Combined tumour treatment by coupling conventional radiotherapy to an additional dose contribution from thermal neutrons

Aim: To employ the thermal neutron background in conventional X-rays radiotherapy treatments in order to add a localized neutron dose boost to the patient, enhancing the treatment effectiveness. Background: Conventional linear accelerators for radiotherapy produce fast secondary neutrons with a mean energy of about 1 MeV due to (\u3b3, n) reaction. This neutron field, isotropically distributed, is considered as an extra unaccounted dose during the treatment. Moreover, considering the moderating effect of human body, a thermal neutron field is localized in the tumour area: this neutron background could be employed for Boron Neutron Capture Therapy (BNCT) by previously administering a boron (10B enriched) carrier to the patient, acting as a localized radiosensitizer. The thermal neutron absorption in the 10B enriched tissue will improve radiotherapy effectiveness. Materials and Methods: The feasibility of the proposed method was investigated by using simplified tissue-equivalent phantoms with cavities in correspondence of relevant tissues or organs, suited for dosimetric measurements. A 10 cm 7 10 cm square photon field with different energies was delivered to the phantoms. Additional exposures were implemented, using a compact neutron photo-converter-moderator assembly, with the purpose of modifying the mixed photon-neutron field in the treatment region. Doses due to photons and neutrons were both measured by using radiochromic films and superheated bubble detectors, respectively, and simulated with Monte Carlo codes. Results: For a 10 cm 7 10 cm square photon field with accelerating potentials 6 MV, 10 MV and 15 MV, the neutron dose equivalent in phantom was measured and its values was 0.07 mGy/Gy (neutron dose equivalent / photon absorbed dose at isocentre), 0.99 mGy/Gy and 2.22 mGy/Gy, respectively. For a 18 MV treatment, simulations and measurements quantified the thermal neutron field in the treatment zone in 1.55 7 107 cm 122 Gy 121. Assuming a BNCT- standard 10B concentration in tumour tissue, the calculated additional BNCT dose at 4 cm depth in phantom would be 1.5 mGy-eq/Gy. This ratio would reach 43 mGy- eq/Gy for an intensity modulated radiotherapy treatment (IMRT). When a specifically designed compact neutron photo-converter-moderator assembly is applied to the LINAC to enhance the thermal neutron field, the photon field is modified. Particularly, a 15 MV photon field produces a dose profile very similar to that would be produced by a 6 MV field in absence of the photo-converter-moderator assembly. As far as the thermal neutron field is concerned, more thermal neutrons are present, and thermal neutrons per photon increase of a factor 3 to 12 according to the depth in phantom and to different photoconverter geometries. By contrast, the photo-converter-moderator assembly was found to reduce fast neutrons of a factor 16 in the direction of the incident beam. Conclusions: The parasitic thermal neutron component during conventional high- energy radiotherapy could be exploited to produce additional therapeutic doses if the 10B-carrier was administered to the patient. This radiosensitization effect could be increased by modifying the treatment field by using the specifically designed neutron photo-converter-moderator assembly

Flattening filter-free accelerators: a report from the AAPM Therapy Emerging Technology Assessment Work Group.

This report describes the current state of flattening filter-free (FFF) radiotherapy beams implemented on conventional linear accelerators, and is aimed primarily at practicing medical physicists. The Therapy Emerging Technology Assessment Work Group of the American Association of Physicists in Medicine (AAPM) formed a writing group to assess FFF technology. The published literature on FFF technology was reviewed, along with technical specifications provided by vendors. Based on this information, supplemented by the clinical experience of the group members, consensus guidelines and recommendations for implementation of FFF technology were developed. Areas in need of further investigation were identified. Removing the flattening filter increases beam intensity, especially near the central axis. Increased intensity reduces treatment time, especially for high-dose stereotactic radiotherapy/radiosurgery (SRT/SRS). Furthermore, removing the flattening filter reduces out-of-field dose and improves beam modeling accuracy. FFF beams are advantageous for small field (e.g., SRS) treatments and are appropriate for intensity-modulated radiotherapy (IMRT). For conventional 3D radiotherapy of large targets, FFF beams may be disadvantageous compared to flattened beams because of the heterogeneity of FFF beam across the target (unless modulation is employed). For any application, the nonflat beam characteristics and substantially higher dose rates require consideration during the commissioning and quality assurance processes relative to flattened beams, and the appropriate clinical use of the technology needs to be identified. Consideration also needs to be given to these unique characteristics when undertaking facility planning. Several areas still warrant further research and development. Recommendations pertinent to FFF technology, including acceptance testing, commissioning, quality assurance, radiation safety, and facility planning, are presented. Examples of clinical applications are provided. Several of the areas in which future research and development are needed are also indicated

Realization of radiobiological in vitro cell experiments at conventional X-ray tubes and unconventional radiation sources

[no abstract available

HIGH-THROUGHPUT MAPPING OF THE BIOLOGICAL EFFECTS OF PARTICLE THERAPY

Radiation therapy is an essential tool in the cure of many cancer patients. Charged particle based radiation therapies are gaining momentum as the physical dose distributions of ions are superior to standard photons due their limited range. Additionally, charged particle radiation has been shown to have linear energy transfer (LET) specific relative biological effectiveness (RBE) when compared to photons. It is essential to employ accurate biophysical models for particle beams in order to maximize the therapeutic potential of particle therapy through the introduction of biologically optimized treatment planning. The development of such models requires the support of large amounts of accurate physical and biological data for each pristine beam. Unfortunately, such data are limited and difficult to obtain. This work presents the development of a high-throughput irradiation methodology that utilizes automated high-throughput screening techniques to sample multiple locations along a therapeutic ion therapy beam in a single irradiation. Using a special irradiation apparatus designed and validated by our group, RBEs of adherent lung cancer cell lines at 12 positions along proton beams at the MD Anderson Proton Therapy Center (PTC) and the Heidelberg Ion Therapy (HIT) facility were measured. RBEs for helium and carbon ion beams were also measured at the HIT facility. This system was further employed to perform image-based, high-throughput mechanistic DNA damage response studies following exposure to particles at varying LETs. Furthermore, the biological response to particles was examined in additional model systems including glioma stem cell spheroids and normal rat brain organoids. For protons, all model systems demonstrated a rapid rise in RBE beyond the Bragg peak. These findings contrast with several current model predictions which assume the RBE trend linearly scales with proton LET. For the heavier particle measurements, we found absolute RBE values and relative trends comparable to literature values. However, overkill effects occurred for lower LETs than previously reported. DNA damage response assays correlated with RBE measurements. The discrepancy between model predictions and experimental data, especially in the high-LET regions, requires rigorous experimental validation to ensure the accuracy of existing models. The developed high-throughput irradiation system enables the rapid measurement of biological response data which will contribute to a more complete mapping of particle biological effects as well as biological susceptibilities of different cell types to charged particle radiation. Ultimately, this knowledge will contribute to more comprehensive biophysical models and the production of biologically optimized intensity-modulated particle therapy plans

Synthesis of multifunctional nanoparticles for imaging and enhancement in therapy

The purpose of this work was to synthesize nanoparticles composed of high atomic number elements and semiconductor material in a core/shell structure for the potential to be used as enhancers for radiotherapy as well as luminescence imaging platforms. Additionally, to quantify their role in free radical production after exposure to ionizing radiation through chemical routes. Spherical gold nanoparticles were synthesized via a citrate stabilizer method. Two sizes of 12nm and 25 nm gold spheres were used as the cores for the europium-doped gadolinium vanadate flower-shaped shell. The production of 7-hydroxycoumarin-3-carboxylic acid in an aqueous environment upon kV irradiation of its precursor, coumarin-3-carboxylic acid, was assessed and used as a fluorescence detector for hydroxyl radicals. The quantification of excess or moderation of hydroxyl radicals in the presence of the nanomaterial as compared to a control sample can indicate the potential for increased DNA damage for purposes such as tumor control. This work indicates the potential for physical and chemical enhancement in the presence of nanomaterials

Dosimetric Tranferability of a Medical Linear Accelerator Mounted Mini-Beam Collimator

The goal of this study was the dosimetric characterization of a mini-beam collimator on three clinically beam matched Varian iX linear accelerators. Measurements of the beam quality (%DD(10)), peak-to-valley dose ratio (PVDR), collimator factor (CF), and relative output factor (OF) were carried out for 2 cm x 2 cm, 3 cm x 3 cm, 4 cm x 4 cm, and 5 cm x 5 cm mini-beam collimated 6 MV fields on each linear accelerator. As well, Monte Carlo simulation of the mini-beam collimated fields were used to link the measurement results to a validated linear accelerator model. The quality of the mini-beam collimated field was clinically equivalent to that of the open field. Changes in the mini-beam collimated field in response to changes in both field size and collimator inclination were consistent across all three linear accelerators. However, PVDR, collimator factors, and relative output factors varied in excess of the measurement uncertainty, revealing a difference in the mini-beam collimated fields of each linear accelerator. The change in PVDR was proportional to that of the collimator factor and relative output factor. The Monte Carlo simulations showed that variation in the full-width half-maximum of the linear accelerators’ electron beam incident on the Bremsstrahlung target correlated to the variation in collimator factor and PVDR across the accelerators. These results demonstrate that while the mini-beam collimated field varies across linear accelerators, the effect can be accounted for in the linear accelerator model, allowing the planning and delivery of mini-beam collimated fields using medical linear accelerators

Monte-Carlo simulation of the Siemens Artiste linear accelerator flat 6 MV and flattening-filter-free 7 MV beam line

There have been a number of Monte Carlo studies of clinical linear accelerators in the past years but only few of them focused on flattening filter free beams and a small handful of them consider a Siemens linear accelerator. The aim of this work is to provide the up-to-now missing information on the Siemens Artiste FFF 7 MV beam line using a Monte-Carlo model fit to the realistic dosimetric measurements at the linear accelerator in clinical use at our department. The main Siemens Artiste 6 MV and FFF 7 MV beams were simulated using the Geant4 toolkit. The simulations are compared with the measurements with an ionization chamber in a water phantom to verify the validation of simulation and tune the primary electron parameters. Hereafter, other parameters such as surface dose, spectrum, symmetry, flatness/unflatness, slope, and characteristic off-axis changes are discussed for both Flat and FFF mode. Fine-tuning the electron beam parameters and of the flattening filter were the most important challenges in this simulation, because these parameters verify the validity of the simulation after creating the geometry. In contrast to other vendors (Varian or Elekta), the Siemens implementation increases the incident electron beam energy for the FFF beam line to create closely similar depth-dose curves for the flat 6 MV and FFF 7 MV beams. Therefore, the mean electron energy for the FFF beam was 8.8 MeV and 7.5 MeV for flat 6 MV, the spread energy and spot size of the selected Gaussian distribution source were 0.4 MeV and 1mm, respectively. There is good agreement between calculation and experimental results; the absolute differences were less than 2% and in the most cases less than 1%. The dose rate of the FFF beam was 2.8 (2.96) times higher than for the flattened beam for a field size of 10×10 (20×20) cm2. The penumbra, surface dose and the mean energy of photons decreased by removing the flattening filter. Finally, the results show that the off-axis changes had no strong effect on the mean energy of FFF beams and this effect was even more considerable for the flattened beamVerschiedene Studien haben Monte Carlo Simulationen für klinische Linearbeschleuniger durchgeführt, allerdings waren nur die wenigsten davon auf flächungsfilterfreie (FFF) Energien ausgelegt. Speziell die an den Siemens Linearbeschleunigern verwendete Implementierung der FFF Technik wurde bisher noch nicht mit Monte-Carlo-dosimetrischen Methoden untersucht. Das Ziel dieser Arbeit ist es, diese bisher fehlenden Informationen für eine Siemens Artiste FFF 7 MV Modalität bereitzustellen, unter Verwendung eines Monte Carlo Models, welches an reale dosimetrische Messungen an einem Linearbeschleuniger in klinischer Nutzung an unserer Einrichtung angepasst wurde. Die Hauptenergien der Siemens Artiste Maschine, 6 MV und FFF 7 MV, wurden mit dem Geant 4 Toolkit simuliert. Diese Simulationen wurden mit Messungen verglichen, die mit einer Ionisationskammer im Wasserphantom aufgenommen wurden, um die Validität der Simulation zu verifizieren und die Parameter für die Primärelektronen einzustellen. Im Anschluss werden andere Parameter wie die Oberflächendosis, das Spektrum, die Symmetrie, die flatness bzw. unflatness, die Steigung und die charakteristischen off-axis Veränderungen sowohl für den flachen, als auch den FFF Modus diskutiert. Die Feinabstimmung der Elektronenstrahlparameter sowie des Ausgleichsfilters waren die größten Herausforderungen dieser Simulation. Im Gegensatz zu anderen Anbietern (Varian oder Elekta, wird bei Siemens die Strahlenergie für den FFF Modus erhöht, um annähernd gleiche Tiefendosiskurven für 6 MV und FFF 7 MV Photonen zu erhalten. Aus diesem Grund war die mittlere Elektronenenergie für die FFF-Modalität 8,8 MeV und für 6 MV 7,5 MeV. Die Energiebreite und Spotgröße der gewählten Gaußschen Quelle waren 0,4 MeV und 1 mm. Die Übereinstimmung zwischen den Berechnungenund den experientellen Ergebnissen war sehr gut; die absoluten Unterschiede betrugen weniger als 2%, in den meisten Fällen sogar weniger als 1%. Die Dosisrate des FFF Strahls war 2,8 (2,96)- mal höher als die des flachen Strahls für eine Feldgröße von 10×10 (20×20) cm2. Der Halbschatten, die Oberflächendosis und die mittlere Energie der Photonen wurden durch die Entfernung des Flächungsfilters verringert. Schlussendlich zeigen die Ergebnisse, dass die off-axis Änderungen keinen starken Effekt auf die Strahlenergie der FFF Modalität haben, wobei dieser Effekt deutlich bedeutender für den flachen Strahl war

Assessing the Potential Clinical Impact of Variable Biological Effectiveness in Proton Radiotherapy

It has long been known that proton radiotherapy has an increased biological effectiveness compared to traditional x-ray radiotherapy. This arises from the clustered nature of DNA damage produced by the energy deposition of protons along their tracks in medium. This effect is currently quantified in clinical settings by assigning protons a relative biological effectiveness (RBE) value of 1.1 corresponding to 10% increased effectiveness compared to photon radiation. Numerous studies have shown, however, that the RBE value of protons is variable and can deviate substantially from 1.1, but experimental data on RBE and clinical evidence of its variability remains limited. The potential for using the variable RBE of proton radiation to improve clinical treatment plans has been theorized, but it is accepted that more experimental in vitro and in vivo data are needed before clinical adaptation of these techniques may occur. Nevertheless, it will be important to identify strategies in which the variable nature of proton RBE may be used to inform treatment planning. The goal of this work is thus to investigate if the assumption of a constant proton RBE has an adverse effect in current clinical applications and if the variable biological effectiveness of protons can be quantified from clinical data. First, results from high-resolution experiments quantifying proton RBE are compared to multiple models for calculating RBE. A new model is then proposed which can more accurately reproduce the experimental results. These models are implemented in a Monte Carlo-based dose calculation system and their output is compared for a cohort of pediatric patients treated for brain tumors with proton radiotherapy who subsequently presented with post-treatment image changes identified on magnetic resonance imaging. One RBE model is identified as the best candidate for further study; however, results of volumetric analyses of RBE-weighted dose prove inconclusive in correlating with image changes. A model is developed that can describe the probability of voxel-level image changes (signifying normal tissue damage) based on proton dose and linear energy transfer. The model constitutes the first clinical evidence for the variable biological effectiveness of protons and holds promise for the improvement of proton therapy treatment planning