Michael Krämer

Treatment planning for heavy-ion radiotherapy: physical beam model and dose optimization

We describe a novel code system, TRiP, dedicated to the planning of radiotherapy with energetic ions, in particular 12C. The software is designed to cooperate with three-dimensional active dose shaping devices like the GSI raster scan system. This unique beam delivery system allows us to select any combination from a list of 253 individual beam energies, 7 different beam spot sizes and 15 intensity levels. The software includes a beam model adapted to and verified for carbon ions. Inverse planning techniques are implemented in order to obtain a uniform target dose distribution from clinical input data, i.e. CT images and patient contours. This implies the automatic generation of intensity modulated fields of heavy ions with as many as 40000 raster points, where each point corresponds to a specific beam position, energy and particle fluence. This set of data is directly passed to the beam delivery and control system. The treatment planning code has been in clinical use since the start of the GSI pilot project in December 1997. Forty-eight patients have been successfully planned and treated.

Quantification of the Relative Biological Effectiveness for Ion Beam Radiotherapy: Direct Experimental Comparison of Proton and Carbon Ion Beams and a Novel Approach for Treatment Planning

PURPOSE To present the first direct experimental in vitro comparison of the biological effectiveness of range-equivalent protons and carbon ion beams for Chinese hamster ovary cells exposed in a three-dimensional phantom using a pencil beam scanning technique and to compare the experimental data with a novel biophysical model. METHODS AND MATERIALS Cell survival was measured in the phantom after irradiation with two opposing fields, thus mimicking the typical patient treatment scenario. The novel biophysical model represents a substantial extension of the local effect model, previously used for treatment planning in carbon ion therapy for more than 400 patients, and potentially can be used to predict effectiveness of all ion species relevant for radiotherapy. A key feature of the new approach is the more sophisticated consideration of spatially correlated damage induced by ion irradiation. RESULTS The experimental data obtained for Chinese hamster ovary cells clearly demonstrate that higher cell killing is achieved in the target region with carbon ions as compared with protons when the effects in the entrance channel are comparable. The model predictions demonstrate agreement with these experimental data and with data obtained with helium ions under similar conditions. Good agreement is also achieved with relative biological effectiveness values reported in the literature for other cell lines for monoenergetic proton, helium, and carbon ions. CONCLUSION Both the experimental data and the new modeling approach are supportive of the advantages of carbon ions as compared with protons for treatment-like field configurations. Because the model predicts the effectiveness for several ion species with similar accuracy, it represents a powerful tool for further optimization and utilization of the potential of ion beams in tumor therapy.

Treatment planning for heavy ion radiotherapy: clinical implementation and application.

The clinical implementation and application of a novel treatment planning system (TPS) for scanned ion beams is described, which is in clinical use for carbon ion treatments at the German heavy ion facility (GSI). All treatment plans are evaluated on the basis of biologically effective dose distributions. For therapy control, in-beam positron emission tomography (PET) and an online monitoring system for the beam intensity and position are used. The absence of a gantry restricts the treatment plans to horizontal beams. Most of the treatment plans consist of two nearly opposing lateral fields or sometimes orthogonal fields. In only a very few cases a single beam was used. For patients with very complex target volumes lateral and even distal field patching techniques were applied. Additional improvements can be achieved when the patients head is fixed in a tilted position, in order to achieve sparing of the organs at risk. In order to test the stability of dose distributions in the case of patient misalignments we routinely simulate the effects of misalignments for patients with critical structures next to the target volume. The uncertainties in the range calculation are taken into account by a margin around the target volume of typically 2-3 mm, which can, however, be extended if the simulation demonstrates larger deviations. The novel TPS developed for scanned ion beams was introduced into clinical routine in December 1997 and was used for the treatment planning of 63 patients with head and neck tumours until July 2000. Planning strategies and methods were developed for this tumour location that facilitate the treatment of a larger number of patients with the scanned heavy ion beam in a clinical setting. Further developments aim towards a simultaneous optimization of the treatment field intensities and more effective procedures for the patient set-up. The results demonstrate that ion beams can be integrated into a clinical environment for treatment planning and delivery.

Treatment planning for scanned ion beams

Since 1997 a radiotherapy unit using fast carbon ions is operational at GSI. An intensity-controlled magnetic raster scanner together with a synchrotron allowing fast energy variation enable a unique method of purely active dose shaping in three dimensions. This contribution describes the necessary steps to establish a treatment planning system for this novel modality. We discuss the requirements for the physical beam model and the radiobiological model. Based on these we chose to implement a home-grown pencil beam model to describe the ion-tissue interaction and the Local Effect Model to calculate the RBE voxel-by-voxel. Given the large number of degrees of freedom biological dose optimization must be achieved by means of inverse treatment planning. All ion-related aspects are collected in our TRiP98 software. Biological dosimetry measuring cell survival in two dimensions turns out to be a good way to verify the model predictions as well as the actual irradiation procedure. We show a patient example and outline the future steps towards a dedicated clinic facility for all light ions.

Positron emission tomography for quality assurance of cancer therapy with light ion beams

Positron emission tomography (PET) offers the possibility of in-situ monitoring the tumour treatment with light ion beams by means of imaging the spatial distribution of β − -activity that is produced as a byproduct of the therapeutic irradiation via nuclear fragmentation reactions between the projectiles and the atomic nuclei of the tissue within the target volume. The implementation of this PET technique at the experimental tumour therapy facility at the Gesellschaft fur Schwerionenforschung (GSI) in Darmstadt and first results of its clinical application are presented.

Biological dose optimization with multiple ion fields

We describe a method to irradiate arbitrarily shaped target volumes with simultaneously optimized multiple fields of fast carbon ions, explicitly taking into account sparing of organs at risk. The method was developed with realistic technical boundary conditions in mind, so that irradiations can be executed with devices like the GSI raster scanner or its successors at the upcoming dedicated ion-beam radiotherapy facilities. By virtue of the local effect model (LEM) biological effects are fully taken into account. Several minimization algorithms were investigated, and plain gradient search was found to be more effective than methods based on conjugate gradients or Newtons root finding algorithm. Two sets of cell survival experiments for the experimental verification of patient-like treatment plans were performed. Chinese hamster cells were used for quasi two-dimensional biological dosimetry. The plans combine a very good target conformation with an excellent sparing of organs-at-risk which was verified by the measurements. The results are compared to predictions of the local effect model in its original formulation and a modified version taking additional effects of clustered DNA damage into account. The new method is implemented in GSIs TRiP98 treatment planning system. It has already been applied clinically for planning and irradiating selected patients within the GSI pilot project.

The FLUKA Monte Carlo code coupled with the local effect model for biological calculations in carbon ion therapy

Clinical Monte Carlo (MC) calculations for carbon ion therapy have to provide absorbed and RBE-weighted dose. The latter is defined as the product of the dose and the relative biological effectiveness (RBE). At the GSI Helmholtzzentrum für Schwerionenforschung as well as at the Heidelberg Ion Therapy Center (HIT), the RBE values are calculated according to the local effect model (LEM). In this paper, we describe the approach followed for coupling the FLUKA MC code with the LEM and its application to dose and RBE-weighted dose calculations for a superimposition of two opposed (12)C ion fields as applied in therapeutic irradiations. The obtained results are compared with the available experimental data of CHO (Chinese hamster ovary) cell survival and the outcomes of the GSI analytical treatment planning code TRiP98. Some discrepancies have been observed between the analytical and MC calculations of absorbed physical dose profiles, which can be explained by the differences between the laterally integrated depth-dose distributions in water used as input basic data in TRiP98 and the FLUKA recalculated ones. On the other hand, taking into account the differences in the physical beam modeling, the FLUKA-based biological calculations of the CHO cell survival profiles are found in good agreement with the experimental data as well with the TRiP98 predictions. The developed approach that combines the MC transport/interaction capability with the same biological model as in the treatment planning system (TPS) will be used at HIT to support validation/improvement of both dose and RBE-weighted dose calculations performed by the analytical TPS.

THE APPLICATION OF PET TO QUALITY ASSURANCE OF HEAVY-ION TUMOR THERAPY

SummaryAt the new heavy ion tumor therapy facility of the Gesellschaft für Schwerionenforschung at Darmstadt positron emission tomography (PET) has been implemented for in-beam and in-situ therapy control, i. e. during the tumor irradiation. The components necessary for this dedicated PET-imaging and their integration into the framework of therapy planning and quality assurance of heavy ion cancer treatments are presented. Results of the first application of this PET-method to patient treatments are reported.

Linear Energy Transfer and Track Structure

Publisher Summary This chapter discusses track structures and linear energy transfer. There are two types of energy dissipation of heavy ions—nuclear and electronic stopping. Nuclear stopping has high RBE values and predominates at extremely low specific energies of a few kiloelectronvolts per mass unit, corresponding to the last micrometers of the particle range. At higher energies, nuclear stopping contributes only a few percent to the total stopping; the predominant process is the electronic stopping. The electronic stopping is proportional to the square of the effective projectile charge and increases up to a maximum value. The predominant process of electronic stopping involves the interaction of the projectile with the target electrons. In the collision process, a spectrum of electrons is produced with different kinetic energies ranging from zero up to a maximum energy that depends on the velocity of the primary ion. From the energy loss of the primary ion, two-thirds are transformed into the kinetic energy of the electrons. The residual energy is used to overcome the binding energy of the electrons and for target excitations. In the center of the track, the ionized atoms are pushed out from their original positions by electrostatic repulsion. This process is called Coulomb explosion and is responsible for the formation of the latent track in nuclear track detectors. In DNA experiments, the influence of track structure on the induction of double- and single-strand breaks is observed for LET values greater than 5 keV/μm. In consequence, the ratio of DSB to SSB increases with decreasing track diameters, and the highest values are found at the very end of the tracks. However, if the radiosensitivity is increased by changing the DNA environment or the repair capacity, additional DSB are produced directly in single events.

LET-painting increases tumour control probability in hypoxic tumours

Abstract LET-painting was suggested as a method to overcome tumour hypoxia. In vitro experiments have demonstrated a well-established relationship between the oxygen enhancement ratio (OER) and linear energy transfer (LET), where OER approaches unity for high-LET values. However, high-LET radiation also increases the risk for side effects in normal tissue. LET-painting attempts to restrict high-LET radiation to compartments that are found to be hypoxic, while applying lower LET radiation to normoxic tissues. Methods. Carbon-12 and oxygen-16 ion treatment plans with four fields and with homogeneous dose in the target volume, are applied on an oropharyngeal cancer case with an identified hypoxic entity within the tumour. The target dose is optimised to achieve a tumour control probability (TCP) of 95% when assuming a fully normoxic tissue. Using the same primary particle energy fluence needed for this plan, TCP is recalculated for three cases assuming hypoxia: first, redistributing LET to match the hypoxic structure (LET-painting). Second, plans are recalculated for varying hypoxic tumour volume in order to investigate the threshold volume where TCP can be established. Finally, a slight dose boost (5–20%) is additionally allowed in the hypoxic subvolume to assess its impact on TCP. Results. LET-painting with carbon-12 ions can only achieve tumour control for hypoxic subvolumes smaller than 0.5 cm3. Using oxygen-16 ions, tumour control can be achieved for tumours with hypoxic subvolumes of up to 1 or 2 cm3. Tumour control can be achieved for tumours with even larger hypoxic subvolumes, if a slight dose boost is allowed in combination with LET-painting. Conclusion. Our findings clearly indicate that a substantial increase in tumour control can be achieved when applying the LET-painting concept using oxygen-16 ions on hypoxic tumours, ideally with a slight dose boost.