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FLASH radiotherapy is considered a new potential breakthrough in cancer treatment. Ultra-high dose rates (>40 Gy/s) have been shown to reduce toxicity in the normal tissue without compromising tumor control, resulting in a widened therapeutic window. These high dose rates are more easily achievable in the clinic with charged particles, and clinical trials are, indeed, ongoing using electrons or protons. FLASH could be an attractive solution also for heavier ions such as carbon and could even enhance the therapeutic window. However, it is not yet known whether the FLASH effect will be the same as for sparsely ionizing radiation when densely ionizing carbons ions are used. Here we discuss the technical challenges in beam delivery and present a promising solution using 3D range-modulators in order to apply ultra-high dose rates (UHDR) compatible with FLASH with carbon ions. Furthermore, we will discuss the possible outcome of C-ion therapy at UHDR on the level of the radiobiological and radiation chemical effects., (© 2021 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: 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., Method: 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)., Results: The implementation of dosimetry equipment as described in this work allowed determining absolute spot sizes and spot positions with an uncertainty better than 0.3 mm. Absolute ranges are determined with an uncertainty comprised of 0.2-0.6 mm, depending on the measured range and were reproduced with a maximum difference of 0.3 mm over a period of 12 months using three different devices., Conclusion: 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., (© 2017 American Association of Physicists in Medicine.)

Purpose: In this work, ion recombination is studied as a function of energy and depth in carbon ion beams., Methods: Measurements were performed in three different passively scattered carbon ion beams with energies of 62 MeV/n, 135 MeV/n, and 290 MeV/n using various types of plane-parallel ionization chambers. Experimental results were compared with two analytical models for initial recombination. One model is generally used for photon beams and the other model, developed by Jaffé, takes into account the ionization density along the ion track. An investigation was carried out to ascertain the effect on the ion recombination correction with varying ionization chamber orientation with respect to the direction of the ion tracks. The variation of the ion recombination correction factors as a function of depth was studied for a Markus ionization chamber in the 62 MeV/n nonmodulated carbon ion beam. This variation can be related to the depth distribution of linear energy transfer., Results: Results show that the theory for photon beams is not applicable to carbon ion beams. On the other hand, by optimizing the value of the ionization density and the initial mean-square radius, good agreement is found between Jaffé's theory and the experimental results. As predicted by Jaffé's theory, the results confirm that ion recombination corrections strongly decrease with an increasing angle between the ion tracks and the electric field lines. For the Markus ionization chamber, the variation of the ion recombination correction factor with depth was modeled adequately by a sigmoid function, which is approximately constant in the plateau and strongly increasing in the Bragg peak region to values of up to 1.06. Except in the distal edge region, all experimental results are accurately described by Jaffé's theory., Conclusions: Experimental results confirm that ion recombination in the investigated carbon ion beams is dominated by initial recombination. Ion recombination corrections are found to be significant and cannot be neglected for reference dosimetry and for the determination of depth dose curves in carbon ion beams.

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.

Purpose: A recent study revealed that polyethylene (PE) would cause extra carbon-ion attenuation per range shift by 0.45%/cm due to compositional differences in nuclear interactions. The present study aims to assess the influence of PE range compensators on tumor dose in carbon-ion radiotherapy., Methods: Carbon-ion radiation was modeled to be composed of primary carbon ions and secondary particles, for each of which the dose and the relative biological effectiveness (RBE) were estimated at a tumor depth in the middle of spread-out Bragg peak. Assuming exponential behavior for attenuation and yield of these components with depth, the PE effect on dose was calculated for clinical carbon-ion beams and was partly tested by experiment. The two-component model was integrated into a treatment-planning system and the PE effect was estimated in two clinical cases., Results: The attenuation per range shift by PE was 0.1%-0.3%/cm in dose and 0.2%-0.4%/cm in RBE-weighted dose, depending on energy and range-modulation width. This translates into reduction of RBE-weighted dose by up to 3% in extreme cases. In the treatment-planning study, however, the effect on RBE-weighted dose to tumor was typically within 1% reduction., Conclusions: The extra attenuation of primary carbon ions in PE was partly compensated by increased secondary particles for tumor dose. In practical situations, the PE range compensators would normally cause only marginal errors as compared to intrinsic uncertainties in treatment planning, patient setup, beam delivery, and clinical response.

Purpose: Particle therapy (PT) has advantages over photon irradiation on static tumors. An increased biological effectiveness and active target conformal dose shaping are strong arguments for PT. However, the sensitivity to changes of internal geometry complicates the use of PT for moving organs. In case of interfractionally moving objects adaptive radiotherapy (ART) concepts known from intensity modulated radiotherapy (IMRT) can be adopted for PT treatments. One ART strategy is to optimize a new treatment plan based on daily image data directly before a radiation fraction is delivered [treatment replanning (TRP)]. Optimizing treatment plans for PT using a scanned beam is a time consuming problem especially for particles other than protons where the biological effective dose has to be calculated. For the purpose of TRP, fast optimization and fast dose calculation have been implemented into the GSI in-house treatment planning system (TPS) TRiP98., Methods: This work reports about the outcome of a code analysis that resulted in optimization of the calculation processes as well as implementation of routines supporting parallel execution of the code. To benchmark the new features, the calculation time for therapy treatment planning has been studied., Results: Compared to the original version of the TPS, calculation times for treatment planning (optimization and dose calculation) have been improved by a factor of 10 with code optimization. The parallelization of the TPS resulted in a speedup factor of 12 and 5.5 for the original version and the code optimized version, respectively. Hence the total speedup of the new implementation of the authors' TPS yielded speedup factors up to 55., Conclusions: The improved TPS is capable of completing treatment planning for ion beam therapy of a prostate irradiation considering organs at risk in this has been overseen in the review process. Also see below 6 min.

Purpose: Laser plasma acceleration can potentially replace large and expensive cyclotrons or synchrotrons for radiotherapy with protons and ions. On the way toward a clinical implementation, various challenges such as the maximum obtainable energy still remain to be solved. In any case, laser accelerated particles exhibit differences compared to particles from conventional accelerators. They typically have a wide energy spread and the beam is extremely pulsed (i.e., quantized) due to the pulsed nature of the employed lasers. The energy spread leads to depth dose curves that do not show a pristine Bragg peak but a wide high dose area, making precise radiotherapy impossible without an additional energy selection system. Problems with the beam quantization include the limited repetition rate and the number of accelerated particles per laser shot. This number might be too low, which requires a high repetition rate, or it might be too high, which requires an additional fluence selection system to reduce the number of particles. Trying to use laser accelerated particles in a conventional way such as spot scanning leads to long treatment times and a high amount of secondary radiation produced when blocking unwanted particles., Methods: The authors present methods of beam delivery and treatment planning that are specifically adapted to laser accelerated particles. In general, it is not necessary to fully utilize the energy selection system to create monoenergetic beams for the whole treatment plan. Instead, within wide parts of the target volume, beams with broader energy spectra can be used to simultaneously cover multiple axially adjacent spots of a conventional dose delivery grid as applied in intensity modulated particle therapy. If one laser shot produces too many particles, they can be distributed over a wider area with the help of a scattering foil and a multileaf collimator to cover multiple lateral spot positions at the same time. These methods are called axial and lateral clustering and reduce the number of particles that have to be blocked in the beam delivery system. Furthermore, the optimization routine can be adjusted to reduce the number of dose spots and laser shots. The authors implemented these methods into a research treatment planning system for laser accelerated particles., Results: The authors' proposed methods can decrease the amount of secondary radiation produced when blocking particles with wrong energies or when reducing the total number of particles from one laser shot. Additionally, caused by the efficient use of the beam, the treatment time is reduced considerably. Both improvements can be achieved without extensively changing the quality of the treatment plan since conventional intensity modulated particle therapy usually includes a certain amount of unused degrees of freedom which can be used to adapt to laser specific properties., Conclusions: The advanced beam delivery and treatment planning methods reduce the need to have a perfect laser-based accelerator reproducing the properties of conventional accelerators that might not be possible without increasing treatment time and secondary radiation to the patient. The authors show how some of the differences to conventional beams can be overcome and efficiently used for radiation treatment.

Purpose: Clinically safe and effective treatment of intrafractionally moving targets with scanned ion beams requires dedicated delivery techniques such as beam tracking. Apart from treatment delivery, also appropriate methods for validation of the actual tumor irradiation are highly desirable, In this contribution the feasibility of four-dimensionally (space and time) resolved, motion-compensated in-beam positron emission tomography (4DibPET) was addressed in experimental studies with scanned carbon ion beams., Methods: A polymethyl methracrylate block sinusoidally moving left-right in beam's eye view was used as target. Radiological depth changes were introduced by placing a stationary ramp-shaped absorber proximal of the moving target. Treatment delivery was compensated for motion by beam tracking. Time-resolved, motion-correlated in-beam PET data acquisition was performed during beam delivery with tracking the moving target and prolonged after beam delivery first with the activated target still in motion and, finally, with the target at rest. Motion-compensated 4DibPET imaging was implemented and the results were compared to a stationary reference irradiation of the same treatment field. Data were used to determine feasibility of 4DibPET but also to evaluate offline in comparison to in-beam PET acquisition., Results: 4D in-beam as well as offline PET imaging was found to be feasible and offers the possibility to verify the correct functioning of beam tracking. Motion compensation of the imaged beta(+)-activity distribution allows recovery of the volumetric extension of the delivered field for direct comparison with the reference stationary condition. Observed differences in terms of lateral field extension and penumbra in the direction of motion were typically less than 1 mm for both imaging strategies in comparison to the corresponding reference distributions. However, in-beam imaging retained a better spatial correlation of the measured activity with the delivered dose., Conclusions: 4DibPET is a feasible and promising method to validate treatment delivery of scanned ion beams to moving targets. Further investigations will focus on more complex geometries and treatment planning studies with clinical data.

The depth absorbed dose and LET (linear energy transfer) distribution of different ions of clinical interest such as 1H, 4He, 7Li, and 12C ions have been investigated using the Monte Carlo code SHIELD-HIT. The energies of the projectiles correspond to ranges in water and soft tissue of approximately 260 mm. The depth dose distributions of the primary particles and their secondaries have been calculated and separated with regard to their low and high LET components. A LET value below 10 eV/nm can generally be regarded as low LET and sparsely ionizing like electrons and photons. The high LET region may be assumed to start at 20 eV/nm where on average two double-strand breaks can be formed when crossing the periphery of a nucleosome, even though strictly speaking the LET limits are not sharp and ought to vary with the charge and mass of the ion. At the Bragg peak of a monoenergetic high energy proton beam, less than 3% of the total absorbed dose is comprised of high LET components above 20 eV/nm. The high LET contribution to the total absorbed dose in the Bragg peak is significantly larger with increasing ion charge as a natural result of higher stopping power and lower range straggling. The fact that the range straggling and multiple scattering are reduced by half from hydrogen to helium increases the possibility to accurately deposit only the high LET component in the tumor with negligible dose to organs at risk. Therefore, the lateral penumbra is significantly improved and the higher dose gradients of 7Li and 12C ions both longitudinally and laterally will be of major advantage in biological optimized radiation therapy. With increasing charge of the ion, the high LET absorbed dose in the beam entrance and the plateau regions where healthy normal tissues are generally located is also increased. The dose distribution of the high LET components in the 7Li beam is only located around the Bragg peak, characterized by a Gaussian-type distribution. Furthermore, the secondary particles produced by high energy 7Li ions in tissuelike media have mainly low LET character both in front of and beyond the Bragg peak.