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![Cumulative positron annihilations per incident primary particle and entrance‐normalized dose as a function of depth for each ion beam. Depth of maximum dose is indicated with Δ; depth of maximum positron annihilation density is indicated with x. Acquisition time was 20 minutes following final the spill. [Color figure can be viewed at wileyonlinelibrary.com]](profile/Daniel-Franklin-4/publication/340591970/figure/fig5/AS:11431281255291398@1719415951130/Cumulative-positron-annihilations-per-incident-primary-particle-and-entrance-normalized.png)
Cumulative positron annihilations per incident primary particle and entrance‐normalized dose as a function of depth for each ion beam. Depth of maximum dose is indicated with Δ; depth of maximum positron annihilation density is indicated with x. Acquisition time was 20 minutes following final the spill. [Color figure can be viewed at wileyonlinelibrary.com]
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Purpose
This work has two related objectives. The first is to estimate the relative biological effectiveness of two radioactive heavy ion beams based on experimental measurements, and compare these to the relative biological effectiveness of corresponding stable isotopes to determine whether they are therapeutically equivalent. The second aim is to...
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Particle therapy in which deep seated tumours are treated using ¹²C ions (Carbon Ions RadioTherapy or CIRT) exploits the high conformity in the dose release, the high relative biological effectiveness and low oxygen enhancement ratio of such projectiles. The advantages of CIRT are driving a rapid increase in the number of centres that are trying to...
Citations
... BIC also showed a consistent underestimation in depth of maximum yield, although the maximum differences were much smaller than for INCL. For context, the difference between the depth of the positron annihilation peak and the Bragg peak with monoenergetic ion beams is of the order of -5.6 ± 0.8 mm for 12 C and -6.6 ± 0.8 mm for 16 O (Augusto et al 2018, Mohammadi et al 2019, Chacon et al 2020. ...
Objective. To compare the accuracy with which different hadronic inelastic physics models across ten Geant4 Monte Carlo simulation toolkit versions can predict positron-emitting fragments produced along the beam path during carbon and oxygen ion therapy. Approach. Phantoms of polyethylene, gelatin, or poly(methyl methacrylate) were irradiated with monoenergetic carbon and oxygen ion beams. Post-irradiation, 4D PET images were acquired and parent ¹¹C, ¹⁰C and ¹⁵O radionuclides contributions in each voxel were determined from the extracted time activity curves. Next, the experimental configurations were simulated in Geant4 Monte Carlo versions 10.0 to 11.1, with three different fragmentation models—binary ion cascade (BIC), quantum molecular dynamics (QMD) and the Liege intranuclear cascade (INCL++) - 30 model-version combinations. Total positron annihilation and parent isotope production yields predicted by each simulation were compared between simulations and experiments using normalised mean squared error and Pearson cross-correlation coefficient. Finally, we compared the depth of the maximum positron annihilation yield and the distal point at which the positron yield decreases to 50% of peak between each model and the experimental results. Main results. Performance varied considerably across versions and models, with no one version/model combination providing the best prediction of all positron-emitting fragments in all evaluated target materials and irradiation conditions. BIC in Geant4 10.2 provided the best overall agreement with experimental results in the largest number of test cases. QMD consistently provided the best estimates of both the depth of peak positron yield (10.4 and 10.6) and the distal 50%-of-peak point (10.2), while BIC also performed well and INCL generally performed the worst across most Geant4 versions. Significance. The best predictions of the spatial distribution of positron annihilations and positron-emitting fragment production along the beam path during carbon and oxygen ion therapy was obtained using Geant4 10.2.p03 with BIC or QMD. These version/model combinations are recommended for future heavy ion therapy research.
... Firstly, production feasibility was considered. As discussed in previous studies [34][35][36], RIB used for therapy are produced through fragmentation of the stable primary beam in thin targets and subsequent magnetic separation of the produced fragments. The secondary particles are immediately directed with relativistic energies to the target, where they subsequently undergo decay. ...
Radiation therapy, one of the most effective methods for cancer treatment, is still limited by the tolerances of normal tissues surrounding the tumor. Innovative techniques like spatially fractionated radiation therapy (SFRT) have been shown to increase normal tissue dose resistance. Heavy ions also offer high-dose conformity and increased relative biological effectiveness (RBE) when compared to protons and X-rays. The alliance of heavy ions and spatial fractionation of the dose has the potential to further increase the therapeutic index for difficult-to-treat cases today. In particular, the use of β -delayed multiple-particle emitters might further improve treatment response, as it holds the potential to increase high linear energy transfer (LET) decay products in the valleys of SFRT (low-dose regions) at the end of the range. To verify this hypothesis, this study compares β -delayed multiple-particle emitters ( ⁸ Li, ⁹ C, ³¹ Ar) with their respective stable isotopes ( ⁷ Li, ¹² C, ⁴⁰ Ar) to determine possible benefits of β -delayed multiple-particle emitters minibeam radiation therapy ( β -MBRT). Monte Carlo simulations were performed using the GATE toolkit to assess the dose distributions of each ion. RBE-weighted dose distributions were calculated and used for the aforementioned comparison. No significant differences were found among carbon isotopes. In contrast, ⁸ Li and ³¹ Ar exhibited improved RBE-weighted dose distributions with an approximately 12–20% increase in the Bragg-peak-to-entrance dose ratio (BEDR) for both peaks and valleys, which favors tissue sparing. Additionally, ⁸ Li and ³¹ Ar exhibited a lower peak-to-valley dose ratio (PVDR) in normal tissues and higher PVDR in the tumor than ⁷ Li and ⁴⁰ Ar. Biological experiments are needed to conclude whether the differences observed make β -delayed multiple-particle emitters advantageous for MBRT.
... The merits of ion beam therapy using positron emitters have been extensively reviewed by multiple authors 19,20 . The Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan, investigated the feasibility of using secondary beams of 11 C and 15 O positron emitters, produced by projectile fragmentation, for both therapy and in-beam PET range verification [21][22][23] . ...
fast and reliable range monitoring method is required to take full advantage of the high linear energy transfer (LET) provided by therapeutic ion beams like carbon and oxygen while minimizing damage to healthy tissue due to range uncertainties. Quasi-real-time range monitoring using in-beam positron emission tomography (PET) with positron-emitting isotopes of carbon and oxygen is a promising approach. The number of implanted ions and the time required for an unambiguous range verification are decisive factors for choosing a candidate isotope. An experimental study was performed at the FRS fragment-separator facility of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany, to investigate the evolution of positron annihilation activity profiles during the implantation of ¹⁴O and ¹⁵O ion beams in a PMMA phantom. The positron activity profile was imaged by a dual-panel version of a Siemens Biograph mCT PET scanner. Results from a similar experiment using ion beams of carbon positron-emitters ¹¹C and ¹⁰C performed at the same experimental setup were used for comparison. Owing to their shorter half-lives, the number of implanted ions required for a precise positron annihilation activity peak determination is lower for ¹⁰C compared to ¹¹C and likewise for ¹⁴O compared to ¹⁵O, but their lower production cross-section makes it challenging to produce them with intensities of therapeutical needs. With a similar production cross-section and a 10 times shorter half-life than ¹¹C, ¹⁵O provides a faster conclusive positron annihilation activity peak position determination for a lower number of implanted ions compared to ¹¹C. We conclude that ¹⁵O is technically the most feasible candidate among positron emitters of carbon and oxygen for quasi-real-time in-beam range monitoring in ion beam therapy. The study also demonstrated that 15O beams of therapeutical quality in terms of purity, energy, and energy spread can be produced by the in-flight production and separation method.
... In the pioneering work at Lawrence Berkeley National Laboratory in the early 1980s, the technique was first used as a low-dose probe beam for pre-treatment localization of malignant tissue prior to the heavy-ion therapy with stable beams (Chatterjee et al 1981, 1982, Llacer et al 1984. Ever since the closure of the ion beam therapy program at Berkeley in 1992, HIMAC, Japan, has been the front-runner in the field of hadron therapy with radioactive beams, focusing on the positron-emitting isotopes of carbon and oxygen (Kanazawa et al 2002, Iseki et al 2004, Mohammadi et al 2019, Chacon et al 2020. At the early stage of ion beam therapy investigations at GSI, the in-beam PET imaging using radioactive ion beams was investigated (Enghardt et al 1992). ...
... For stable beams, there is a shift between the dose range and the PET activity range, whose magnitude is proportional to the implantation depth (Fiedler et al 2012). In our case, this shift is 3 mm for 12 C, and for 10,11 C there is no difference within the systematic errors, see table 2. See also similar studies by (Mohammadi et al 2019, Chacon et al 2020). Considering patient treatment, the accuracy of PET scanner positioning relative to the patient and the beam isocenter will play a role as well. ...
\textit{Objective}. Beams of stable ions have been a well-established tool for radiotherapy for many decades. In the case of ion beam therapy with stable $^{12}$C ions, the positron emitters $^{10,11}$C are produced via projectile and target fragmentation, and their decays enable visualization of the beam via positron emission tomography (PET). However, the PET activity peak matches the Bragg peak only roughly and PET counting statistics is low. These issues can be mitigated by using a short-lived positron emitter as a therapeutic beam. \textit{Approach.} An experiment studying the precision of the measurement of ranges of positron emitting carbon isotopes by means of PET has been performed at the FRS fragment-separator facility of GSI Helmholtzzentrum f"ur Schwerionenforschung GmbH, Germany. The PET scanner used in the experiment is a dual-panel version of a Siemens Biograph mCT PET scanner. \textit{Main results.} High quality in-beam PET images and activity distributions have been measured from the in-flight produced positron emitting isotopes $^{11}$C and $^{10}$C implanted into homogeneous PMMA phantoms. Taking advantage of the high statistics obtained in this experiment, we investigated the time evolution of the uncertainty of the range determined by means of PET during the course of an irradiation, and show that the uncertainty improves with the inverse square root of the number of PET counts. The uncertainty is thus fully determined by the PET counting statistics. During the delivery of 1.6$\times$10$^7$ ions in 4 spills for a total duration of 19.2~s, the PET activity range uncertainty for $^{10}$C, $^{11}$C and $^{12}$C is 0.04, 0.7 and 1.3~mm, respectively. The gain in precision related to the PET counting statistics is thus much larger when going from $^{11}$C to $^{10}$C than when going from $^{12}$C to $^{11}$C. The much better precision for $^{10}$C is due to its much shorter half-life, which, contrary to the case of $^{11}$C, also enables to include the in-spill data in the image formation. \textit{Significance}. Our results can be used to estimate the contribution from PET counting statistics to the precision of range determination in a particular carbon therapy situation, taking into account the irradiation scenario, the required dose and the PET scanner characteristics.
... With modern, high-intensity accelerators, it is possible to produce radioactive ion beams with an intensity sufficient for therapeutic treatment 50 , and such beams would pave the way to PET-guided heavy ion treatment. Several studies are ongoing to assess the advantages of radioactive ion beams for therapy 51 , and a prototype for a compact PET cyclotron producing 11 C beams as an injector for a medical synchrotron has been proposed by CERN 52 . ...
Radiotherapy should have low toxicity in the entrance channel (normal tissue) and be very effective in cell killing in the target region (tumour). In this regard, ions heavier than protons have both physical and radiobiological advantages over conventional X-rays. Carbon ions represent an excellent combination of physical and biological advantages. There are a dozen carbon-ion clinical centres in Europe and Asia, and more under construction or at the planning stage, including the first in the USA. Clinical results from Japan and Germany are promising, but a heated debate on the cost-effectiveness is ongoing in the clinical community, owing to the larger footprint and greater expense of heavy ion facilities compared with proton therapy centres. We review here the physical basis and the clinical data with carbon ions and the use of different ions, such as helium and oxygen. Research towards smaller and cheaper machines with more effective beam delivery is necessary to make particle therapy affordable. The potential of heavy ions has not been fully exploited in clinics and, rather than there being a single ‘silver bullet’, different particles and their combination can provide a breakthrough in radiotherapy treatments in specific cases.
... LEM assumes that the RBE depends on the charge and velocity of the ion, so no significant differences are expected between radioactive isotopes and stable 12 C and 16 O ions. Similar RBE values for stable and radioactive light ions at different depths in the spread-out-Braggpeak (SOBP) are also predicted by the microdosimetric kinetic model (64,65). However, models are affected by large uncertainties (66,67) and differences may be caused by the different nuclear interactions and the production of secondary particles. ...
Several techniques are under development for image-guidance in particle therapy. Positron (β⁺) emission tomography (PET) is in use since many years, because accelerated ions generate positron-emitting isotopes by nuclear fragmentation in the human body. In heavy ion therapy, a major part of the PET signals is produced by β⁺-emitters generated via projectile fragmentation. A much higher intensity for the PET signal can be obtained using β⁺-radioactive beams directly for treatment. This idea has always been hampered by the low intensity of the secondary beams, produced by fragmentation of the primary, stable beams. With the intensity upgrade of the SIS-18 synchrotron and the isotopic separation with the fragment separator FRS in the FAIR-phase-0 in Darmstadt, it is now possible to reach radioactive ion beams with sufficient intensity to treat a tumor in small animals. This was the motivation of the BARB (Biomedical Applications of Radioactive ion Beams) experiment that is ongoing at GSI in Darmstadt. This paper will present the plans and instruments developed by the BARB collaboration for testing the use of radioactive beams in cancer therapy.
... Optical beam imaging has also been recently used to visualize RIB at HIMAC [77]. The HIMAC studies demonstrate that RIB have similar radiobiological properties as stable isotopes of the same atomic number but produce far better quality images for range verification, with 5-11-fold improvements in the PET signal/noise ratio [78]. ...
Heavy ion therapy can deliver high doses with high precision. However, image guidance is needed to reduce range uncertainty. Radioactive ions are potentially ideal projectiles for radiotherapy because their decay can be used to visualize the beam. Positron-emitting ions that can be visualized with PET imaging were already studied for therapy application during the pilot therapy project at the Lawrence Berkeley Laboratory, and later within the EULIMA EU project, the GSI therapy trial in Germany, MEDICIS at CERN, and at HIMAC in Japan. The results show that radioactive ion beams provide a large improvement in image quality and signal-to-noise ratio compared to stable ions. The main hindrance toward a clinical use of radioactive ions is their challenging production and the low intensities of the beams. New research projects are ongoing in Europe and Japan to assess the advantages of radioactive ion beams for therapy, to develop new detectors, and to build sources of radioactive ions for medical synchrotrons.
The measurement of linear energy transfer (LET) is crucial for the evaluation of the radiation effect in heavy ion therapy. As two detectors which are convenient to implant into the phantom, the performance of CR-39 and thermoluminescence detector (TLD) for LET measurement was compared by experiment and simulation in this study. The results confirmed the applicability of both detectors for LET measurements, but also revealed that the CR-39 detector would lead to potential overestimation of dose-averaged LET compared with the simulation by PHITS, while the TLD would have a large uncertainty measuring ions with LET larger than 20 keV μm-1. The results of this study were expected to improve the detection method of LET for therapeutic carbon beam and would finally be benefit to the quality assurance of heavy ion radiotherapy.
A fast and reliable range monitoring method is required to take full advantage of the high linear energy transfer provided by therapeutic ion beams like carbon and oxygen while minimizing damage to healthy tissue due to range uncertainties. Quasi-real-time range monitoring using in-beam positron emission tomography (PET) with therapeutic beams of positron-emitters of carbon and oxygen is a promising approach. The number of implanted ions and the time required for an unambiguous range verification are decisive factors for choosing a candidate isotope. 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Owing to their shorter half-lives, the number of implanted ions required for a precise positron annihilation activity peak determination is lower for 10\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{10}$$\end{document}C compared to 11\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{11}$$\end{document}C and likewise for 14\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{14}$$\end{document}O compared to 15\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{15}$$\end{document}O, but their lower production cross-sections make it difficult to produce them at therapeutically relevant intensities. With a similar production cross-section and a 10 times shorter half-life than 11\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{11}$$\end{document}C, 15\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{15}$$\end{document}O provides a faster conclusive positron annihilation activity peak position determination for a lower number of implanted ions compared to 11\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{11}$$\end{document}C. A figure of merit formulation was developed for the quantitative comparison of therapy-relevant positron-emitting beams in the context of quasi-real-time beam monitoring. In conclusion, this study demonstrates that among the positron emitters of carbon and oxygen, 15\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{15}$$\end{document}O is the most feasible candidate for quasi-real-time range monitoring by in-beam PET that can be produced at therapeutically relevant intensities. Additionally, this study demonstrated that the in-flight production and separation method can produce beams of therapeutic quality, in terms of purity, energy, and energy spread.
