Nina Tilly

The influence of RBE variations in a clinical proton treatment plan for a hypopharynx cancer

Currently, most clinical range-modulated proton beams are assumed to have a fixed overall relative biological effectiveness (RBE) of 1.1. However, it is well known that the RBE increases with depth in the spread-out Bragg peak (SOBP) and becomes about 10% higher than mid-SOBP RBE at 2 mm from the distal edge (Paganetti 2003 Technol. Cancer Res. Treat. 2 413-26) and can reach values of 1.3-1.4 in vitro at the distal edge (Robertson et al 1975 Cancer 35 1664-77, Courdi et al 1994 Br. J. Radiol. 67 800-4). We present a fast method for applying a variable RBE correction with linear energy transfer (LET) dependent tissue-specific parameters based on the alpharef/betaref ratios suitable for implementation in a treatment planning system. The influence of applying this variable RBE correction on a clinical multiple beam proton dose plan is presented here. The treatment plan is evaluated by RBE weighted dose volume histograms (DVHs) and the calculation of tumour control probability (TCP) and normal tissue complication probability (NTCP) values. The variable RBE correction yields DVHs for the clinical target volumes (CTVs), a primary advanced hypopharynx cancer and subclinical disease in the lymph nodes, that are slightly higher than those achieved by multiplying the absorbed dose with RBE=1.1. Although, more importantly, the RBE weighted DVH for an organ at risk, the spinal cord is considerably increased for the variable RBE. As the spinal cord in this particular case is located 8 mm behind the planning target volume (PTV) and hence receives only low total doses, the NTCP values are zero in spite of the significant increase in the RBE weighted DVHs for the variable RBE. However, high NTCP values for the non-target normal tissue were obtained when applying the variable RBE correction. As RBE variations tend to be smaller for in vivo systems, this study-based on in vitro data since human tissue RBE values are scarce and have large uncertainties-can be interpreted as showing the upper limits of the possible effects of utilizing a variable RBE correction. In conclusion, the results obtained here still indicate a significant difference in introducing a variable RBE compared to applying a generic RBE of 1.1, suggesting it is worth considering such a correction in clinical proton therapy planning, especially when risk organs are located immediately behind the target volume.

Limitations (and merits) of PENELOPE as a track-structure code

Abstract Purpose: To outline the limitations of PENELOPE (acronym of PENetration and Energy LOss of Positrons and Electrons) as a track-structure code, and to comment on modifications that enable its fruitful use in certain microdosimetry and nanodosimetry applications. Methods: Attention is paid to the way in which inelastic collisions of electrons are modelled and to the ensuing implications for microdosimetry analysis. Results: Inelastic mean free paths and collision stopping powers calculated with PENELOPE and two well-known optical-data models are compared. An ad hoc modification of PENELOPE is summarized where ionization and excitation of liquid water by electron impact is simulated using tables of realistic differential and total cross sections. Conclusions: PENELOPE can be employed advantageously in some track-structure applications provided that the default model for inelastic interactions of electrons is replaced by suitable tables of differential and total cross sections.

Comparison of cell survival models for mixed LET radiation

PURPOSE Biophysical models for predicting survival for mixed LET radiations have been investigated by comparisons with experimental results from heavy ion irradiations. The aim was to choose a model for further theoretical studies on the effects of a variable RBE for protons. METHODS AND MATERIALS Predicted survival curves by the Katz track-structure model, the linear quadratic model, LQ model, by Kellerer and Rossi and the lesion additivity model of Lam were compared to experimental survival curves for V79 cells that were irradiated with a mixture of nitrogen ions with an LET of either 78 or 165 keV/microm and 60Co gamma-rays. RESULTS Results showed that all three models could predict survival within the uncertainty of the measurements for the different mixed radiation schedules used in this study. CONCLUSION The choice of model could be made on other grounds, such as the type of model parameters and the availability of biological data for these parameters. Also, the possibility of including dose-rate effects and repair functions should be considered. For the purpose of carrying out theoretical studies on the effects of a variable RBE for protons, the LQ model was preferred.

Development and verification of the pulsed scanned proton beam at The Svedberg Laboratory in Uppsala.

In this paper we present the recent developments made for the scanning system for proton beams at TSL in Uppsala, showing that this system is now fully functional being able to produce conformal intensity modulated scan patterns with sufficient accuracy. A new control and supervising system handling the beam delivery including the control of the synchrocyclotron and the scanning system is developed and described in detail. A complete dosimetry system with transmission ionization chambers and a multi-wire ionization chamber for monitoring of the beam during scanning has been constructed. The details of the dose monitors and the position sensitive multi-wire ionization chamber are presented in this work. Furthermore, we have established procedures for verification measurements to ensure the quality of the beam and also methods for calibration of the beam monitors and relative and absolute dosimetry for complex scanned beams.

A beam source model for scanned proton beams

A beam source model, i.e. a model for the initial phase space of the beam, for scanned proton beams has been developed. The beam source model is based on parameterized particle sources with characteristics found by fitting towards measured data per individual beam line. A specific aim for this beam source model is to make it applicable to the majority of the various proton beam systems currently available or under development, with the overall purpose to drive dose calculations in proton beam treatment planning. The proton beam phase space is characterized by an energy spectrum, radial and angular distributions and deflections for the non-modulated elementary pencil beam. The beam propagation through the scanning magnets is modelled by applying experimentally determined focal points for each scanning dimension. The radial and angular distribution parameters are deduced from measured two-dimensional fluence distributions of the elementary beam in air. The energy spectrum is extracted from a depth dose distribution for a fixed broad beam scan pattern measured in water. The impact of a multi-slab range shifter for energy modulation is calculated with an own Monte Carlo code taking multiple scattering, energy loss and straggling, non-elastic and elastic nuclear interactions in the slab assembly into account. Measurements for characterization and verification have been performed with the scanning proton beam system at The Svedberg Laboratory in Uppsala. Both in-air fluence patterns and dose points located in a water phantom were used. For verification, dose-in-water was calculated with the Monte Carlo code GEANT 3.21 instead of using a clinical dose engine with approximations of its own. For a set of four individual pencil beams, both with the full energy and range shifted, 96.5% (99.8%) of the tested dose points satisfied the 1%/1 mm (2%/2 mm) gamma criterion.

Reference dosimetry in a scanned pulsed proton beam using ionisation chambers and a Faraday cup.

In order to give the correct dose to a patient, the monitor chamber for a proton scanning system has to be calibrated. As recombination of ion pairs occurs in the monitor chamber, the relation between the number of particles traversing it per time unit and the ionization chamber signal is not linear. A method developed for a scanned pulsed proton beam taking the nonlinear monitor signal into account is described. A vital part of the reference dosimetry procedure is to determine the absorbed dose under reference conditions, which is recommended to be done with an ionization chamber. For a scanned pulsed proton beam, the recombination in the ionization chamber is not negligible and the signal from the ionization chamber has to be corrected. In this work, it is shown that although the pulse length is comparable to the ion transit time the beam can be considered as continuously scanned if the applied high voltage is not too small. Also shown is that the two-voltage formula for a continuous beam is under some conditions applicable for a continuous scanned beam as well.

Dose mapping sensitivity to deformable registration uncertainties in fractionated radiotherapy – applied to prostate proton treatments

BackgroundCalculation of accumulated dose in fractionated radiotherapy based on spatial mapping of the dose points generally requires deformable image registration (DIR). The accuracy of the accumulated dose thus depends heavily on the DIR quality. This motivates investigations of how the registration uncertainty influences dose planning objectives and treatment outcome predictions.A framework was developed where the dose mapping can be associated with a variable known uncertainty to simulate the DIR uncertainties in a clinical workflow. The framework enabled us to study the dependence of dose planning metrics, and the predicted treatment outcome, on the DIR uncertainty. The additional planning margin needed to compensate for the dose mapping uncertainties can also be determined. We applied the simulation framework to a hypofractionated proton treatment of the prostate using two different scanning beam spot sizes to also study the dose mapping sensitivity to penumbra widths.ResultsThe planning parameter most sensitive to the DIR uncertainty was found to be the target D95. We found that the registration mean absolute error needs to be ≤0.20 cm to obtain an uncertainty better than 3% of the calculated D95 for intermediate sized penumbras. Use of larger margins in constructing PTV from CTV relaxed the registration uncertainty requirements to the cost of increased dose burdens to the surrounding organs at risk.ConclusionsThe DIR uncertainty requirements should be considered in an adaptive radiotherapy workflow since this uncertainty can have significant impact on the accumulated dose. The simulation framework enabled quantification of the accuracy requirement for DIR algorithms to provide satisfactory clinical accuracy in the accumulated dose.

Development of a compact proton scanning system in Uppsala with a moveable second magnet

A scanned proton beam yields dose distributions that in most cases are superior to passively scattered proton beams and to other external radiation treatment modalities. The present paper gives a description of the scanning system that has been developed at the Svedberg Laboratory (TSL) in Uppsala. The scanning technique and the technical design are described. The solution with a small pole gap of the magnets and a moveable second magnet results in a very compact scanning head, which can therefore be incorporated in a gantry of relatively limited size. A prototype was constructed that has been used to realize various dose distributions with a scanned beam of 180 MeV protons at TSL.

Dose and time dependent apoptotic response in a human melanoma cell line exposed to accelerated boron ions at four different LET.

The aim was to investigate and compare the influence of linear energy transfer (LET), dose and time on the induction of apoptosis in a human melanoma cell line exposed to accelerated light boron (10B) ions and photons. Cells were exposed in vitro to doses up to 6 Gy accelerated boron ions (40, 80, 125 and 160 eV nm – 1) and up to 12 Gy photons (0.2 eV nm – 1). The induction of apoptosis was measured up to 9 days after irradiation using morphological characterization of apoptotic cells and bodies. In parallel, measurements of cell-cycle distribution, monitored by DNA flow cytometry, and cell survival based on the clonogenic cell survival assay, were performed. In addition, the induction and repair of DNA double-strand breaks (DSB), using pulsed-field gel electrophoresis (PFGE) were studied. Accelerated boron ions induced a significant increase in apoptosis as compared with photons at all time points studied. At 1 – 5 h the percentage of radiation-induced apoptotic cells increased with both dose and LET. At the later time points (24 – 216 h) the apoptotic response was more complex and did not increase in a strictly LET-dependent manner. The early premitotic apoptotic cells disappeared at 24 h following exposure to the highest LET (160 eV nm – 1). A postmitotic apoptotic response was seen after release of the dose-, time- and LET-dependent G2/M accumulations. The loss of clonogenic ability was dose- and LET-dependent and the fraction of unrejoined DSB increased with increasing LET. Despite the LET-dependent clonogenic cell killing, it was not possible to measure quantitatively a LET-dependent apoptotic response. This was due to the different time course of appearance and disappearance of apoptotic cells.

Experimental test of Monte Carlo proton transport at grazing incidence in GEANT4, FLUKA and MCNPX

The ability of the Monte Carlo (MC) particle transport codes GEANT4.8.1 and GEANT4.8.2, FLUKA2006 and MCNPX2.4.0 to model proton transport at grazing incidence onto tungsten blocks has been tested and compared to experimental measurements. The test geometry consisted of a narrow proton beam of two energies, 98 MeV and 180 MeV, impinging on a thick tungsten alloy block at grazing incidence. The distribution of forward out-scatter from the tungsten alloy block was measured with a fluorescent screen viewed with a CCD camera via a mirror. In the MC simulations, the experimental setup was modelled and the dose deposited to the fluorescent screen material was scored. Simulations and measurements were made for four different incidence angles (3.5, 5.0, 7.5 and 10 degrees ). Several different sets of calculations were performed, studying the impact of different user-defined settings in the different MC packages. The study of different parameters settings in the GEANT4.8.1 simulation showed a strong dependence of the calculated out-scatter probability on the maximum allowed step length. For the largest incidence angle an increase of 60% in the out-scatter probability was found when restricting the maximum allowed step length to 0.05 cm. We also observed that the stepping algorithm of GEANT4.8.1 and 4.8.2 introduces a small non-physical directional and positional asymmetry at the exit boundary of the tungsten alloy block. The shape of the energy spectrum of protons being out-scattered agreed between the codes. The dose-weighted forward out-scatter probability, i.e. the ratio between the total signal from the unscattered beam and the out-scattered beam, showed a qualitative agreement of simulations compared to measurements. Quantitatively, the deviation of the simulations reached as high as 37%, while the experimental uncertainty was 14%. The mean emission angle of the simulations was within 16% of the measurement for all incidence angles with a measurement uncertainty of 8%.