Light Ion Beam Therapy Research Articles

Secondary neutrons in proton and light ion beam therapy: a review of current status, needs and potential solutions

The advantages of proton and light ion beam therapy compared to conventional photon radiation therapy are well-known, mainly thanks to the characteristic depth dose distribution of ions and their radio-biological effectiveness. Nevertheless, the use of ions implies different nuclear reactions that generate secondary particles, with neutrons among them. These secondary neutrons can travel far away from the treatment volume, their measurement is a challenging complex task, and their biological effects are particularly high for neutrons with energies in the MeV range. In this review, a comprehensive description of secondary neutron dosimetry in proton and light ion beam therapy is given. Many studies have been conducted on the quantification of the secondary neutron dose, most of them have been performed for proton beams, whereas for other ions like carbon, the available information is scarce. The main measurement campaigns are summarised, focusing on the type of detectors used. In line with the detectors’ advantages and limitations, measurements performed inside and outside anthropomorphic phantoms are considered. The role of Monte Carlo radiation transport simulations is discussed since many experimental detection techniques need additional simulations to provide dose estimates. A focus on the current challenges for the measurements of neutrons with energies above 20 MeV is given, as this is one of the main components of secondary neutrons produced by therapeutic ion beams. Finally, the potential clinical relevance of the available and needed secondary neutron dose data is discussed, in terms of its impact on the treatment of patients. For this, the relative biological effectiveness of neutrons and the potential risk of cancer induction re-incidence or secondary cancer due to secondary neutron doses play a key role.

Dosimetric validation of a GPU-based dose engine for a fast in silico patient-specific quality assurance program in light ion beam therapy.

With rapid evolutions of fast and sophisticated calculation techniques and delivery technologies, clinics are almost facing a daily patient-specific (PS) plan adaptation, which would make a conventional experimental quality assurance (QA) workflow unlikely to be routinely feasible. Therefore, in silico approaches are foreseen by means of second-check independent dose calculation systems possibly handling machine log-files. To validate the in-house developed GPU-dose engine, FRoG, for light ion beam therapy (protons and carbon ions) as a second-check independent calculation system and to integrate machine log-file analysis into the patient-specific quality assurance (PSQA) program. Spot sizes, depth-dose distributions, and absolute dose calibrations were configured into FRoG and a set of nine regular-shaped targets in combination with more than 170 clinical treatment fields were tested against pinpoint ionization chamber measurements. Both the treatment planning system DICOM RTplans and machine treatment log-files were used as input for the dose kernel in water, and a 3D local γ (1mm/2%) index was used as the main evaluation metric. Calculated configuration data matched experimental measurements with submillimetric agreement. For regular-shaped targets, the unsigned average relative difference between calculated and measured dose values was less than 2% for both protons and carbon ions. The mean γ passing rate (PR) was around 98% for both particle species. For clinical treatment beams, DICOM-based recalculations showed a γ-PR more than 99% for both particle species. The same level of agreement was preserved for protons when moving to log-file-based recalculations. A score of around 95% was registered for carbon ion beams, once excluding low-quality machine log-files. Unsigned average relative difference against acquired data was less than 2% also for real clinical beams. FRoG was proven as an accurate and reliable tool for PSQA in scanning light ion beam therapy. The proposed method allows for an extremely efficient workflow, without compromising the quality of the plan verification procedure.

A review on reference dosimetry in radiation therapy with proton and light ion beams: status and impact of new developments

This review focuses on reference dosimetry of proton and light ion beams used for cancer treatments. The background is the recommendation from the International Atomic Energy Agency in the Technical Report Series 398 and the recent publication of the International Commission on Radiation Units and Measurements Report 93 (Prescribing, Recording, and Reporting Light Ion Beam Therapy). These recommendations are briefly summarised, focusing on protons and carbon ions, as the most used ion types worldwide. Following these guidelines, the different aspects involving absolute dose measurements with ionisation chambers are discussed. A description of the current challenges and adaptions for the future is given for new developments. One of them, with a direct impact on ionisation chambers, is the influence of magnetic fields since efforts are made to integrate magnetic resonance imaging techniques into ion beam treatments, allowing online imaging with high soft-tissue contrast. Additionally, upcoming treatments with helium beams call for more experimental studies and simulations characterising the response of ionisation chambers, and at the same time following the international recommendations. Lastly, since the use of helium ion beams may present the advantage of reduced number of secondary particles as compared to carbon ion beams, the role of secondary neutrons and their impact on secondary cancer incidence needs to be assessed.

The GATE-RTion/IDEAL Independent Dose Calculation System for Light Ion Beam Therapy

Patient specific quality assurance can be improved using an independent dose calculation system. In addition, the implementation of such a system may support light ion beam therapy facilities in reducing the needs for beam time, by substituting some of the experimental patient-specific quality assurance procedures by independent dose calculation. The GATE-RTion-based IDEAL system for light ion beam therapy was developed for this purpose. It was built in a DICOM-in, DICOM-out fashion, for easy integration into a state-of-the-art technology-based workflow for scanned ion beam therapy. This article describes the IDEAL system, followed by its clinical implementation at MedAustron for proton and carbon ion beams. Medical physics acceptance and commissioning steps are presented together with key results: for 3D proton and carbon ion reference boxes, 97% of the points agreed within 5% from the measurements. Experimental validation of stopping powers using real pig samples were between 1.8% and 3.8% for soft tissues. Finally, five clinical cases are described, i.e. two proton and three carbon ion treatments. Dosimetric benchmarking against TPS calculations are presented and discussed in details. As expected, the IDEAL software evidenced limitations arising from the pencil beam algorithm available in the TPS for carbon ions, especially in the presence of air cavities. The IDEAL system was found to satisfy the clinical requirements for independent dose calculation of scanned ion beam delivery systems and is being clinically implemented at MedAustron. The open-source code as well as the documentation was released on the OpenGATE collaboration website, thus allowing for long term maintenance and future upgrades based on a more widespread utilization.

Monte Carlo computation of 3D distributions of stopping power ratios in light ion beam therapy using GATE-RTion.

This paper presents a novel method for the calculation of three-dimensional (3D) Bragg-Gray water-to-detector stopping power ratio (sw,det ) distributions for proton and carbon ion beams. Contrary to previously published fluence-based calculations of the stopping power ratio, the sw,det calculation method used in this work is based on the specific way GATE/Geant4 scores the energy deposition. It only requires the use of the so-called DoseActor, as available in GATE, for the calculation of the sw,det at any point of a 3D dose distribution. The simulations are performed using GATE-RTion v1.0, a dedicated GATE release that was validated for the clinical use in light ion beam therapy. The Bragg-Gray water-to-air stopping power ratio (sw,air ) was calculated for monoenergetic proton and carbon ion beams with the default stopping power data in GATE-RTion v1.0 and the new ICRU90 recommendation. The sw,air differences between the use of the default and the ICRU90 configuration were 0.6% and 5.4% at the physical range (R80 - 80% dose level in the distal dose fall-off) for a 70MeV proton beam and a 120MeV/u carbon ion beam, respectively. For protons, the sw,det results for lithium fluoride, silicon, gadolinium oxysulfide, and the active layer material of EBT2 (radiochromic film) were compared with the literature and a reasonable agreement was found. For a real patient treatment plan, the 3D distributions of sw,det in proton beams were calculated. Our method was validated by comparison with available literature data. Its equivalence with Bragg-Gray cavity theory was demonstrated mathematically. The capability of GATE-RTion v1.0 for the sw,det calculation at any point of a 3D dose distribution for simple and complex proton and carbon ion plans was presented.

The practical radius of a pencil beam in proton therapy

The central Gaussian shaped high dose region of a pencil beam (PB) in light ion beam therapy (LIBT) is enveloped by a low dose region causing non-negligible field size effects and impairs the dose calculation accuracy considerably if the low dose envelope is not well modeled. The purpose of this study was to calculate the practical radius, Rc, at which a PB does not influence a field more than a certain accuracy level.Lateral dose profiles of proton beams in water were simulated using GATE/Geant4. Those lateral dose profiles were integrated numerically and used to calculate field size factors (FSFs). The Rc was then determined such, that the lateral dose at radii exceeding Rc can be neglected without compromising the FSF of a 20cm×20cm field more than a desired accuracy level c. The practical radius Rc yielding c=0.5% was compared to the frequently applied concept of full width at a ratio x of the maximum (FWxM). The sensitivity to variations of the beam width was tested by increasing the initial beam width σC of the clinical beam model by 0.5 and 1mm, respectively.Neglecting the dose at radii exceeding Rc resulted in the desired FSF accuracy, whereas using the FW0.01%M cut resulted in varying accuracy. In order to yield a constant FSF accuracy, the ratio x in FWxM ranged from 0.003% to 0.065% of the maximum. In contrast to Rc, FWxM was sensitive to variations of the initial beam width. The maximum Rc over all depths was less than 7cm for the low(62.4MeV) and medium(148.2MeV) proton energy beam, which suggests that a plane parallel ionization chamber exceeding that radius is sufficient to acquire laterally integrated depth dose distributions for those energies. However, this holds not true for the highest energy (252.7MeV) or when including a range shifter (RaShi). The values of Rc are specific to our beam line configuration as the maximum Rc was depending on both, the scattering material in the Nozzle as well as the distance of the air-gap between Nozzle and phantom.

Technical Note: GATE-RTion: a GATE/Geant4 release for clinical applications in scanned ion beam therapy.

GATE-RTion is a validated version of GATE for clinical use in the field of light ion beam therapy. This paper describes the GATE-RTion project and illustrates its potential through clinical applications developed in three European centers delivering scanned proton and carbon ion treatments. GATE-RTion is a collaborative framework provided by the OpenGATE collaboration. It contains a validated GATE release based on a specific Geant4 version, a set of tools to integrate GATE into a clinical environment and a network for clinical users. Three applications are presented: Proton radiography at the Centre Antoine Lacassagne (Nice, France); Independent dose calculation for proton therapy at the Christie NHS Foundation Trust (Manchester, UK); Independent dose calculation for protons and carbon ions at the MedAustron Ion Therapy center (Wiener Neustadt, Austria). GATE-RTion builds the bridge between researchers and clinical users from the OpenGATE collaboration in the field of Light Ion Beam Therapy. The applications presented in three European facilities using three completely different machines (three different vendors, cyclotron- and synchrotron-based systems, protons, and carbon ions) demonstrate the relevance and versatility of this project.

Methodology paper: a novel phantom setup for commissioning of scanned ion beam delivery and TPS

BackgroundCommissioning of treatment planning systems (TPS) and beam delivery for scanned light ion beams is an important quality assurance task. This requires measurement of large sets of high quality dosimetric data in anthropomorphic phantoms to benchmark the TPS and dose delivery under realistic conditions.MethodA novel measurement setup is described, which allows for an efficient collection of a large set of accurate dose data in complex phantom geometries. This setup allows dose measurements based on a set of 24 small volume ionization chambers calibrated in dose to water and mounted in a holder, which can be freely positioned in a water phantom with various phantoms mounted in front of the water tank. The phantoms can be scanned in a CT and a CT-based treatment planning can be performed for a direct benchmark of the dose calculation algorithm in various situations.ResultsThe system has been used for acceptance testing in scanned light ion beam therapy at Heidelberg Ion Beam Therapy Center for scanned proton and carbon ion beams. It demonstrated to be useful to collect large amounts of high quality data for comparison with the TPS calculation using various phantom geometries.ConclusionThe setup is an efficient tool for commissioning and verification of treatment planning systems. It is especially suited for dynamic beam delivery, as many data points can be obtained during a single plan delivery, but can be adapted also for other dynamic therapies, like rotational IMRT.

Characterization of a multilayer ionization chamber prototype for fast verification of relative depth ionization curves and spread-out-Bragg-peaks in light ion beam therapy.

To dosimetrically characterize a multilayer ionization chamber (MLIC) prototype for quality assurance (QA) of pristine integral ionization curves (ICs) and spread-out-Bragg-peaks (SOBPs) for scanning light ion beams. QUBE (De.Tec.Tor., Torino, Italy) is a modular detector designed for QA in particle therapy (PT). Its main module is a MLIC detector, able to evaluate particle beam relative depth ionization distributions at different beam energies and modulations. The charge collecting electrodes are made of aluminum, for a nominal water equivalent thickness (WET) of ~75mm. The detector prototype was calibrated by acquiring the signals in the initial plateau region of a pristine BP and in terms of WET. Successively, it was characterized in terms of repeatability response, linearity, short-term stability and dose rate dependence. Beam-induced measurements of activation in terms of ambient dose equivalent rate were also performed. To increase the detector coarse native spatial resolution (~2.3mm), several consecutive acquisitions with a set of certified 0.175-mm-thick PMMA sheets (Goodfellow, Cambridge Limited, UK), placed in front of the QUBE mylar entrance window, were performed. The ICs/SOBPs were achieved as the result of the sum of the set of measurements, made up of a one-by-one PMMA layer acquisition. The newly obtained detector spatial resolution allowed the experimental measurements to be properly comparable against the reference curves acquired in water with the PTW Peakfinder. Furthermore, QUBE detector was modeled in the FLUKA Monte Carlo (MC) code following the technical design details and ICs/SOBPs were calculated. Measurements showed a high repeatability: mean relative standard deviation within ±0.5% for all channels and both particle types. Moreover, the detector response was linear with dose (R2 >0.998) and independent on the dose rate. The mean deviation over the channel-by-channel readout respect to the reference beam flux (100%) was equal to 0.7% (1.9%) for the 50% (20%) beam flux level. The short-term stability of the gain calibration was very satisfying for both particle types: the channel mean relative standard deviation was within ±1% for all the acquisitions performed at different times. The ICs obtained with the MLIC QUBE at improved resolution satisfactorily matched both the MC simulations and the reference curves acquired with Peakfinder. Deviations from the reference values in terms of BP position, peak width and distal fall-off were submillimetric for both particle types in the whole investigated energy range. For modulated SOBPs, a submillimetric deviation was found when comparing both experimental MLIC QUBE data against the reference values and MC calculations. The relative dose deviations for the experimental MLIC QUBE acquisitions, with respect to Peakfinder data, ranged from ~1% to ~3.5%. Maximum value of 14.1μSv/h was measured in contact with QUBE entrance window soon after a long irradiation with carbon ions. MLIC QUBE appears to be a promising detector for accurately measuring pristine ICs and SOBPs. A simple procedure to improve the intrinsic spatial resolution of the detector is proposed. Being the detector very accurate, precise, fast responding, and easy to handle, it is therefore well suited for daily checks in PT.

46. Medical commissioning of a Light Ion Beam Therapy facility: The MedAustron experience of starting up using innovative technology

Introduction One of the methods of acquiring equipment for a Light Ion Beam Therapy (LIBT) facility is to establish collaboration between the customer and one or more manufacturers, so all parties work towards developing the best equipment for the facility. Following this strategy the specifications for a dual particle synchrotron-based facility including accelerator, beam delivery system (BDS), patient alignment systems (PAS), treatment planning systems (TPS), and medical software treatment system have been developed at MedAustron and cooperation activity with the correspondent manufacturers was established. The advantage of having multiple manufacturers was that the MedAustron could select the best equipment available for each component, but on another side the drawback was that in many cases the delivered equipment was at the level of “working prototype” and the acceptance and even commissioning process was used to bring with common effort the prototype to the status of a medical product. This type of implementation requires careful planning and distribution of measurement equipment and human resources. For example, to save time the commissioning of BDS was performed in one treatment room and the commissioning of PAS was simultaneously done in the second room. This allowed effectively using beam time and on later stage to “copy and paste” the calibration results from one room to another. The paper is describing the MedAustron experience in commissioning of a LIBT facility. Methods The major tasks for commissioning of LIBT facility are to calibrate the various parameters of the BDS and PAS and test these systems under varying clinical conditions, to determine appropriate intervention thresholds, acquire data for entry into the TPS, and perform end-to-end tests for planned patient treatments. Since MedAustron is a dual particle facility, the BDS in two fixed beam rooms is based on the nozzles without movable snouts and hence the same setup is used for carbon ions and protons. In order to preserve ballistic capabilities of protons in a dual-particle facility, the patient needs to be positioned as close as possible to the nozzle and we chose as design a non-isocentric treatment planning and patient positioning system to reduce the air gap. This workflow is supported by a collision avoidance system at different stages of the treatment. It starts with an automated collision detection integrated into the treatment planning phase. In the treatment room robotic table movements, imaging and beam delivery are supported by the record and verify system and checked upfront for collision. Finally, during robot movements the same checks are performed in real time for avoiding potential collision. Results All involved systems were successfully commissioned and are already in clinical routine operation beginning with the first patient. Using TPS RayStation and specific software there is the possibility at the planning stage to reduce the air gap for each specific proton beam. All parts involved like e.g. the treatment room, patient position system, nozzles, the patient as avatar are modelled and the treatment position is checked for collisions and consequently potential collisions are displayed. In addition the Record and Verify system supports the whole workflow starting from patient step-on, position verification with the ImagingRing™ system and application of the correction vector at the treatment position including the non-isocentric setup. The patient positioning system and the patient position verification system (ImagingRing™) including the tracking camera for correction of the table sag due to the patient weight and application of the correction vector from image registration were also additionally commissioned for that purpose. Conclusions The MedAustron LIBT facility was successfully commissioned, including setup for non-isocentric proton treatments. In addition the whole workflow was tested via several end-to-end test procedures. With all the effort spend and the highly integrated workflow a high quality of proton treatment within a dual particle facility could be achieved. All patients treated up to now at MedAustron benefited from this possibility.

Implementation of dosimetry equipment and phantoms at the MedAustron light ion beam therapy facility.

To describe the implementation of dosimetry equipment and phantoms into clinical practice of light ion beam therapy facilities. This work covers not only standard dosimetry equipment such as computerized water scanners, films, 2D-array, thimble, and plane parallel ionization chambers, but also dosimetry equipment specifically devoted to the pencil beam scanning delivery technique such as water columns, scintillating screens or multilayer ionization chambers. Advanced acceptance testing procedures developed at MedAustron and complementary to the standard acceptance procedures proposed by the manufacturer are presented. Detailed commissioning plans have been implemented for each piece of dosimetry equipment and include an estimate of the overall uncertainty budget for the range of clinical use of each device. Some standard dosimetry equipment used in many facilities was evaluated in detail: for instance, the recombination of a 2D-array or the potential use of a microdiamond detector to measure reference transverse dose profiles in water in the core of the primary pencil beams and in the low-dose nuclear halo (over four orders of magnitude in dose). The implementation of dosimetry equipment as described in this work allowed determining absolute spot sizes and spot positions with an uncertainty better than 0.3mm. Absolute ranges are determined with an uncertainty comprised of 0.2-0.6mm, depending on the measured range and were reproduced with a maximum difference of 0.3mm over a period of 12months using three different devices. The detailed evaluation procedures of dosimetry equipment and phantoms proposed in this work could serve as a guidance for other medical physicists in ion beam therapy facilities and also in conventional radiation therapy.

The technological basis for adaptive ion beam therapy at MedAustron: Status and outlook

The ratio of patients who need a treatment adaptation due to anatomical variations at least once during the treatment course is significantly higher in light ion beam therapy (LIBT) than in photon therapy. The ballistic behaviour of ion beams makes them more sensitive to changes. Hence, the delivery of LIBT has always been supported by state of art image guidance. On the contrary CBCT technology was adapted for LIBT quite late. Adaptive concepts are being implemented more frequently in photon therapy and also efficient workflows are needed for LIBT. The MedAustron Ion Beam Therapy Centre was designed to allow the clinical implementation of adaptive image-guided concepts. The aim of this paper is to describe the current status and the potential future use of the technology installed at MedAustron. Specifically addressed is the beam delivery system, the patient alignment system, the treatment planning system as well as the Record & Verify system. Finally, an outlook is given on how high quality X-ray imaging, MR image guidance, fast and automated treatment planning as well as in vivo range verification methods could be integrated.

EP-1450: Implementation of dosimetry equipment and phantoms in clinical practice of light ion beam therapy

EP-1450: Implementation of dosimetry equipment and phantoms in clinical practice of light ion beam therapy

Cross section measurements for production of positron emitters for PET imaging in carbon therapy

In light ion beam therapy, positron (β+) emitters are produced by the tissue nuclei through nuclear interactions with the beam ions. They can be used for the verification of the delivered dose using positron emission tomography by comparing the spatial distribution of the β+ emitters activity to a computer simulation taking into account the patient morphology and the treatment plan. However, the accuracy of the simulation greatly depends on the method used to generate the nuclear interactions producing these emitters. In the case of Monte Carlo (MC) simulations, the nuclear interaction models still lack the required accuracy due to insufficient experimental cross section data. This is particularly true for carbon therapy where literature data on fragmentation cross sections of a carbon beam with targets of medical interest are very scarce. Therefore, we performed at GANIL in July 2016 measurements on β+ emitter production cross sections with a carbon beam at 25, 50, and 95 MeV/nucleon on thin targets (C, N, O, and PMMA). We extracted the production cross section of C10,11, N13, and O14,15 that are essential to constrain or develop MC nuclear fragmentation models.

1. New technologies for light ion beam therapy facilities

Introduction The use of Light Ion Beam Therapy (LIBT) in the context of cancer treatment has been increasing over the past 25 years and the technology is still developing. The main areas of development include accelerator technology, gantries, beam delivery techniques, patient positioning and alignment systems, as well as medical software systems. While protons are becoming more and more available worldwide, carbon ion facilities are still seldom. Other type of ions such as Helium or Oxygen ions are also investigated at a research level, but were not considered in this presentation. Methods This presentation proposes an overview of the current technology available in LIBT facilities, as well the current trends and developments for the near future. Results While scattering techniques are still most used worldwide, active scanning techniques are considered to be the future of LIBT as they allow better tumor conformation, sparing of organs at risks and facilitate Intensity-Modulated Ion Therapy. Robotic Patient Positioning Systems (PPS) have been used since 1991 and allow very accurate and precise positioning of the patient. However, it is only since recently that IGRT capabilities similar to conventional radiation therapy are offered as a standard option by many vendors. A general trend is the reduction of the size and consequently the costs of the facilities, in order become more widely accessible. Compact single room proton therapy solutions are now proposed by many companies and include all necessary features for delivering high quality treatments (active scanning delivery, rotating gantries, robotic PPS and IGRT capabilities including CBCT). For carbon ions, the reduction of the size of the accelerators and gantries is still a challenge. Conclusions The technology used in LIBT is still under rapid development. Today the vendors are proposing more affordable proton solutions having fully equipped treatment rooms and including the latest technology in terms of beam delivery and imaging systems. Developments allowing carbon ions to become more widely affordable are more complex.

Assessment of improved organ at risk sparing for meningioma: Light ion beam therapy as boost versus sole treatment option

PurposeTo compare photons, protons and carbon ions and their combinations for treatment of atypical and anaplastical skull base meningioma. Material and methodsTwo planning target volumes (PTVinitial/PTVboost) were delineated for 10 patients (prescribed doses 50Gy(RBE) and 10Gy(RBE)). Plans for intensity modulated photon (IMXT), proton (IMPT) and carbon ion therapy (12C) were generated assuming a non-gantry scenario for particles. The following combinations were compared: IMXT+IMXT/IMPT/12C; IMPT+IMPT/12C; and 12C+12C. Plan quality was evaluated by target conformity and homogeneity (CI, HI), V95%, D2% and D50% and dose-volume-histogram (DVH) parameters for organs-at-risk (OAR). If dose escalation was possible, it was performed until OAR tolerance levels were reached. ResultsCI was worst for IMXT. HI<0.05±0.01 for 12C was significantly better than for IMXT. For all treatment options dose escalation above 60Gy(RBE) was possible for four patients, but impossible for six patients. Compared to IMXT+IMXT, ion beam therapy showed an improved sparing for most OARs, e.g. using protons and carbon ions D50% was reduced by more than 50% for the ipsilateral eye and the brainstem. ConclusionHighly conformal IMPT and 12C plans could be generated with a non-gantry scenario. Improved OAR sparing favors both sole 12C and/or IMPT plans.

Relative biological effectiveness of high linear energy transfer α-particles for the induction of DNA-double-strand breaks, chromosome aberrations and reproductive cell death in SW-1573 lung tumour cells

Ionizing radiation-induced foci (IRIF) of DNA repair-related proteins accumulated at DNA double-strand break (DSB) sites have been suggested to be a powerful biodosimetric tool. However, the relationship between IRIF induction and biologically relevant endpoints, such as cell death and formation of chromosome rearrangements is less clear, especially for high linear energy transfer (LET) radiation. It is thus not sufficiently established whether IRIF are valid indicators of biological effectiveness of the various radiation types. This question is more significant in light of the recent advancements in light ion-beam and radionuclide therapy. Dose-effect relationships were determined for the induction of DNA-DSBs, chromosome aberrations and reproductive cell death in cultured SW-1573 cells irradiated with γ-rays from a Cs-137 source or with α-particles from an Am-241 source. Values of relative biological effectiveness (RBE) of the high LET α-particles were derived for these effects. DNA-DSB were detected by scoring of γ-H2AX foci, chromosome aberrations by fragments and translocations using premature chromosome condensation and cell survival by colony formation. Analysis of dose-effect relations was based on the linear-quadratic model. Except for the survival curves, for other effects no significant contribution was derived of the quadratic term in the range of doses up to 2Gy of γ-rays. Calculated RBE values derived for the linear component of dose-effect relations for γ-H2AX foci, cell reproductive death, chromosome fragments and colour junctions are 1.0±0.3, 14.7±5.1, 15.3±5.9 and 13.3±6.0, respectively. RBE values calculated at a certain biological effect level are 1, 4, 13 and 13, respectively. The RBE values derived from the LQ model are preferred as they are based on clinically relevant doses. The results show that with low LET radiation only a small fraction of the numerous DNA-DSBs yield chromosome damage and reproductive cell death. It is concluded that many of the chromosomal aberrations detected by premature chromosome condensation do not cause reproductive cell death. Furthermore, RBE values for DNA-DSB detectable by γ-H2AX foci shortly after irradiation, provide no information relevant to applications of high LET radiation in radiotherapy. The RBE values of chromosome aberrations assessed by premature chromosome condensation are close to the value for reproductive cell death. This suggests possible relevance to assess RBE values for radiotherapy with high LET ions.

Clinical and radiobiological advantages of single-dose stereotactic light-ion radiation therapy for large intracranial arteriovenous malformations

Radiation treatment of large arteriovenous malformations (AVMs) remains difficult and not very effective, even though seemingly promising methods such as staged volume treatments have been proposed by some radiation treatment centers. In symptomatic patients harboring large intracranial AVMs not amenable to embolization or resection, single-session high-dose stereotactic radiation therapy is a viable option, and the special characteristics of high-ionization-density light-ion beams offer several treatment advantages over photon and proton beams. These advantages include a more favorable depth-dose distribution in tissue, an almost negligible lateral scatter of the beam, a sharper penumbra, a steep dose falloff beyond the Bragg peak, and a higher probability of vascular response due to high ionization density and associated induction of endothelial cell proliferation and/or apoptosis. Carbon ions were recently shown to be an effective treatment for skull-base tumors. Bearing that in mind, the authors postulate that the unique physical and biological characteristics of light-ion beams should convey considerable clinical advantages in the treatment of large AVMs. In the present meta-analysis the authors present a comparison between light-ion beam therapy and more conventional modalities of radiation treatment with respect to these lesions. Dose-volume histograms and data on peripheral radiation doses for treatment of large AVMs were collected from various radiation treatment centers. Dose-response parameters were then derived by applying a maximum likelihood fitting of a binomial model to these data. The present binomial model was needed because the effective number of crucial blood vessels in AVMs (the number of vessels that must be obliterated to effect a cure, such as large fistulous nidus vessels) is low, making the Poisson model less suitable. In this study the authors also focused on radiobiological differences between various radiation treatments. Light-ion Bragg-peak dose delivery has the precision required for treating very large AVMs as well as for delivering extremely sharp, focused beams to irregular lesions. Stereotactic light-ion radiosurgery resulted in better angiographically defined obliteration rates, less white-matter necrosis, lower complication rates, and more favorable clinical outcomes. In addition, in patients treated by He ion beams, a sharper dose-response gradient was observed, probably due to a more homogeneous radiosensitivity of the AVM nidus to light-ion beam radiation than that seen when low-ionization-density radiation modalities, such as photons and protons, are used. Bragg-peak radiosurgery can be recommended for most large and irregular AVMs and for the treatment of lesions located in front of or adjacent to sensitive and functionally important brain structures. The unique physical and biological characteristics of light-ion beams are of considerable advantage for the treatment of AVMs: the densely ionizing beams of light ions create a better dose and biological effect distribution than conventional radiation modalities such as photons and protons. Using light ions, greater flexibility can be achieved while avoiding healthy critical structures such as diencephalic and brainstem nuclei and tracts. Treatment with the light ion He or Li is more suitable for AVMs <or= 10 cm(3), whereas treatment with the light ion Li, Be, or C may be more appropriate for larger AVMs. A binomial model based on the effective number of crucial vessels in the AVM may be used quite well to predict AVM obliteration probabilities for both small and large AVMs when therapies involving either photons or light ions are used.

On the clinical spatial resolution achievable with protons and heavier charged particle radiotherapy beams

The ‘sub-millimetre precision’ often claimed to be achievable in protons and light ion beam therapy is analysed using the Monte Carlo code SHIELD-HIT for a broad range of energies. Based on the range of possible values and uncertainties of the mean excitation energy of water and human tissues, as well as of the composition of organs and tissues, it is concluded that precision statements deserve careful reconsideration for treatment planning purposes. It is found that the range of I-values of water stated in ICRU reports 37, 49 and 73 (1984, 1993 and 2005) for the collision stopping power formulae, namely 67 eV, 75 eV and 80 eV, yields a spread of the depth of the Bragg peak of protons and heavier charged particles (carbon ions) of up to 5 or 6 mm, which is also found to be energy dependent due to other energy loss competing interaction mechanisms. The spread is similar in protons and in carbon ions having analogous practical range. Although accurate depth–dose distribution measurements in water can be used at the time of developing empirical dose calculation models, the energy dependence of the spread causes a substantial constraint. In the case of in vivo human tissues, where distribution measurements are not feasible, the problem poses a major limitation. In addition to the spread due to the currently accepted uncertainties of their I-values, a spread of the depth of the Bragg peak due to the varying compositions of soft tissues is also demonstrated, even for cases which could be considered practically identical in clinical practice. For these, the spreads found were similar to those of water or even larger, providing support to international recommendations advising that body-tissue compositions should not be given the standing of physical constants. The results show that it would be necessary to increase the margins of a clinical target volume, even in the case of a water phantom, due to an ‘intrinsic basic physics uncertainty’, adding to those margins usually considered in normal clinical practice due to anatomical or therapeutic strategy reasons. Individualized patient determination of tissue composition along the complete beam path, rather than CT Hounsfield numbers alone, would also probably be required even to reach ‘sub-centimetre precision’.

Osteosarcomas and adult soft tissue sarcomas: is there a place for high LET radiation therapy?

The treatment policy for non-operable or unresectable osteosarcoma and adult soft tissue sarcoma remains unclear or controversial, despite the progress achieved in multimodality treatments. The poor results obtained by radiotherapy alone led to consider these tumours as radioresistant and to use high Linear Energy Transfer (LET) particles, such as neutrons. These particles benefit from a higher Relative Biological Efficiency (RBE) and other biological properties tending to decrease radioresistance phenomenas. From the non randomized studies previously published, neutron-therapy seems to give better local control rates, compared to photons and/or electrons. But these results are not strongly convincing, due to the large heterogeneities in patient recruitment, histological types, sizes, sites and moreover to the high complication rates encountered in some studies, even if they are mainly imputable to the use of low energy machines. The use of high-energy hospital-based accelerators combined to the possibilities of accurate dose distribution offered by conformal therapy, the potential value of light ion beam therapy combining the dose distribution advantages of protons to the biological properties of high LET particles, represent the directions in which progresses might be made for further improvement of non-operable or unresectable osteosarcoma and soft tissue sarcomas treatment results.