'Survival': a simulation toolkit introducing a modular approach for radiobiological evaluations in ion beam therapy.

One major rationale for the application of heavy ion beams in tumour therapy is their increased relative biological effectiveness (RBE). The complex dependencies of the RBE on dose, biological endpoint, position in the field etc require the use of biophysical models in treatment planning and clinical analysis. This study aims to introduce a new software, named 'Survival', to facilitate the radiobiological computations needed in ion therapy. The simulation toolkit was written in C++ and it was developed with a modular architecture in order to easily incorporate different radiobiological models. The following models were successfully implemented: the local effect model (LEM, version I, II and III) and variants of the microdosimetric-kinetic model (MKM). Different numerical evaluation approaches were also implemented: Monte Carlo (MC) numerical methods and a set of faster analytical approximations. Among the possible applications, the toolkit was used to reproduce the RBE versus LET for different ions (proton, He, C, O, Ne) and different cell lines (CHO, HSG). Intercomparison between different models (LEM and MKM) and computational approaches (MC and fast approximations) were performed. The developed software could represent an important tool for the evaluation of the biological effectiveness of charged particles in ion beam therapy, in particular when coupled with treatment simulations. Its modular architecture facilitates benchmarking and inter-comparison between different models and evaluation approaches. The code is open source (GPL2 license) and available at https://github.com/batuff/Survival.

A novel algorithm for the calculation of physical and biological irradiation quantities in scanned ion beam therapy: the beamlet superposition approach.

The calculation algorithm of a modern treatment planning system for ion-beam radiotherapy should ideally be able to deal with different ion species (e.g. protons and carbon ions), to provide relative biological effectiveness (RBE) evaluations and to describe different beam lines. In this work we propose a new approach for ion irradiation outcomes computations, the beamlet superposition (BS) model, which satisfies these requirements. This model applies and extends the concepts of previous fluence-weighted pencil-beam algorithms to quantities of radiobiological interest other than dose, i.e. RBE- and LET-related quantities. It describes an ion beam through a beam-line specific, weighted superposition of universal beamlets. The universal physical and radiobiological irradiation effect of the beamlets on a representative set of water-like tissues is evaluated once, coupling the per-track information derived from FLUKA Monte Carlo simulations with the radiobiological effectiveness provided by the microdosimetric kinetic model and the local effect model. Thanks to an extension of the superposition concept, the beamlet irradiation action superposition is applicable for the evaluation of dose, RBE and LET distributions. The weight function for the beamlets superposition is derived from the beam phase space density at the patient entrance. A general beam model commissioning procedure is proposed, which has successfully been tested on the CNAO beam line. The BS model provides the evaluation of different irradiation quantities for different ions, the adaptability permitted by weight functions and the evaluation speed of analitical approaches. Benchmarking plans in simple geometries and clinical plans are shown to demonstrate the model capabilities.

The CNAO dose delivery system for modulated scanning ion beam radiotherapy.

PURPOSE: This paper describes the system for the dose delivery currently used at the Centro Nazionale di Adroterapia Oncologica (CNAO) for ion beam modulated scanning radiotherapy. METHODS: CNAO Foundation, Istituto Nazionale di Fisica Nucleare and University of Torino have designed, built, and commissioned a dose delivery system (DDS) to monitor and guide ion beams accelerated by a dedicated synchrotron and to distribute the dose with a full 3D scanning technique. Protons and carbon ions are provided for a wide range of energies in order to cover a sizable span of treatment depths. The target volume, segmented in several layers orthogonally to the beam direction, is irradiated by thousands of pencil beams which must be steered and held to the prescribed positions until the prescribed number of particles has been delivered. For the CNAO beam lines, these operations are performed by the DDS. The main components of this system are two independent beam monitoring detectors, called BOX1 and BOX2, interfaced with two control systems performing the tasks of real-time fast and slow control, and connected to the scanning magnets and the beam chopper. As a reaction to any condition leading to a potential hazard, a DDS interlock signal is sent to the patient interlock system which immediately stops the irradiation. The essential tasks and operations performed by the DDS are described following the data flow from the treatment planning system through the end of the treatment delivery. RESULTS: The ability of the DDS to guarantee a safe and accurate treatment was validated during the commissioning phase by means of checks of the charge collection efficiency, gain uniformity of the chambers, and 2D dose distribution homogeneity and stability. A high level of reliability and robustness has been proven by three years of system activity needing rarely more than regular maintenance and working with 100% uptime. Four identical and independent DDS devices have been tested showing comparable performances and are presently in use on the CNAO beam lines for clinical activity. CONCLUSIONS: The dose delivery system described in this paper is one among the few worldwide existing systems to operate ion beam for modulated scanning radiotherapy. At the time of writing, it has been used to treat more than 350 patients and it has proven to guide and control the therapeutic pencil beams reaching performances well above clinical requirements. In particular, in terms of dose accuracy and stability, daily quality assurance measurements have shown dose deviations always lower than the acceptance threshold of 5% and 2.5%, respectively.

Direct evaluation of radiobiological parameters from clinical data in the case of ion beam therapy: an alternative approach to the relative biological effectiveness.

The relative biological effectiveness (RBE) concept is commonly used in treatment planning for ion beam therapy. Whether models based on in vitro/in vivo RBE data can be used to predict human response to treatments is an open issue. In this work an alternative method, based on an effective radiobiological parameterization directly derived from clinical data, is presented. The method has been applied to the analysis of prostate cancer trials with protons and carbon ions.Prostate cancer trials with proton and carbon ion beams reporting 5 year-local control (LC5) and grade 2 (G2) or higher genitourinary toxicity rates (TOX) were selected from literature to test the method. Treatment simulations were performed on a representative subset of patients to produce dose and linear energy transfer distribution, which were used as explicative physical variables for the radiobiological modelling. Two models were taken into consideration: the microdosimetric kinetic model (MKM) and a linear model (LM). The radiobiological parameters of the LM and MKM were obtained by coupling them with the tumor control probability and normal tissue complication probability models to fit the LC5 and TOX data through likelihood maximization. The model ranking was based on the Akaike information criterion.Results showed large confidence intervals due to the limited variety of available treatment schedules. RBE values, such as RBE = 1.1 for protons in the treated volume, were derived as a by-product of the method, showing a consistency with current approaches. Carbon ion RBE values were also derived, showing lower values than those assumed for the original treatment planning in the target region, whereas higher values were found in the bladder. Most importantly, this work shows the possibility to infer the radiobiological parametrization for proton and carbon ion treatment directly from clinical data.

Analysis of the reliability of the local effect model for the use in carbon ion treatment planning systems.

In radiotherapy with carbon ions, biological effects of treatments have to be predicted. For this purpose, one of the most used models is the local effect model (LEM) developed at the Gesellschaft für Schwerionenforschung (GSI), Germany. At the Istituto Nazionale di Fisica Nucleare, Italy, the reliability of the last published version of LEM (LEM III) in reproducing radiobiological data has been checked under both monoenergetic and spread-out Bragg peak (SOBP) carbon-ion irradiation. The reproduction of the monoenergetic measurements with the LEM was rather successful for some cell lines, while it failed for the less-radioresistant ones. The SOBP experimental trend was predicted by the LEM, but a large shift between model curves and measured points was observed.

Online beam monitoring in the treatment of ocular pathologies at the INFN Laboratori Nazionali del Sud-Catania.

A detector (MOPI) has been developed for the online monitoring of the beam at the Centro di AdroTerapia e Applicazioni Nucleari Avanzate (CATANA), where shallow tumours of the ocular region are treated with 62 MeV protons. At CATANA the beam is passively spread to match the tumour shape. The uniformity of the delivered dose depends on beam geometrical quantities which are checked before each treatment. However, beam instabilities might develop during the irradiation affecting the dose distribution. This paper reports on the use of the MOPI detector to measure the stability of the beam profile during the irradiation in the clinical practice. The results obtained in the treatment of 54 patients are also presented.

Heuristic optimization of the scanning path of particle therapy beams.

Quasidiscrete scanning is a delivery strategy for proton and ion beam therapy in which the beam is turned off when a slice is finished and a new energy must be set but not during the scanning between consecutive spots. Different scanning paths lead to different dose distributions due to the contribution of the unintended transit dose between spots. In this work an algorithm to optimize the scanning path for quasidiscrete scanned beams is presented. The classical simulated annealing algorithm is used. It is a heuristic algorithm frequently used in combinatorial optimization problems, which allows us to obtain nearly optimal solutions in acceptable running times. A study focused on the best choice of operational parameters on which the algorithm performance depends is presented. The convergence properties of the algorithm have been further improved by using the next-neighbor algorithm to generate the starting paths. Scanning paths for two clinical treatments have been optimized. The optimized paths are found to be shorter than the back-and-forth, top-to-bottom (zigzag) paths generally provided by the treatment planning systems. The gamma method has been applied to quantify the improvement achieved on the dose distribution. Results show a reduction of the transit dose when the optimized paths are used. The benefit is clear especially when the fluence per spot is low, as in the case of repainting. The minimization of the transit dose can potentially allow the use of higher beam intensities, thus decreasing the treatment time. The algorithm implemented for this work can optimize efficiently the scanning path of quasidiscrete scanned particle beams. Optimized scanning paths decrease the transit dose and lead to better dose distributions.

A treatment planning code for inverse planning and 3D optimization in hadrontherapy.

The therapeutic use of protons and ions, especially carbon ions, is a new technique and a challenge to conform the dose to the target due to the energy deposition characteristics of hadron beams. An appropriate treatment planning system (TPS) is strictly necessary to take full advantage. We developed a TPS software, ANCOD++, for the evaluation of the optimal conformal dose. ANCOD++ is an analytical code using the voxel-scan technique as an active method to deliver the dose to the patient, and provides treatment plans with both proton and carbon ion beams. The iterative algorithm, coded in C++ and running on Unix/Linux platform, allows the determination of the best fluences of the individual beams to obtain an optimal physical dose distribution, delivering a maximum dose to the target volume and a minimum dose to critical structures. The TPS is supported by Monte Carlo simulations with the package GEANT3 to provide the necessary physical lookup tables and verify the optimized treatment plans. Dose verifications done by means of full Monte Carlo simulations show an overall good agreement with the treatment planning calculations. We stress the fact that the purpose of this work is the verification of the physical dose and a next work will be dedicated to the radiobiological evaluation of the equivalent biological dose.

A method for the inter-calibration of a matrix of sensors.

We present a quick and easy method for the calibration of a matrix of sensors. The algorithm is based on a three-step irradiation procedure which relies only on the constancy of the delivered fluence at each step. With this method the gain of each sensor is derived relative to a reference detector. The algorithm has been applied to a matrix of (32 x 32) ionization chambers. After the calibration coefficients have been applied, by comparing the response of the matrix of chambers to a reference detector over a large field, we determined that the fluence measurement of individual chambers is better than 0.7%. The algorithm solves the cumbersome problem of the relative gain calibration of a matrix of a large number of sensors.

D-IMRT verification with a 2D pixel ionization chamber: dosimetric and clinical results in head and neck cancer.

Dynamic intensity-modulated radiotherapy (D-IMRT) using the sliding-window technique is currently applied for selected treatments of head and neck cancer at Institute for Cancer Research and Treatment of Candiolo (Turin, Italy). In the present work, a PiXel-segmented ionization Chamber (PXC) has been used for the verification of 19 fields used for four different head and neck cancers. The device consists of a 32x32 matrix of 1024 parallel-plate ionization chambers arranged in a square of 24x24 cm2 area. Each chamber has 0.4 cm diameter and 0.55 cm height; a distance of 0.75 cm separates the centre of adjacent chambers. The sensitive volume of each single ionization chamber is 0.07 cm3. Each of the 1024 independent ionization chambers is read out with a custom microelectronics chip.The output factors in water obtained with the PXC at a depth of 10 cm were compared to other detectors and the maximum difference was 1.9% for field sizes down to 3x3 cm2. Beam profiles for different field dimensions were measured with the PXC and two other types of ionization chambers; the maximum distance to agreement (DTA) in the 20-80% penumbra region of a 3x3 cm2 field was 0.09 cm. The leaf speed of the multileaf collimator was varied between 0.07 and 2 cm s-1 and the detector response was constant to better than 0.6%. The behaviour of the PXC was measured while varying the dose rate between 0.21 and 1.21 Gy min-1; the mean difference was 0.50% and the maximum difference was 0.96%. Using fields obtained with an enhanced dynamic wedge and a staircase-like (step) IMRT field, the PXC has been tested for simple 1D modulated beams; comparison with film gave a maximum DTA of 0.12 cm. The PXC was then used to check four different IMRT plans for head and neck cancer treatment: cervical chordoma, parotid, ethmoid and skull base. In the comparison of the PXC versus film and PXC versus treatment planning system, the number of pixels with gamma parameter

Two-dimensional and quasi-three-dimensional dosimetry of hadron and photon beams with the Magic Cube and the Pixel Ionization Chamber.

Two detectors for fast two-dimensional (2D) and quasi-three-dimensional (quasi-3D) verification of the dose delivered by radiotherapy beams have been developed at University and Istituto Nazionale di Fisica Nucleare (INFN) of Torino. The Magic Cube is a stack of strip-segmented ionization chambers interleaved with water-equivalent slabs. The parallel plate ionization chambers have a sensitive area of 24 x 24 cm2, and consist of 0.375 cm wide and 24 cm long strips. There are a total of 64 strips per chamber. The Magic Cube has been tested with the clinical proton beam at Loma Linda University Medical Centre (LLUMC), and was shown to be capable of fast and precise quasi-3D dose verification. The Pixel Ionization Chamber (PXC) is a detector with pixel anode segmentation. It is a 32 x 32 matrix of 1024 cylindrical ionization cells arranged in a square 24 x 24 cm2 area. Each cell has 0.4 cm diameter and 0.55 cm height, at a pitch of 0.75 cm separates the centre of adjacent cells. The sensitive volume of each single ionization cell is 0.07 cm3. The detectors are read out using custom designed front-end microelectronics and a personal computer-based data acquisition system. The PXC has been used to verify dynamic intensity-modulated radiotherapy for head-and-neck and breast cancers.

Dosimetric characterization of a large area pixel-segmented ionization chamber.

A pixel-segmented ionization chamber has been designed and built by Torino University and INFN. The detector features a 24 x 24 cm2 active area divided in 1024 independent cylindrical ionization chambers and can be read out in 500 micros without introducing dead time; the digital charge quantum can be adjusted between 100 fC and 800 fC. The sensitive volume of each single ionization chamber is 0.07 cm3. The purpose of the detector is to ease the two-dimensional (2D) verifications of fields with complex shapes and large gradients. The detector was characterized in a PMMA phantom using 60Co and 6 MV x-ray photon beams. It has shown good signal linearity with respect to dose and dose rate to water. The average sensitivity of a single ionization chamber was 2.1 nC/Gy, constant within 0.5% over one month of daily measurements. Charge collection efficiency was 0.985 at the operating polarization voltage of 400 V and 3.5 Gy/min dose rate. Tissue maximum ratio and output factor have been compared with a Farmer ionization chamber and were found in good agreement. The dose profiles have been compared with the ones obtained with an ionization chamber in water phantom for the field sizes supplied by a 3D-Line dynamic multileaf collimator. These results show that this detector can be used for 2D dosimetry of x-ray photon beams, supplying a good spatial resolution and sensibly reducing the time spent in dosimetric verification of complex radiation fields.

A code for hadrontherapy treatment planning with the voxelscan method.

A code for the implementation of treatment plannings in hadrontherapy with an active scan beam is presented. The package can determine the fluence and energy of the beams for several thousand voxels in a few minutes. The performances of the program have been tested with a full simulation.