Microdosimetric measurements in the secondary radiation field produced in (12)C-therapy irradiations.

The ambient dose equivalent from the secondary radiation produced during irradiation of a cylindrical water phantom with 200 MeV/u (12)C-ions was investigated at the biophysics cave at GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt, Germany. Pencil-like ion beams were delivered by the heavy-ion synchrotron SIS18 using the slow extraction mode. Since the secondary radiation field outside the phantom is complex in its particle composition and particle energy distribution, microdosimetric methods developed for the dosimetry of the cosmic radiation field at flight altitudes, which is similar in terms of complexity, were applied. Lineal energy distributions and the ambient dose equivalent were measured with a tissue-equivalent proportional counter at different particle emission angles. An additional veto counter allowed the identification of the different contributions of charged and neutral particles. A significant increase in the mean quality factor was observed at large emission angles which could be attributed to the decreasing contributions of charged particles compared to the (relative) contributions from neutrons.

Real-time monitoring of the Bragg-peak position in ion therapy by means of single photon detection.

For real-time monitoring of the longitudinal position of the Bragg-peak during an ion therapy treatment, a novel non-invasive technique has been recently proposed that exploits the detection of prompt gamma-rays issued from nuclear fragmentation. Two series of experiments have been performed at the GANIL and GSI facilities with 95 and 305 MeV/u (12)C(6+) ion beams stopped in PMMA and water phantoms. In both experiments, a clear correlation was obtained between the carbon ion range and the prompt photon profile. Additionally, an extensive study has been performed to investigate whether a prompt neutron component may be correlated with the carbon ion range. No such correlation was found. The present paper demonstrates that a collimated set-up can be used to detect single photons by means of time-of-flight measurements, at those high energies typical for ion therapy. Moreover, the applicability of the technique both at cyclotron and at synchrotron facilities is shown. It is concluded that the detected photon count rates provide sufficiently high statistics to allow real-time control of the longitudinal position of the Bragg-peak under clinical conditions.

The relevance of very low energy ions for heavy-ion therapy.

Heavy-ion radiotherapy exploits the high biological effectiveness of localized energy deposition delivered by so-called Bragg-peak particles. Recent publications have challenged the established procedures to calculate biological effective dose distributions in treatment planning. They emphasize the importance of very low energy (<500 keV amu(-1)) ions, either as primary particles or originating from molecular and nuclear fragmentations. We show, however, that slow heavy ions with energies below 500 keV amu(-1) only play a negligible role in cancer treatments for several reasons. Their residual range is very small compared to the relevant length scale of treatment planning. Moreover, their relative frequency and also their relative dose distribution are insignificant, since energy loss and range straggling in ion slowing down processes as well as the necessary superposition of Bragg peaks wash out small-scale special effects. Additionally, we show that even a 1000 times larger biological damage of such slow ions would not result in a clinically relevant increase of the photon-equivalent dose. Therefore, neither a more precise physical description of ions in the very distal part of the Bragg peak nor the consideration of radiation damage induced by hyperthermal ions would result in a meaningful improvement of current models for heavy-ion treatment planning.

Experimental and theoretical study of the neutron dose produced by carbon ion therapy beams.

High-energy (12)C ions offer favourable conditions for the treatment of deep-seated local tumours. Several facilities for the heavy ion therapy are planned or under construction, for example the new clinical ion-therapy unit HIT at the Radiological University Clinics in Heidelberg. In order to improve existing treatment planning models, it is essential to evaluate the secondary fragment production and to include these contributions to the therapy dose with higher accuracy. Secondary neutrons are most abundantly produced in the reactions between (12)C beams and tissues. The dose contribution to tissues by a neutron is fairly small compared with the projectile and the other charged fragments due to no ionisation and the small reaction cross-sections; however, it distributes in a considerably wider region beyond the bragg-peak because of the strong penetrability. Systematic data on energy spectra and doses of secondary neutrons produced by (12)C beams using water targets of different thicknesses for various detection angles have therefore been measured in this study at GSI Darmstadt.

Fragmentation of 120 and 200 MeV u-14He ions in water and PMMA targets.

Recently, the use of 4He particles in cancer radiotherapy has been reconsidered as they potentially represent a good compromise between protons and 12C ions. The first step to achieve this goal is the development of a dedicated treatment planning system, for which basic physics information such as the characterization of the beam lateral scattering and fragmentation cross sections are required. In the present work, the attenuation of 4He primary particles and the build-up of secondary charged fragments at various depths in water and polymethyl methacrylate were investigated experimentally for 120 and 200 MeV u-1 beams delivered by the synchrotron at the Heidelberg Ion-Beam Therapy Center, Heidelberg. Species and isotope identification was accomplished combining energy loss and time-of-flight measurements. Differential yields and energy spectra of all fragments types were recorded between 0° and 20° with respect to the primary beam direction.

Absorbed dose to water determination with ionization chamber dosimetry and calorimetry in restricted neutron, photon, proton and heavy-ion radiation fields.

Absolute dose measurements with a transportable water calorimeter and ionization chambers were performed at a water depth of 20 mm in four different types of radiation fields, for a collimated (60)Co photon beam, for a collimated neutron beam with a fluence-averaged mean energy of 5.25 MeV, for collimated proton beams with mean energies of 36 MeV and 182 MeV at the measuring position, and for a (12)C ion beam in a scanned mode with an energy per atomic mass of 430 MeV u(-1). The ionization chambers actually used were calibrated in units of air kerma in the photon reference field of the PTB and in units of absorbed dose to water for a Farmer-type chamber at GSI. The absorbed dose to water inferred from calorimetry was compared with the dose derived from ionometry by applying the radiation-field-dependent parameters. For neutrons, the quantities of the ICRU Report 45, for protons the quantities of the ICRU Report 59 and for the (12)C ion beam, the recommended values of the International Atomic Energy Agency (IAEA) protocol (TRS 398) were applied. The mean values of the absolute absorbed dose to water obtained with these two independent methods agreed within the standard uncertainty (k = 1) of 1.8% for calorimetry and of 3.0% for ionometry for all types and energies of the radiation beams used in this comparison.

Experimental fragmentation studies with 12C therapy beams.

High-energy beams of (12)C ions in the range of 80-430 MeV u(-1) delivered by the heavy-ion synchrotron SIS-18 are used for radiotherapy of deep-seated localized tumors at the treatment unit at GSI Darmstadt. In order to improve the physical database, the fragmentation characteristics along the penetration path in tissue were investigated experimentally by using a water phantom as tissue-equivalent absorber. Measurements were performed at specific energies of 200 and 400 MeV u(-1) of the incident (12)C ions and at six different depths before and behind the Bragg peak. Secondary fragments with nuclear charges Z(f) = 1-5 were identified by scintillation detectors using DeltaE-E and time-of-flight techniques. The preliminary results include energy- and angular distributions, fragment yields, build-up curves and attenuation of the primary carbon projectiles.

Radiological protection in ion beam radiotherapy: practical guidance for clinical use of new technology.

Recently introduced technologies in radiotherapy have significantly improved the clinical outcome for patients. Ion beam radiotherapy, involving proton and carbon ion beams, provides excellent dose distributions in targeted tumours, with reduced doses to the surrounding normal tissues. However, careful treatment planning is required in order to maximise the treatment efficiency and minimise the dose to normal tissues. Radiation exposure from secondary neutrons and photons, particle fragments, and photons from activated materials should also be considered for radiological protection of the patient and medical staff. Appropriate maintenance is needed for the equipment and air in the treatment room, which may be activated by the particle beam and its secondary radiation. This new treatment requires complex procedures and careful adjustment of parameters for each patient. Therefore, education and training for the personnel involved in the procedure are essential for both effective treatment and patient protection. The International Commission on Radiological Protection (ICRP) has provided recommendations for radiological protection in ion beam radiotherapy in Publication 127 Medical staff should be aware of the possible risks resulting from inappropriate use and control of the equipment. They should also consider the necessary procedures for patient protection when new technologies are introduced into clinical practice.

Comparison between calculation and measured data on secondary neutron energy spectra by heavy ion reactions from different thick targets.

Measured neutron energy fluences from high-energy heavy ion reactions through targets several centimeters to several hundred centimeters thick were compared with calculations made using the recently developed general-purpose particle and heavy ion transport code system (PHITS). It was confirmed that the PHITS represented neutron production by heavy ion reactions and neutron transport in thick shielding with good overall accuracy.

Absolute prompt-gamma yield measurements for ion beam therapy monitoring.

Prompt-gamma emission detection is a promising technique for hadrontherapy monitoring purposes. In this regard, obtaining prompt-gamma yields that can be used to develop monitoring systems based on this principle is of utmost importance since any camera design must cope with the available signal. Herein, a comprehensive study of the data from ten single-slit experiments is presented, five consisting in the irradiation of either PMMA or water targets with lower and higher energy carbon ions, and another five experiments using PMMA targets and proton beams. Analysis techniques such as background subtraction methods, geometrical normalization, and systematic uncertainty estimation were applied to the data in order to obtain absolute prompt-gamma yields in units of prompt-gamma counts per incident ion, unit of field of view, and unit of solid angle. At the entrance of a PMMA target, where the contribution of secondary nuclear reactions is negligible, prompt-gamma counts per incident ion, per millimetre and per steradian equal to (124 ± 0.7stat ± 30sys) × 10(-6) for 95 MeV u(-1) carbon ions, (79 ± 2stat ± 23sys) × 10(-6) for 310 MeV u(-1) carbon ions, and (16 ± 0.07stat ± 1sys) × 10(-6) for 160 MeV protons were found for prompt gammas with energies higher than 1 MeV. This shows a factor 5 between the yields of two different ions species with the same range in water (160 MeV protons and 310 MeV u(-1) carbon ions). The target composition was also found to influence the prompt-gamma yield since, for 300/310 MeV u(-1) carbon ions, a 42% greater yield ((112 ± 1stat ± 22sys) × 10(-6) counts ion(-1) mm(-1) sr(-1)) was obtained with a water target compared to a PMMA one.

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.

Relation between carbon ion ranges and x-ray CT numbers.

Measurements of carbon ion ranges in various phantom materials and real bones are presented. Together with measured Hounsfield values, an empirical relation between ranges and Hounsfield units is derived, which is an important prerequisite for treatment planning in carbon ion therapy.

Limited-angle 3D reconstruction of PET images for dose localization in light ion tumour therapy.

In vivo dose localization in light ion tumour therapy can be performed by measuring the range distributions of beta+ active ions in tissue employing positron emission tomographic techniques. For this purpose a multiplicative iteration scheme for reconstructing three-dimensional images from shift-variant, limited-angle data is presented. In the iterative correction steps the algorithm uses the geometric means of quotients calculated from the three-dimensional Radon transforms of the backprojected measured and approximated source distributions. When sources measured with poor statistics are reconstructed, an effective noise suppression is achieved.

Effective point of measurement of cylindrical ionization chambers for heavy charged particles.

Cylindrical ionization chambers are used for the determination of absorbed dose in beams of heavy charged particles, where the effective point of measurement, Peff (the point in depth to which the measured dose refers), is a priori not known. A measurement of Peff for a Farmer-type chamber in a carbon ion beam is presented. It is based on a comparison of relative depth dose curves measured with a cylindrical chamber and a plane-parallel Markus chamber. Both measurements were compared against another high-precision relative depth dose measurement using large-area plane-parallel chambers. For Peff, a value of 72 +/- 7% of the inner radius of the chamber is obtained. The relative depth dose curve for the cylindrical chamber is calculated using an averaging of the depth dose values over the curved inner surface of the active volume while taking account of the different depths of points on the inner surface. Within the measurement uncertainty of 0.2 mm the measurements agree well with the calculated Bragg curve for the Farmer chamber. The result for Peff is in correspondence with the value suggested in a new code of practice by the IAEA for protons and ions, and somewhat less than that suggested by Palmans for protons. The measurements show that cylindrical chambers are in general well suited for depth dose measurements in fields of heavy charged particles if the correct Peff is used.

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.

The investigation of different cameras for in-beam PET imaging.

In situ and in vivo treatment plan verification and beam monitoring as well as dose control during heavy-ion tumour therapy can be performed in principle by measurements of range distributions of beta(+)-emitting nuclei by means of PET techniques. For this purpose the performance of different types of positron camera as well as the results of in-beam PET experiments using beams of beta(+)-active heavy ions (15O, 17F and 19Ne with energies of 300-500 A MeV) are presented. Following the deduced performance requirements a PET scanner that is designed for clinical use in experimental heavy-ion therapy at GSI Darmstadt has been built. This limited angle tomograph consists of two large-area detector heads based on position sensitive BGO detectors and is predicted to perform the measurement of the end point of a beta(+)-emitting ion beam for the verification of a treatment plan with a precision better than 1 mm. The maximum dose applied in the patient thereby is of the magnitude of 10 mGy.

Nuclear fragmentation of high-energy heavy-ion beams in water.

As a part of the physical-technical program of the heavy-ion therapy project at GSI we have investigated the nuclear fragmentation of high-energy ion beams delivered by the heavy-ion synchrotron SIS, using water as a tissue-equivalent target. For a direct comparison of fragmentation properties, beams of 10B, 12C, 14N, and 16O were produced simultaneously as secondary beams from a primary 18O beam and separated in flight by magnetic beam analysis. The Z-distributions of beam fragments produced in the water target were measured via energy loss in a large ionisation chamber and a scintillator telescope. From these data we obtained both total and partial charge-changing cross sections. In addition we have performed Bragg measurements using two parallel-plate ionization chambers and a water target of variable length. The detailed shape of the measured Bragg curves and the measured cross sections are in good agreement with model calculations based on semi-empirical formulae.

Effects of heavy ions on visual function and electrophysiology of rodents: the ALTEA-MICE project.

ALTEA-MICE will supplement the ALTEA project on astronauts and provide information on the functional visual impairment possibly induced by heavy ions during prolonged operations in microgravity. Goals of ALTEA-MICE are: (1) to investigate the effects of heavy ions on the visual system of normal and mutant mice with retinal defects; (2) to define reliable experimental conditions for space research; and (3) to develop animal models to study the physiological consequences of space travels on humans. Remotely controlled mouse setup, applied electrophysiological recording methods, remote particle monitoring, and experimental procedures were developed and tested. The project has proved feasible under laboratory-controlled conditions comparable in important aspects to those of astronauts' exposure to particle in space. Experiments are performed at the Brookhaven National Laboratories [BNL] (Upton, NY, USA) and the Gesellschaft für Schwerionenforschung mbH [GSI]/Biophysik (Darmstadt, FRG) to identify possible electrophysiological changes and/or activation of protective mechanisms in response to pulsed radiation. Offline data analyses are in progress and observations are still anecdotal. Electrophysiological changes after pulsed radiation are within the limits of spontaneous variability under anesthesia, with only indirect evidence of possible retinal/cortical responses. Immunostaining showed changes (e.g. increased expression of FGF2 protein in the outer nuclear layer) suggesting a retinal stress reaction to high-energy particles of potential relevance in space.

The ALTEA/ALTEINO projects: studying functional effects of microgravity and cosmic radiation.

The ALTEA project investigates the risks of functional brain damage induced by particle radiation in space. A modular facility (the ALTEA facility) is being implemented and will be operated in the International Space Station (ISS) to record electrophysiological and behavioral descriptors of brain function and to monitor their time dynamics and correlation with particles and space environment. The focus of the program will be on abnormal visual perceptions (often reported as "light flashes" by astronauts) and the impact on retinal and brain visual structures of particle in microgravity conditions. The facility will be made available to the international scientific community for human neurophysiological, electrophysiological and psychophysics experiments, studies on particle fluxes, and dosimetry. A precursor of ALTEA (the 'Alteino' project) helps set the experimental baseline for the ALTEA experiments, while providing novel information on the radiation environment onboard the ISS and on the brain electrophysiology of the astronauts during orbital flights. Alteino was flown to the ISS on the Soyuz TM34 as part of mission Marco Polo. Controlled ground experiments using mice and accelerator beams complete the experimental strategy of ALTEA. We present here the status of progress of the ALTEA project and preliminary results of the Alteino study on brain dynamics, particle fluxes and abnormal visual perceptions.

Fragmentation of 200 and 244 MeV/u carbon beams in thick tissue-like absorbers.

Stacks consisting of thin CR-39 sheets sandwiched between thick lucite and water absorbers were perpendicularly bombarded by 12C ions at 200 and 244 MeV/u. Track radius distributions representing the charge composition of the fragmented beams were automatically measured by a particle track analysis system. After analysis of the nuclear charge distributions, the total charge removal cross-sections and elemental production cross-sections of fragments with atomic numbers from 5 to 3, were obtained down to the lower energies (approximately 50 and 100 MeV/u, respectively). It has been found that the measured total charge removal cross-section agrees with theoretical predictions within approximately 10% and very well with previous experiments in corresponding energy regions. Two model calculations for production of B fragment are in good agreement with our measured data while a third model overestimates it by approximately 12%. Theoretical cross-sections for Be and Li fragments differ strongly among the different models and from measured values.