[en] As the relative biological effectiveness of protons depends on the linear energy transfer (LET), simple methods for LET calculations are desired for the optimization of proton therapy. This work provides an analytical model for the LET on the central axis of broad proton beams in water, which can also be applied to spread-out Bragg peaks. For realistic treatment situations with polyenergetic beams, the LET is here defined as a local mean of the proton stopping power, weighted by the local energy spectrum. The proposed model considers only Coulomb interactions and neglects nonelastic nuclear interactions. By assuming a Gaussian shape for the energy spectrum and by using a suitable parametrization of the stopping power, analytical expressions for the track averaged and the dose averaged LET are derived, which account for range straggling as well as for the initial width of the energy spectrum. The analytical model was evaluated by Monte Carlo simulations with GEANT 3.21. Local energy spectra were simulated to obtain LET distributions for several cases, using clinical energies between 70 and 250 MeV and varying widths of the initial energy spectrum. Good agreement was found between the analytical model and the Monte Carlo simulations (with maximum deviations of 0.5 keV per micrometer), which justifies the assumptions used in the derivation of the analytical model

[en] As an approach towards more biology-oriented treatment planning for external beam radiation therapy, we present the incorporation of local radiation damage models into three dimensional treatment planning. This allows effect based instead of dose based plan optimization which could potentially better match the biologically relevant tradeoff between target and normal tissues. In particular, our approach facilitates an effective comparison of different fractionation schemes. It is based on the linear quadratic model to describe the biological radiation effect. Effect based optimization was integrated into our inverse treatment planning software KonRad, and we demonstrate the resulting differences between conventional and biological treatment planning. Radiation damage can be analyzed both qualitatively and quantitatively in dependence of the fractionation scheme and tissue specific parameters in a three dimensional voxel based system. As an example the potential advantages as well as the associated risks of hypofractionation for prostate cancer are analyzed and visualized with the help of effective dose volume histograms. Our results suggest a very conservative view regarding alternative fractionation schemes since uncertainties in biological parameters are still too big to make reliable clinical predictions. (orig.)

[en] Currently, treatment planning for intensity modulated proton therapy (IMPT) usually disregards variations of the relative biological effectiveness (RBE). To investigate the potential clinical relevance of a variable RBE for beam scanning techniques, new strategies for the evaluation of radiobiological effects and for the incorporation of the RBE into the inverse planning process are presented. These strategies are based on a fast algorithm for three-dimensional calculations of the dose averaged linear energy transfer (LET) as a measure of the local radiation quality, and on a simple phenomenological approach for the RBE as a function of dose, LET and tissue type. It was found that the biological effect depended strongly on the type of scanning technique used, mainly due to differences in the LET distributions. New objective functions that account for LET and RBE were integrated into an inverse planning software, which now allows simultaneous multifield optimization of the biological effect in a reasonable time. With these methods, unfavorable RBE effects can be identified and compensated for by direct optimization of the product of RBE and dose, which is demonstrated for several clinical examples. The proposed strategies are therefore valuable tools to evaluate and improve the quality of treatment plans in IMPT

[en] Besides surgery and chemotherapy, radiation therapy is one of the three main treatment options for cancer patients. This paper provides an introduction to the basic principles of radiotherapy with photons and electrons. It includes a brief summary of the physical properties for photon and electron beams as well as a description of treatment machines used to create these beams. The second part introduces the treatment planning process as it is commonly employed in radiotherapy. It covers dose calculation algorithms, conventional planning strategies for three-dimensional conformal radiotherapy, and optimization techniques for intensity modulated radiotherapy (IMRT)

[en] Purpose: Laser plasma acceleration can potentially replace large and expensive cyclotrons or synchrotrons for radiotherapy with protons and ions. On the way toward a clinical implementation, various challenges such as the maximum obtainable energy still remain to be solved. In any case, laser accelerated particles exhibit differences compared to particles from conventional accelerators. They typically have a wide energy spread and the beam is extremely pulsed (i.e., quantized) due to the pulsed nature of the employed lasers. The energy spread leads to depth dose curves that do not show a pristine Bragg peak but a wide high dose area, making precise radiotherapy impossible without an additional energy selection system. Problems with the beam quantization include the limited repetition rate and the number of accelerated particles per laser shot. This number might be too low, which requires a high repetition rate, or it might be too high, which requires an additional fluence selection system to reduce the number of particles. Trying to use laser accelerated particles in a conventional way such as spot scanning leads to long treatment times and a high amount of secondary radiation produced when blocking unwanted particles. Methods: The authors present methods of beam delivery and treatment planning that are specifically adapted to laser accelerated particles. In general, it is not necessary to fully utilize the energy selection system to create monoenergetic beams for the whole treatment plan. Instead, within wide parts of the target volume, beams with broader energy spectra can be used to simultaneously cover multiple axially adjacent spots of a conventional dose delivery grid as applied in intensity modulated particle therapy. If one laser shot produces too many particles, they can be distributed over a wider area with the help of a scattering foil and a multileaf collimator to cover multiple lateral spot positions at the same time. These methods are called axial and lateral clustering and reduce the number of particles that have to be blocked in the beam delivery system. Furthermore, the optimization routine can be adjusted to reduce the number of dose spots and laser shots. The authors implemented these methods into a research treatment planning system for laser accelerated particles. Results: The authors' proposed methods can decrease the amount of secondary radiation produced when blocking particles with wrong energies or when reducing the total number of particles from one laser shot. Additionally, caused by the efficient use of the beam, the treatment time is reduced considerably. Both improvements can be achieved without extensively changing the quality of the treatment plan since conventional intensity modulated particle therapy usually includes a certain amount of unused degrees of freedom which can be used to adapt to laser specific properties. Conclusions: The advanced beam delivery and treatment planning methods reduce the need to have a perfect laser-based accelerator reproducing the properties of conventional accelerators that might not be possible without increasing treatment time and secondary radiation to the patient. The authors show how some of the differences to conventional beams can be overcome and efficiently used for radiation treatment.

[en] This work is a feasibility study of a radiation treatment unit with laser-driven protons based on a state-of-the-art energy selection system employing four dipole magnets in a compact shielded beamline. The secondary radiation emitted from the beamline and its energy selection system and the resulting effective dose to the patient are assessed. Further, it is evaluated whether or not such a compact system could be operated in a conventional treatment vault for clinical linear accelerators under the constraint of not exceeding the effective dose limit of 1 mSv per year to the general public outside the treatment room. The Monte Carlo code Geant4 is employed to simulate the secondary radiation generated while irradiating a hypothetical tumor. The secondary radiation inevitably generated inside the patient is taken into account as well, serving as a lower limit. The results show that the secondary radiation emanating from the shielded compact therapy system would pose a serious secondary dose contamination to the patient. This is due to the broad energy spectrum and in particular the angular distribution of the laser-driven protons, which make the investigated beamline together with the employed energy selection system quite inefficient. The secondary radiation also cannot be sufficiently absorbed in a conventional linear accelerator treatment vault to enable a clinical operation. A promising result, however, is the fact that the secondary radiation generated in the patient alone could be very well shielded by a regular treatment vault, allowing the application of more than 100 fractions of 2 Gy per day with protons. It is thus theoretically possible to treat patients with protons in such treatment vaults. Nevertheless, the results show that there is a clear need for alternative more efficient energy selection solutions for laser-driven protons.

[en] The increased resistance of hypoxic cells to ionizing radiation is usually believed to be the primary reason for treatment failure in tumors with oxygen-deficient areas. This oxygen effect can be expressed quantitatively by the oxygen enhancement ratio (OER). Here we investigate theoretically the dependence of the OER on the applied local dose for different types of ionizing irradiation and discuss its importance for clinical applications in radiotherapy for two scenarios: small dose variations during hypoxia-based dose painting and larger dose changes introduced by altered fractionation schemes. Using the widespread Alper-Howard-Flanders and standard linear-quadratic (LQ) models, OER calculations are performed for T1 human kidney and V79 Chinese hamster cells for various dose levels and various hypoxic oxygen partial pressures (pO2) between 0.01 and 20 mmHg as present in clinical situations in vivo. Our work comprises the analysis for both low linear energy transfer (LET) treatment with photons or protons and high-LET treatment with heavy ions. A detailed analysis of experimental data from the literature with respect to the dose dependence of the oxygen effect is performed, revealing controversial opinions whether the OER increases, decreases or stays constant with dose. The behavior of the OER with dose per fraction depends primarily on the ratios of the LQ parameters alpha and beta under hypoxic and aerobic conditions, which themselves depend on LET, pO2 and the cell or tissue type. According to our calculations, the OER variations with dose in vivo for low-LET treatments are moderate, with changes in the OER up to 11% for dose painting (1 or 3 Gy per fraction compared to 2 Gy) and up to 22% in hyper-/hypofractionation (0.5 or 20 Gy per fraction compared to 2 Gy) for oxygen tensions between 0.2 and 20 mmHg typically measured clinically in hypoxic tumors. For extremely hypoxic cells (0.01 mmHg), the dose dependence of the OER becomes more pronounced (up to 36%). For high LET, OER variations up to 4% for the whole range of oxygen tensions between 0.01 and 20 mmHg were found, which were much smaller than for low LET. The formalism presented in this paper can be used for various tissue and radiation types to estimate OER variations with dose and help to decide in clinical practice whether some dose changes in dose painting or in fractionation can bring more benefit in terms of the OER in the treatment of a specific hypoxic tumor

[en] In this paper, we present a new technique for simultaneous multifield optimization of the biological effect (i.e. relative biological effectiveness times dose) for intensity modulated radiotherapy with ion beams. It offers complete inverse treatment planning by taking into account planning constraints for the target volume as well as for organs at risk. The approach is based on the mixed irradiation formalism of the linear-quadratic model from radiobiology. We employ a novel objective function to directly optimize the biological effect rather than the physical dose. The required biological input data are reduced to a minimum and are completely independent from the optimization itself. They can be derived from any radiobiological model or even from directly measured data. The new optimization method was fully integrated into our inverse treatment planning tool KonRad. Comparisons with the TRiP98 treatment planning code were done for simple spread-out Bragg peaks as well as for three-dimensional treatment plans, where all fields were optimized separately. While the agreement between both planning systems was very good, the calculation time was substantially reduced in KonRad. By enabling the multifield optimization, the quality of the treatment plans and the sparing of healthy tissues can be clearly improved

[en] The poor treatment prognosis for tumours with oxygen-deficient areas is usually attributed to the increased radioresistance of hypoxic cells. It can be expressed by the oxygen enhancement ratio (OER), which decreases with increasing linear energy transfer (LET) suggesting a potential clinical advantage of high-LET radiotherapy with heavy ion beams compared to low-LET photon or proton irradiation. The aim of this work is to review the experimental cell survival data from the literature and, based on them, to develop a simple OER model to estimate the clinical impact of OER variations. For this purpose, the standard linear-quadratic model and the Alper-Howard-Flanders model are used. According to our calculations for a carbon ion spread-out Bragg peak at clinically relevant intermediate oxygen levels (0.5-20 mmHg), the advantage of carbon ions might be relatively moderate, with OER values about 1%-15% smaller than for protons. Furthermore, the variations of OER with LET are much smaller in vivo than in vitro due to different oxygen partial pressures used in cell experiments or measured inside tumours. The proposed OER model is a simple tool to quantify the oxygen effect in a practical way and provides the possibility to do hypoxia-based biological optimization in treatment planning.

[en] A three-dimensional (3D) intensity modulated proton therapy treatment plan to be delivered by magnetic scanning may comprise thousands of discrete beam positions. This research presents the minimization of the total scan path length by application of a fast simulated annealing (FSA) optimization algorithm. Treatment plans for clinical prostate and head and neck cases were sequenced for continuous raster scanning in two ways, and the resulting scan path lengths were compared: (1) A simple back-and-forth, top-to-bottom (zigzag) succession, and (2) an optimized path produced as a solution of the FSA algorithm. Using a first approximation of the scanning dynamics, the delivery times for the scan sequences before and after path optimization were calculated for comparison. In these clinical examples, the FSA optimization shortened the total scan path length for the 3D target volumes by approximately 13%-56%. The number of extraneous spilled particles was correspondingly reduced by about 13%-54% due to the more efficient scanning maps that eliminated multiple crossings through regions of zero fluence. The relative decrease in delivery time due to path length minimization was estimated to be less than 1%, due to both a high scanning speed and time requirements that could not be altered by optimization (e.g., time required to change the beam energy). In a preliminary consideration of application to rescanning techniques, the decrease in delivery time was estimated to be 4%-20%