Production and separation of positron emitters for hadron therapy at FRS-Cave M.

The FRagment Separator FRS at GSI is a versatile spectrometer and separator for experiments with relativistic in-flight separated short-lived exotic beams. One branch of the FRS is connected to the target hall where the bio-medical cave (Cave M) is located. Recently a joint activity between the experimental groups of the FRS and the biophysics at the GSI and Department of physics at LMU was started to perform biomedical experiments relevant for hadron therapy with positron emitting carbon and oxygen beams. This paper presents the new ion-optical mode and commissioning results of the FRS-Cave M branch where positron emitting 15O-ions were provided to the medical cave for the first time. An overall conversion efficiency of 2.9±0.2×10-4 15O fragments per primary 16O ion accelerated in the synchrotron SIS18 was reached.

Quasi-real-time range monitoring by in-beam PET: a case for 15O.

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. An experimental study was performed at the FRS fragment-separator of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany, to investigate the evolution of positron annihilation activity profiles during the implantation of [Formula: see text]O and [Formula: see text]O 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 [Formula: see text]C and [Formula: see text]C 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 [Formula: see text]C compared to [Formula: see text]C and likewise for [Formula: see text]O compared to [Formula: see text]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 [Formula: see text]C, [Formula: see text]O provides a faster conclusive positron annihilation activity peak position determination for a lower number of implanted ions compared to [Formula: see text]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, [Formula: see text]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.

Precision of the PET activity range during irradiation with10C,11C, and12C beams.

Objective. Beams of stable ions have been a well-established tool for radiotherapy for many decades. In the case of ion beam therapy with stable12C ions, the positron emitters10,11C 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.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 für Schwerionenforschung GmbH, Germany. The PET scanner used in the experiment is a dual-panel version of a Siemens Biograph mCT PET scanner.Main results.High-quality in-beam PET images and activity distributions have been measured from the in-flight produced positron emitting isotopes11C and10C 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 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 × 107ions in 4 spills for a total duration of 19.2 s, the PET activity range uncertainty for10C,11C and12C is 0.04 mm, 0.7 mm and 1.3 mm, respectively. The gain in precision related to the PET counting statistics is thus much larger when going from11C to10C than when going from12C to11C. The much better precision for10C is due to its much shorter half-life, which, contrary to the case of11C, also enables to include the in-spill data in the image formation.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.

Systematic quantification of nanoscopic dose enhancement of gold nanoparticles in ion beams.

High-Z material nanoparticles are being studied as localized dose enhancers in radiotherapeutic applications. Here, the nano-scale physical dose enhancement of proton, carbon and oxygen ion beam radiation by gold nanoparticles was studied by means of Monte Carlo track structure simulation with the TRAX code. We present 2D distributions and radial profiles of the additional dose and the dose enhancement factor for two geometries which consider an isolated and a water-embedded nanoparticle, respectively. Different nanoparticle sizes (radius of 1.2-22 nm) were found to yield qualitatively different absolute and relative dose enhancement distributions and different maximum dose enhancement factors (up to 20). Whereas the smallest nanoparticles produced the highest local dose enhancement factor close to the metal, larger ones led to lower, more diffuse dose enhancement factors that contributed more at larger distances. Differential absorption effects inside the metal were found to be responsible for those characteristics. For the energy range 15-204 MeVu-1, also a mild trend with ion E/A, regardless of the ion species, was found for embedded nanoparticles. In analogy to the width of the ion track itself, slower ions increased the enhancement at the nanoparticle surface. In contrast, no dependence on linear energy transfer was encountered. For slower ions (3-10 MeVu-1), the enhancement effect began to break down over all distances. Finally, the significance of any indirect physical effect was excluded, giving important hints especially in view of the low probabilities (at realistic concentrations and fluences) of direct ion-NP-hits. The very localized nature of the physical dose enhancement found suggests a strong action upon targets closeby, but no relevant effect at cellular distances. When pondering different possible damage enhancement mechanisms of gold nanoparticles in the context of published in vitro and in vivo experimental results, biological pathways are likely to play the key role.

Oxygen beams for therapy: advanced biological treatment planning and experimental verification.

Nowadays there is a rising interest towards exploiting new therapeutical beams beyond carbon ions and protons. In particular, [Formula: see text]O ions are being widely discussed due to their increased LET distribution. In this contribution, we report on the first experimental verification of biologically optimized treatment plans, accounting for different biological effects, generated with the TRiP98 planning system with [Formula: see text]O beams, performed at HIT and GSI. This implies the measurements of 3D profiles of absorbed dose as well as several biological measurements. The latter includes the measurements of relative biological effectiveness along the range of linear energy transfer values from ≈20 up to ≈750 keV µ [Formula: see text], oxygen enhancement ratio values and the verification of the kill-painting approach, to overcome hypoxia, with a phantom imitating an unevenly oxygenated target. With the present implementation, our treatment planning system is able to perform a comparative analysis of different ions, according to any given condition of the target. For the particular cases of low target oxygenation, [Formula: see text]O ions demonstrate a higher peak-to-entrance dose ratio for the same cell killing in the target region compared to [Formula: see text]C ions. Based on this phenomenon, we performed a short computational analysis to reveal the potential range of treatment plans, where [Formula: see text]O can benefit over lighter modalities. It emerges that for more hypoxic target regions (partial oxygen pressure of ≈0.15% or lower) and relatively low doses (≈4 Gy or lower) the choice of [Formula: see text]O over [Formula: see text]C or [Formula: see text]He may be justified.