression patterns specific to radiation type and proton beam position, and to assess whether individual radiation sensitivity influences gene expression levels in fibroblast cultures irradiated in vitro. Methods: The study includes 30 primary fibroblast cell cultures from patients previously classified as either radiosensitive or radioresistant. Cells were irradiated at three different positions in the proton beam profile: entrance, mid-SOBP and at the SOBP distal edge. Dose was delivered in three fractions ×u20093.5u2009Gy(RBE) (RBE 1.1). Cobalt-60 (Co-60) irradiation was used as reference. Real-time qPCR was performed to determine gene expression levels for 17 genes associated with inflammation response, fibrosis and angiogenesis. Results: Differences in median gene expression levels were observed for multiple genes such as IL6, IL8 and CXCL12. Median IL6 expression was 30%, 24% and 47% lower in entrance, mid-SOBP and SOBP distal edge groups than in Co-60 irradiated cells. No genes were found to be oppositely regulated by different radiation qualities. Radiosensitive patient samples had the strongest regulation of gene expression; irrespective of radiation type. Conclusions: Our findings indicate that the increased LET at the SOBP distal edge position did not generally lead to increased transcriptive response in primary fibroblast cultures. Inflammatory factors were generally less extensively upregulated by proton irradiation compared with Co-60 photon irradiation. These effects may possibly influence the development of normal tissue damage in patients treated with proton beam therapy.

Development of an interlaced-crossfiring geometry for proton grid therapy

Abstract Background: Grid therapy has in the past normally been performed with single field photon-beam grids. In this work, we evaluated a method to deliver grid therapy based on interlacing and crossfiring grids of mm-wide proton beamlets over a target volume, by Monte Carlo simulations. Material and methods: Dose profiles for single mm-wide proton beamlets (1, 2 and 3u2009mm FWHM) in water were simulated with the Monte Carlo code TOPAS. Thereafter, grids of proton beamlets were directed toward a cubic target volume, located at the center of a water tank. The aim was to deliver a nearly homogeneous dose to the target, while creating high dose heterogeneity in the normal tissue, i.e., high gradients between valley and peak doses in the grids, down to the close vicinity of the target. Results: The relative increase of the beam width with depth was largest for the smallest beams (+6.9u2009mm for 1u2009mm wide and 150u2009MeV proton beamlets). Satisfying dose coverage of the cubic target volume (σ <u2009±5%) was obtained with the interlaced-crossfiring setup, while keeping the grid pattern of the dose distribution down to the target (valley-to-peak dose ratio <0.5 less than 1u2009cm before the target). Center-to-center distances around 7–8u2009mm between the beams were found to give the best compromise between target dose homogeneity and low peak doses outside of the target. Conclusions: A nearly homogeneous dose distribution can be obtained in a target volume by crossfiring grids of mm-wide proton-beamlets, while maintaining the grid pattern of the dose distribution at large depths in the normal tissue, close to the target volume. We expect that the use of this method will increase the tumor control probability and improve the normal tissue sparing in grid therapy.

Optimal reference genes for normalization of qPCR gene expression data from proton and photon irradiated dermal fibroblasts

The transcriptional response of cells exposed to proton radiation is not equivalent to the response induced by traditional photon beams. Changes in cellular signalling is most commonly studied using the method Quantitative polymerase chain reaction (qPCR). Stable reference genes must be used to accurately quantify target transcript expression. The study aim was to identify suitable reference genes for normalisation of gene expression levels in normal dermal fibroblasts irradiated with either proton or photon beams. The online tool RefFinder was used to analyse and identify the most stably expressed genes from a panel of 22 gene candidates. To assess the reliability of the identified reference genes, a selection of the most and least stable reference genes was used to normalise target transcripts of interest. Fold change levels varied considerably depending on the used reference gene. The top ranked genes IPO8, PUM1, MRPL19 and PSMC4 produced highly similar target gene expression, while expression using the worst ranked genes, TFRC and HPRT1, was clearly modified due to reference gene instability.

Quantitative evaluation of potential irradiation geometries for carbon‐ion beam grid therapy

PURPOSEnRadiotherapy using grids containing cm-wide beam elements has been carried out sporadically for more than a century. During the past two decades, preclinical research on radiotherapy with grids containing small beam elements, 25 μm-0.7 mm wide, has been performed. Grid therapy with larger beam elements is technically easier to implement, but the normal tissue tolerance to the treatment is decreasing. In this work, a new approach in grid therapy, based on irradiations with grids containing narrow carbon-ion beam elements was evaluated dosimetrically. The aim formulated for the suggested treatment was to obtain a uniform target dose combined with well-defined grids in the irradiated normal tissue. The gain, obtained by crossfiring the carbon-ion beam grids over a simulated target volume, was quantitatively evaluated.nnnMETHODSnThe dose distributions produced by narrow rectangular carbon-ion beams in a water phantom were simulated with the PHITS Monte Carlo code. The beam-element height was set to 2.0 cm in the simulations, while the widths varied from 0.5 to 10.0 mm. A spread-out Bragg peak (SOBP) was then created for each beam element in the grid, to cover the target volume with dose in the depth direction. The dose distributions produced by the beam-grid irradiations were thereafter constructed by adding the dose profiles simulated for single beam elements. The variation of the valley-to-peak dose ratio (VPDR) with depth in water was thereafter evaluated. The separation of the beam elements inside the grids were determined for different irradiation geometries with a selection criterion.nnnRESULTSnThe simulated carbon-ion beams remained narrow down to the depths of the Bragg peaks. With the formulated selection criterion, a beam-element separation which was close to the beam-element width was found optimal for grids containing 3.0-mm-wide beam elements, while a separation which was considerably larger than the beam-element width was found advantageous for grids containing 0.5-mm-wide beam elements. With the single-grid irradiation setup, the VPDRs were close to 1.0 already at a distance of several cm from the target. The valley doses given to the normal tissue at 0.5 cm distance from the target volume could be limited to less than 10% of the mean target dose if a crossfiring setup with four interlaced grids was used.nnnCONCLUSIONSnThe dose distributions produced by grids containing 0.5- and 3.0-mm wide beam elements had characteristics which could be useful for grid therapy. Grids containing mm-wide carbon-ion beam elements could be advantageous due to the technical ease with which these beams can be produced and delivered, despite the reduced threshold doses observed for early and late responding normal tissue for beams of millimeter width, compared to submillimetric beams. The treatment simulations showed that nearly homogeneous dose distributions could be created inside the target volumes, combined with low valley doses in the normal tissue located close to the target volume, if the carbon-ion beam grids were crossfired in an interlaced manner with optimally selected beam-element separations. The formulated selection criterion was found useful for the quantitative evaluation of the dose distributions produced by the different irradiation setups.

PD-0491: Development of an angle dependent robustness quality factor for proton/ion beam in cancer treatment

Purpose/Objective: Dose-painting by numbers (DBPN) is gaining interest and has the potential to improve tumor local control with minimal increase of side effects. Because of the voxel-by-voxel nonuniform dose prescription in DPBN, usual margin recipes to account for geometric and random uncertainties do not apply. Robust treatment plans may be achieved by incorporating geometric uncertainties during plan optimization. Although powerful, this method is not available in most treatment planning systems (TPS) and may be time-consuming. Our approach aims at providing a universal solution (i.e. TPS independent), by including systematic and random geometric uncertainties implicitly in the prescription for DPBN. Materials and Methods: We propose here a method that modifies the heterogeneous dose prescription DP to ensure robustness of planned dose DPlanned against standard deviations of systematic errors Σ and random errors σ. The prescription is based in this study on FDG-PET images with an escalation from 70 to 86 Gy. The objective was that 95% of all voxels in the GTVPET received at least 95% of their respective prescribed dose even in the presence of geometric errors (Q0.95>95%). The prescription DP was modified by a morphological dilation of αΣ and a deconvolution by σ (assuming Gaussian distribution). The GTVPET was also extended by αΣ, to generate a PTVPET volume. For a 90% confidence interval, α=2.5. The planning process was performed on a TomoTherapy system such that 95% of the points within PTVPET received at least 95% of the modified prescription (Q0.95>95%) and less than 5% of the points received more than 105% of the modified prescription (quality factors Q0.95 and Q1.05 are derived from the cumulative quality volume histograms, the quality factor Q being the ratio in each CT voxel between the planned dose and the prescribed dose). Robustness was evaluated by translating and blurring DPlanned and by comparing the resulting dose with the unmodified dose prescription within GTVPET. The methodology was illustrated for two head-and-neck tumors treated by helical TomoTherapy. Results: For both patients, the TomoTherapy system was capable to reproduce modified non-uniform prescriptions with Q0.95>95% and Q1.05<5%. Coverage was preserved when systematic and random displacements were smaller than αΣ and σ. For larger displacements, coverage was degraded. The figure illustrates two examples for one patient. In figure (a), no correction of the prescription was performed, leading to significant underdosage when geometric errors were simulated (down to 62.8% for Q0.95). In figure (b) target coverage was preserved even in the presence of geometric errors.

SU‐E‐T‐712: An Antiproton Depth‐Dose Curve Benchmark of Geant4

Purpose: Experimental and theoretical studies of the potential use of antiproton beams for cancer therapy have been greatly aided by Monte Carlo based calculations. Previously published data from the AD‐4/ACE collaboration has shown excellent agreement between the Fluka Monte Carlo code and experimental absorbed dose data. In this research we investigate the suitability of the open source Geant4 Monte Carlo package for antiproton absorbed dose calculations.Methods: Ionization chamber depth‐dose data collected at the CERN Antiproton Decelerator and previously published by Bassler et al were used as the experimental benchmark. Version 9.3.p01 of Geant4 and Fluka version 2008.3b‐02 were used. The antiproton beam was incident on a 20 × 20 × 20 cm3 water phantom with parameters set to match the experimental 126 MeV beam at CERN as closely as possible. Several reference physics lists were used covering electromagnetic and nuclear physics processes.Results: Geant4 consistently placed the Bragg peak at the correct depth, but the shape of the depth‐dose curve was inaccurate overall, regardless of physics lists chosen. In some cases, the peak‐to‐plateau ratio was off by an order of magnitude with fully enabled hadronic physics. This appeared to be the result of excessive in‐flight annihilation and a corresponding overproduction of secondaries as well as a dearth of at‐rest antiproton annihilations. Conclusions: Currently Geant4 does appear to have the necessary physics implemented, however in‐flight annihilation cross sections and low energy annihilation thresholds seem to be off in its default reference or standard physics lists. We plan to help improve this by sharing data and working with Geant4 developers.