Validation of Geant4 for silicon microdosimetry in heavy ion therapy.

Microdosimetry is a particularly powerful method to estimate the relative biological effectiveness (RBE) of any mixed radiation field. This is particularly convenient for therapeutic heavy ion therapy (HIT) beams, referring to ions larger than protons, where the RBE of the beam can vary significantly along the Bragg curve. Additionally, due to the sharp dose gradients at the end of the Bragg peak (BP), or spread out BP, to make accurate measurements and estimations of the biological properties of a beam a high spatial resolution is required, less than a millimetre. This requirement makes silicon microdosimetry particularly attractive due to the thicknesses of the sensitive volumes commonly being ∼10 [Formula: see text]m or less. Monte Carlo (MC) codes are widely used to study the complex mixed HIT radiation field as well as to model the response of novel microdosimeter detectors when irradiated with HIT beams. Therefore it is essential to validate MC codes against experimental measurements. This work compares measurements performed with a silicon microdosimeter in mono-energetic [Formula: see text], [Formula: see text] and [Formula: see text] ion beams of therapeutic energies, against simulation results calculated with the Geant4 toolkit. Experimental and simulation results were compared in terms of microdosimetric spectra (dose lineal energy, [Formula: see text]), the dose mean lineal energy, y  D and the RBE10, as estimated by the microdosimetric kinetic model (MKM). Overall Geant4 showed reasonable agreement with experimental measurements. Before the distal edge of the BP, simulation and experiment agreed within ∼10% for y  D and ∼2% for RBE10. Downstream of the BP less agreement was observed between simulation and experiment, particularly for the [Formula: see text] and [Formula: see text] beams. Simulation results downstream of the BP had lower values of y  D and RBE10 compared to the experiment due to a higher contribution from lighter fragments compared to heavier fragments.

MICRODOSIMETRIC APPLICATIONS IN PROTON AND HEAVY ION THERAPY USING SILICON MICRODOSIMETERS.

Using the CMRP 'bridge' µ+ probe, microdosimetric measurements were undertaken out-of-field using a therapeutic scanning proton pencil beam and in-field using a 12C ion therapy field. These measurements were undertaken at Mayo Clinic, Rochester, USA and at HIMAC, Chiba, Japan, respectively. For a typical proton field used in the treatment of deep-seated tumors, we observed dose-equivalent values ranging from 0.62 to 0.99 mSv/Gy at locations downstream of the distal edge. Lateral measurements at depths close to the entrance and along the SOBP plateau were found to reach maximum values of 3.1 mSv/Gy and 5.3 mSv/Gy at 10 mm from the field edge, respectively, and decreased to ~0.04 mSv/Gy 120 mm from the field edge. The ability to measure the dose-equivalent with high spatial resolution is particularly relevant to healthy tissue dose calculations in hadron therapy treatments. We have also shown qualitatively and quantitively the effects critical organ motion would have in treatment using microdosimetric spectra. Large differences in spectra and RBE10 were observed for treatments where miscalculations of 12C ion range would result in critical structures being irradiated, showing the importance of motion management.

The FLUKA Monte Carlo code coupled with the NIRS approach for clinical dose calculations in carbon ion therapy.

Particle therapy facilities often require Monte Carlo (MC) simulations to overcome intrinsic limitations of analytical treatment planning systems (TPS) related to the description of the mixed radiation field and beam interaction with tissue inhomogeneities. Some of these uncertainties may affect the computation of effective dose distributions; therefore, particle therapy dedicated MC codes should provide both absorbed and biological doses. Two biophysical models are currently applied clinically in particle therapy: the local effect model (LEM) and the microdosimetric kinetic model (MKM). In this paper, we describe the coupling of the NIRS (National Institute for Radiological Sciences, Japan) clinical dose to the FLUKA MC code. We moved from the implementation of the model itself to its application in clinical cases, according to the NIRS approach, where a scaling factor is introduced to rescale the (carbon-equivalent) biological dose to a clinical dose level. A high level of agreement was found with published data by exploring a range of values for the MKM input parameters, while some differences were registered in forward recalculations of NIRS patient plans, mainly attributable to differences with the analytical TPS dose engine (taken as reference) in describing the mixed radiation field (lateral spread and fragmentation). We presented a tool which is being used at the Italian National Center for Oncological Hadrontherapy to support the comparison study between the NIRS clinical dose level and the LEM dose specification.

Adaptation of the microdosimetric kinetic model to hypoxia.

Ion beams present a potential advantage in terms of treatment of lesions with hypoxic regions. In order to use this potential, it is important to accurately model the cell survival of oxic as well as hypoxic cells. In this work, an adaptation of the microdosimetric kinetic (MK) model making it possible to account for cell hypoxia is presented. The adaptation relies on the modification of damage quantity (double strand breaks and more complex lesions) due to the radiation. Model parameters such as domain size and nucleus size are then adapted through a fitting procedure. We applied this approach to two cell lines, HSG and V79 for helium, carbon and neon ions. A similar behaviour of the parameters was found for the two cell lines, namely a reduction of the domain size and an increase in the sensitive nuclear volume of hypoxic cells compared to those of oxic cells. In terms of oxygen enhancement ratio (OER), the experimental data behaviour can be reproduced, including dependence on particle type at the same linear energy transfer (LET). Errors on the cell survival prediction are of the same order of magnitude than for the original MK model. Our adaptation makes it possible to account for hypoxia without modelling the OER as a function of the LET of the particles, but directly accounting for hypoxic cell survival data.

Objective assessment in digital images of skin erythema caused by radiotherapy.

PURPOSE: Skin toxicity caused by radiotherapy has been visually classified into discrete grades. The present study proposes an objective and continuous assessment method of skin erythema in digital images taken under arbitrary lighting conditions, which is the case for most clinical environments. The purpose of this paper is to show the feasibility of the proposed method. METHODS: Clinical data were gathered from six patients who received carbon beam therapy for lung cancer. Skin condition was recorded using an ordinary compact digital camera under unfixed lighting conditions; a laser Doppler flowmeter was used to measure blood flow in the skin. The photos and measurements were taken at 3 h, 30, and 90 days after irradiation. Images were decomposed into hemoglobin and melanin colors using independent component analysis. Pixel values in hemoglobin color images were compared with skin dose and skin blood flow. The uncertainty of the practical photographic method was also studied in nonclinical experiments. RESULTS: The clinical data showed good linearity between skin dose, skin blood flow, and pixel value in the hemoglobin color images; their correlation coefficients were larger than 0.7. It was deduced from the nonclinical that the uncertainty due to the proposed method with photography was 15%; such an uncertainty was not critical for assessment of skin erythema in practical use. CONCLUSIONS: Feasibility of the proposed method for assessment of skin erythema using digital images was demonstrated. The numerical relationship obtained helped to predict skin erythema by artificial processing of skin images. Although the proposed method using photographs taken under unfixed lighting conditions increased the uncertainty of skin information in the images, it was shown to be powerful for the assessment of skin conditions because of its flexibility and adaptability.

Carbon-ion radiotherapy: clinical aspects and related dosimetry.

The features of relativistic carbon-ion beams are attractive from the viewpoint of radiotherapy. They exhibit not only a superior physical dose distribution but also an increase in biological efficiency with depth, because energy loss of the beams increases as they penetrate the body. This paper reviews clinical aspects of carbon-beam radiotherapy using the experience at the National Institute of Radiological Sciences. The paper also outlines the dosimetry related to carbon-beam radiotherapy, including absolute dosimetry of the carbon beam, neutron measurements and radiation protection measurements.

Field size effect of radiation quality in carbon therapy using passive method.

The authors have investigated the dependency of radiation quality and absorbed dose on radiation field size in therapeutic carbon beams. The field size of the broad beam, formed using the passive technique, was controlled from 20 to 100 mm per side with a multileaf collimator. The absorbed dose and radiation quality on the beam center were evaluated at several depths in a water phantom using microdosimetric technique in experiments and Monte Carlo simulations. With an increase in the field size, the radiation quality was reduced, although the absorbed dose grew at the center of the field. This indicates that the dose and radiation quality at the center of the broad beam are influenced by particles from the off-center region via large-angle scattering and that such particles have relatively low radiation quality and mainly consist of fragment particles. Because such a tendency appeared to be more remarkable in the deeper region of the water phantom, it is likely that fragment particles that are born in a water phantom have a marked role in determining the field size effect.

Extension of applicable neutron energy of DARWIN up to 1 GeV.

The radiation-dose monitor, DARWIN, needs a set of response functions of the liquid organic scintillator to assess a neutron dose. SCINFUL-QMD is a Monte Carlo based computer code to evaluate the response functions. In order to improve the accuracy of the code, a new light-output function based on the experimental data was developed for the production and transport of protons deuterons, tritons, (3)He nuclei and alpha particles, and incorporated into the code. The applicable energy of DARWIN was extended to 1 GeV using the response functions calculated by the modified SCINFUL-QMD code.

Test of the local effect model using clinical data: tumour control probability for lung tumours after treatment with carbon ion beams.

The treatment planning approach used within the heavy ion tumour therapy project at GSI Darmstadt includes a biological optimisation, which is based on a biophysical model, the Local Effect Model (LEM). Here we show that the predictions of the LEM are in good agreement with clinical data obtained at the HIMAC in Chiba for the treatment of non-small-cell lung cancer, and the steep dose response for carbon ions is reproduced correctly. This steeper increase corresponds to an increasing RBE with increasing dose, which apparently is in contradiction to the systematics observed in general for in vitro measurements. A possible explanation of this discrepancy is based on the interindividual variation of photon sensitivity.

Chromosomal aberrations induced by high-energy iron ions with shielding.

Biophysical models are commonly used to evaluate the effectiveness of shielding in reducing the biological damage caused by cosmic radiation in space flights. To improve and validate these codes biophysical experiments are needed. We have measured the induction of chromosomal aberrations in human peripheral blood lymphocytes exposed in vitro to 500 MeV/n iron ion beams (dose range 0.1-1 Gy) after traversing shields of different material (lucite, aluminium, or lead) and thickness (0-11.3 g/cm2). For comparison, cells were exposed to 200 MeV/n iron ions and to X-rays. Chromosomes were prematurely condensed by a phosphatase inhibitor (calyculin A) to avoid cell-cycle selection produced by the exposure to high-LET heavy-ion beams. Aberrations were scored in chromosomes 1, 2, and 4 following fluorescence in situ hybridization. The fraction of aberrant lymphocytes has been evaluated as a function of the dose at the sample position, and of the fluence of primary 56Fe ions hitting the shield. The influence of shield thickness on the action cross-section for the induction of exchange-type aberrations has been analyzed, and the dose average-LET measured as a function of the shield thickness. These preliminary results prove that the effectiveness of heavy ions is modified by shielding, and the biological damage is dependent upon shield thickness and material.

Characterisation of an ultra-miniature counter for microdosimetric measurements in a therapeutic 400 MeV/A carbon beam.

Single event spectra of a clinical carbon beam have been measured by an ultra-miniature tissue-equivalent proportional counter (UMC). In order to cover the energy range of the Bragg peak, the incident energy of the carbon beam was degraded by aluminium plates. Single event spectra for carbon-events incident to the UMC were analysed and selected at several carbon energies using thin scintillation counters. It was found that the dose weighted lineal energy distributions have a doublet peak structure due to incident carbon beam and fragment contributions.

[Development of a multi-layer ion chamber for measurement of depth dose distributions of heavy-ion therapeutic beam for individual patients].

In heavy-ion radiotherapy, an accelerated beam is modified to realize a desired dose distribution in patients. The setup of the beam-modifying devices in the irradiation system is changed according to the patient, and it is important to check the depth dose distributions in the patient. In order to measure dose distributions realized by an irradiation system for heavy-ion radiotherapy, a multi-layer ionization chamber(MLIC) was developed. The MLIC consists of 64 ionization chambers, which are stacked mutually. The interval between each ionization chamber is about 4.1 mm water. There are signal and high voltage plates in the MILC, which are used as electrodes of the ionization chambers and phantom. Depth dose distribution from 5.09 mm to 261.92 mm water can be measured in about 30 seconds using this MLIC. Thus, it is possible to check beam quality in a short amount of time.

Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy.

PURPOSE: The irradiation system and biophysical characteristics of carbon beams are examined regarding radiation therapy. METHODS AND MATERIALS: An irradiation system was developed for heavy-ion radiotherapy. Wobbler magnets and a scatterer were used for flattening the radiation field. A patient-positioning system using X ray and image intensifiers was also installed in the irradiation system. The depth-dose distributions of the carbon beams were modified to make a spread-out Bragg peak, which was designed based on the biophysical characteristics of monoenergetic beams. A dosimetry system for heavy-ion radiotherapy was established to deliver heavy-ion doses safely to the patients according to the treatment planning. A carbon beam of 80 keV/microm in the spread-out Bragg peak was found to be equivalent in biological responses to the neutron beam that is produced at cyclotron facility in National Institute Radiological Sciences (NIRS) by bombarding 30-MeV deuteron beam on beryllium target. The fractionation schedule of the NIRS neutron therapy was adapted for the first clinical trials using carbon beams. RESULTS: Carbon beams, 290, 350, and 400 MeV/u, were used for a clinical trial from June of 1994. Over 300 patients have already been treated by this irradiation system by the end of 1997.

Relationship between CT number and electron density, scatter angle and nuclear reaction for hadron-therapy treatment planning.

The precise conversion of CT numbers to their electron densities is essential in treatment planning for hadron therapy. Although some conversion methods have already been proposed, it is hard to check the conversion accuracy during practical therapy. We have estimated the CT numbers of real tissues by a calculational method established by Mustafa and Jackson. The relationship between the CT numbers and the electron densities was investigated for various body tissues as well as some tissue-equivalent materials used for a conversion to check the accuracy of the current conversion methods. The result indicates a slight disagreement at the high-CT-number region. A precise estimation of the multiple scattering, nuclear reaction and range straggling of incident particles has been considered as being important to realize higher-level conformal therapy in the future. The relationship between these parameters and the CT numbers was also investigated for tissues and water. The result shows that it is sufficiently practical to replace these parameters for real tissues with those for water by adjusting the density.

Carbon beam dosimetry intercomparison at HIMAC.

To verify international uniformity in carbon beam dosimetry, an intercomparison programme was carried out at the heavy ion medical accelerator (HIMAC). Dose measurements with ionization chambers were performed for both unmodulated and 6 cm modulated 290 MeV/nucleon carbon beams. Although two different dosimetry procedures were employed, the evaluated values of absorbed dose were in good agreement. This comparison established a common framework for ionization chamber dosimetry between two different carbon beam therapy facilities.

Initial recombination in a parallel-plate ionization chamber exposed to heavy ions.

For exact determination of absorbed dose in heavy-ion irradiation fields which are used in radiation therapy and biological experiments, ionization chambers have been characterized with defined heavy-ion beams and correction factors. The LET (linear energy transfer) dependence of columnar recombination in a parallel-plate ionization chamber has been examined. Using 135 MeV/u carbon and neon beams, the ion collection efficiency was measured for several gases (air, carbon dioxide, argon and tissue-equivalent gas). 95 MeV/u argon beams and 90 MeV/u iron beams were also used for measurements of columnar recombination in air. As expected by Jaffe theory, the inverse of the ratio of the ionization charge to the saturated ionization charge had a linear relationship with the inverse of the electric field strength in the region below 0.002 V(-1) cm. The gradient of the line increases as the LET of the heavy ions increases. A strong LET dependence of the gradient was observed in air and carbon dioxide. The LET dependence was not observed in tissue-equivalent gas, nitrogen or argon. The exact depth-dose distribution of the heavy-ion beam was obtained by this correction of the initial recombination effect for the collected ionization charge. The columnar recombination in air was analysed using Jaffe theory; the obtained parameter b (a track radius) should be in the range between 0.001 cm and 0.005 cm, whereas the value obtained by Jaffe is 0.00179 cm. The value of the parameter b should increase as the LET of the heavy-ion beam increases in order to reproduce the experimental values of the initial recombination.

Rejoining and misrejoining of radiation-induced chromatin breaks. IV. Charged particles.

We have recently reported the kinetics of chromosome rejoining and exchange formation in human lymphocytes exposed to gamma rays using the techniques of fluorescence in situ hybridization (FISH) and premature chromosome condensation (PCC). In this paper, we have extended previous measurements to cells exposed to charged particles. Our goal was to determine differences in chromatin break rejoining and misrejoining after exposure to low- and high-linear energy transfer (LET) radiation. Cells were irradiated with hydrogen, neon, carbon or iron ions in the LET range 0.3-140 keV/microm and were incubated at 37 degrees C for various times after exposure. Little difference was observed in the yield of early prematurely condensed chromosome breaks for the different ions. The kinetics of break rejoining was exponential for all ions and had similar time constants, but the residual level of unrejoined breaks after prolonged incubation was higher for high-LET radiation. The kinetics of exchange formation was also similar for the different ions, but the yield of chromosome interchanges measured soon after exposure was higher for high-LET particles, suggesting that a higher fraction of DNA breaks are misrejoined quickly. On the other hand, the rate of formation of complete exchanges was slightly lower for densely ionizing radiation. The ratios between the yields of different types of aberrations observed at 10 h postirradiation in prematurely condensed chromosome preparations were dependent on LET. We found significant differences between the yields of aberrations measured in interphase (after repair) and metaphase for densely ionizing radiation. This difference might be caused by prolonged mitotic delay and/or interphase death. Overall, the results point out significant differences between low- and high-LET radiation for the formation of chromosome aberrations.