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The physical range uncertainty limits the exploitation of the full potential of charged particle therapy. In this work, we face this issue aiming to measure the absolute Bragg peak position in the target. We investigate p, 4 He, 12 C and 16 O beams accelerated at the Heidelberg Ion-Beam Therapy Center. The residual range of the primary 12 C ions is correlated to the energy spectrum of the prompt gamma radiation. The prompt gamma spectroscopy method was demonstrated for proton beams accelerated by cyclotrons and is developed here for the first time for heavier ions accelerated by a synchrotron. We develop a detector system that includes (i) a spectroscopic unit based on cerium(III) bromide and bismuth germanium oxide scintillating crystals, (ii) a beam trigger based on an array of scintillating fibers and (iii) a data acquisition system based on a FlashADC. We test the system in two different scenarios. In the first series of experiments, we detect and identify 19 independent spectral lines over a wide gamma energy spectrum in the presence of the four ion species for different targets, including a water target with a titanium insert. In the second series of experiments, we introduce a collimator aiming to relate the spectral information to the range of the primary particles. We perform extensive measurements for a 12 C beam and demonstrate submillimetric precision for the measurement of its Bragg peak position in the experimental setup. The features of the energy and time spectra for gamma radiation induced by p, 4 He and 16 O are investigated upstream and downstream from the Bragg peak position. We conclude the analysis by extrapolating the required future developments, which would be needed to achieve range verification with a 2 mm accuracy during a single fraction delivery of [Formula: see text] physical dose.

Proton and ion beam therapy has proven to benefit tumour control with lower side-effects, mostly in paediatrics. Here we demonstrate a feasible technique for proton and ion beam spectroscopy (PIBS) capable of determining the elemental compositions of the irradiated tissues during particle therapy. This follows the developments in prompt gamma imaging for online range verification and the inheritance from prompt gamma neutron activation analysis. Samples of water solutions were prepared to emulate varying oxygen and carbon concentrations. The irradiation of those samples and other tissue surrogate inserts by protons and ion beams under clinical conditions clearly showed a logarithmic relationship between the target elemental composition and the prompt gamma production. This finding is in line with the known logarithmic dependence of the pH with the proton molar concentration. Elemental concentration changes of 1% for calcium and 2% for oxygen in adipose, brain, breast, liver, muscle and bone-related tissue surrogates were clearly identified. Real-time in vivo measurements of oxygen, carbon and calcium concentrations will be evaluated in a pre-clinical and clinical environment. This technique should have an important impact in the assessment of tumour hypoxia over the course of several treatment fractions and the tracking of calcifications in brain metastases.

Purpose: To perform dosimetric characterization of a minibeam collimator in both carbon and oxygen ion beams to guide optimal setup geometry and irradiation for future radiobiological studies., Methods: Carbon and oxygen minibeams were generated using a prototype tungsten multislit collimator presenting line apertures 700 μm wide, which are spaced 3500 μm centre-to-centre distance apart. Several radiation beam spots generated the desired field size of 15 × 15 mm 2 and production of a 50 mm long spread out Bragg peak (SOBP) centered at 80 mm depth in water. Dose evaluations were performed with two different detectors: a PTW microDiamond® single crystal diamond detector and radiochromic films (EBT3). Peak-to-valley dose ratio (PVDR) values, output factors (OF), penumbras, and full width at half maximum (FWHM) were measured., Results: Measured lateral dose profiles exhibited spatial fractionation of dose at depth in a water phantom in the expected form of peaks and valleys for both carbon and oxygen radiation fields. The diamond detector and radiochromic film provided measurements of PVDR in good agreement. PVDR values at shallow depth were about 60 and decreased to about 10 at 80 mm depth in water. OF in the center of the SOBP was about 0.4; this value is larger than the corresponding one in proton minibeam radiation therapy measured using a comparable collimator due to a reduced lateral scattering for carbon and oxygen minibeams., Conclusions: Carbon and oxygen minibeams may be produced by a mechanical collimator. PVDR values and output factors measured in this first study of these minibeam radiation types indicate there is potential for their therapeutic use. Optimization of minibeam collimator design and the number and size of focal spots for irradiation are advocated to improve PDVR values and dose distributions for each specific applied use., (© 2017 American Association of Physicists in Medicine.)

At the Heidelberg Ion Beam Therapy Center, scanned helium and oxygen ion beams are available in addition to the clinically used protons and carbon ions for physical and biological experiments. In this work, a study of the basic dosimetric features of the different ions is performed in the entire therapeutic energy range. Depth dose distributions are investigated for pencil-like beam irradiation, with and without a modulating ripple filter, focusing on the extraction of key Bragg curve parameters, such as the range, the peak-width and the distal 80%-20% fall-off. Pencil-beam lateral profiles are measured at different depths in water, and parameterized with multiple Gaussian functions. A more complex situation of an extended treatment field is analyzed through a physically optimized spread-out Bragg peak, delivered with beam scanning. The experimental results of this physical beam characterization indicate that helium ions could afford a more conformal treatment and in turn, increased tumor control. This is mainly due to a smaller lateral scattering than with protons, leading to better lateral and distal fall-off, as well as a lower fragmentation tail compared to carbon and oxygen ions. Moreover, the dosimetric dataset can be used directly for comparison with results from analytical dose engines or Monte Carlo codes. Specifically, it was used at the Heidelberg Ion Beam Therapy Center to generate a new input database for a research analytical treatment planning system, as well as for validation of a general purpose Monte Carlo program, in order to lay the groundwork for biological experiments and further patient planning studies.

Purpose: Sublethal doses of photon irradiation (IR) are suspected to increase tumor cell migration and support locoregional recurrence of disease, which has already been shown in other cell lines. This manuscript describes the effect of photon and carbon-ion IR on WHO class I meningioma cell migration and provides an approach to the underlying cellular mechanisms., Materials and Methods: Meningioma cells were gained operatively at the university hospital in Homburg/Saar, Germany. For migration, membranes (8-µm pore sizes) were coated with collagen I, with collagen IV, and with fibronectin. Cells were analyzed in migration experiments with or without serum stimulation, with or without photon and carbon IR 24 h prior to experiments, and with or without integrin antibodies. Fluorescence-activated cell sorting (FACS) analyses of the integrins ανβ1, ανβ3, and ανβ5 were performed without IR and 6, 12 and 24 h after IR. Enzyme-linked immunosorbent assay (ELISA) analyses of matrix metalloproteinases (MMP)-2 and MMP-9 were realized with and without IR after cells were cultured on collagen I, collagen IV, or fibronectin for 24 h. Cells and supernatants for FACS and ELISA were stored at - 18 °C. The significance level was set at 5 % using both Student's t test and two-way ANOVA., Results: Migration of meningioma cells was serum-inducible (p < 0.001). It could be increased by photon IR (p < 0.02). The integrins ανβ1 and ανβ5 showed a 21 and 11 % higher expression after serum stimulation (not significant), respectively, and ανβ1 expression was raised by 14 % (p = 0.0057) after photon IR. Antibody blockage of the integrins ανβ1 and ανβ5 inhibited serum- and photon-induced migration. Expression of MMP-2 and MMP-9 remained unchanged after both IR and fetal bovine serum (FBS). Carbon-ion IR left both integrin expression and meningioma cell migration unaffected., Conclusion: Photon but not carbon-ion IR promotes serum-based meningioma cell migration. Fibronectin receptor integrin ανβ1 signaling can be identified as an important mechanism for serum- and photon-induced migration of WHO class I meningioma cells.

Ion beams offer an excellent tumor-dose conformality due to their inverted depth-dose profile and finite range in tissue, the Bragg peak (BP). However, they introduce sensitivity to range uncertainties. Imaging techniques play an increasingly important role in ion beam therapy to support precise diagnosis and identification of the target volume at the planning stage as well as to ensure the correspondence between the planning and treatment situation at the actual irradiation. For the purpose of improved treatment quality, ion-based radiographic images could be acquired at the treatment site before or during treatment and be employed to monitor the patient positioning and to check the patient-specific ion range. This work presents the initial experimental investigations carried out to address the feasibility of carbon ion radiography at the Heidelberg ion therapy center using a prototype range telescope set-up and an active raster scanning ion beam delivery system. Bragg curves are measured with a stack of ionization chambers (IC) synchronously to the beam delivery. The position of the BP is extracted from the data by locating the channel of maximum current signal for each delivered beam. Each BP is associated to the lateral and vertical positions of the scanned raster point extrapolated from the beam monitor system to build up a radiography. The radiographic images are converted into water equivalent thickness (WET) based on two calibrations of the detector. Radiographies of two phantoms of different complexities are reconstructed and their image quality is analyzed. A novel method proposed to increase the nominal range resolution of the IC stack is applied to the carbon ion radiography of an Alderson head phantom. Moreover, an x-ray digitally reconstructed radiography of the same anthropomorphic head phantom is converted in WET through the clinically used ion range calibration curve and compared with the carbon ion radiography based on a γ-index approach, yielding a good correspondence in terms of absolute WET within ±3%, 3 mm distance-to-agreement and, 87% passing ratio. Imaging artifacts at interfaces within the irradiated phantom due to the finite size of the beam, resulting in multiple maxima, are addressed. Overall, this work demonstrates the feasibility of the prototype range telescope to acquire ion-based transmission imaging with a resolution of up to 0.8 mm WET.

Background: Characterization of combination effects of chemotherapy drugs with carbon ions in comparison to photons in vitro., Methods: The human colon adenocarcinoma cell line WiDr was tested for combinations with camptothecin, cisplatin, gemcitabine and paclitaxel. In addition three other human tumour cell lines (A549: lung, LN-229: glioblastoma, PANC-1: pancreas) were tested for the combination with camptothecin. Cells were irradiated with photon doses of 2, 4, 6 and 8 Gy or carbon ion doses of 0.5, 1, 2 and 3 Gy. Cell survival was assessed using the clonogenic growth assay. Treatment dependent changes in cell cycle distribution (up to 12 hours post-treatment) were measured by FACS analysis after propidium-iodide staining. Apoptosis was monitored for up to 36 hours post-treatment by Nicoletti-assay (with qualitative verification using DAPI staining)., Results: All cell lines exhibited the well-known increase of killing efficacy per unit dose of carbon ion exposure, with relative biological efficiencies at 10% survival (RBE10) ranging from 2.3 to 3.7 for the different cell lines. In combination with chemotherapy additive toxicity was the prevailing effect. Only in combination with gemcitabine or cisplatin (WiDr) or camptothecin (all cell lines) the photon sensitivity was slightly enhanced, whereas purely independent toxicities were found with the carbon ion irradiation, in all cases. Radiation-induced cell cycle changes displayed the generally observed dose-dependent G2-arrest with little effect on S-phase fraction for all cell lines for photons and for carbon ions. Only paclitaxel showed a significant induction of apoptosis in WiDr cell line but independent of the used radiation quality., Conclusions: Combined effects of different chemotherapeutics with photons or with carbon ions do neither display qualitative nor substantial quantitative differences. Small radiosensitizing effects, when observed with photons are decreased with carbon ions. The data support the idea that a radiochemotherapy with common drugs and carbon ion irradiation might be as feasible as respective photon-based protocols. The present data serve as an important radiobiological basis for further combination experiments, as well as clinical studies on combination treatments.

Purpose: To extend the application area of particle therapy with carbon ions the many already established treatment regimens for different tumor entities have to be taken into consideration. The present study investigates the effect of combined radiochemotherapy with temozolomide (TMZ) and high linear energy transfer (LET) irradiation with carbon ions versus photons., Materials and Methods: Clonogenic survival was analyzed for human glioma cell lines with different O6-methylguanine-DNA methyltransferase (MGMT) status, LN18 (MGMT+) and LN-229 (MGMT-), after exposure to different doses of either carbon ion or photon irradiation at different time points relative to TMZ application. Cell cycle distribution was measured by flow cytometry. MGMT status of the cell lines was verified by Western blot., Results: LN-18 and LN-229 reacted in accordance to their MGMT status with different sensitivity to TMZ treatment. Combined treatment with irradiation showed additive cytotoxic effects for both cell lines with low radiation doses but no radiosensitization. With increasing photon doses the combination effect was reduced, and the efficacy of the combined treatment was not dependent on administration schedule. Carbon ion irradiation showed the well known increased relative biological efficiency (RBE), overcame the above-mentioned antagonism and was also not schedule-dependent., Conclusions: The in vitro effectiveness of TMZ in combined radiochemotherapy is independent of administration time or MGMT-expression. Both cell lines are significantly more sensitive to combined treatment with carbon ion radiation than to photon radiation but do not show any super-additive effects.

Ion beams exhibit a finite range and an inverted depth-dose profile, the Bragg peak. These favorable physical properties allow excellent tumor-dose conformality. However, they introduce sensitivity to range uncertainties. Although these uncertainties are typically taken into account in treatment planning, delivery of the intended dose to the patient has to be ensured daily to prevent underdosage of the tumor or overdosage of surrounding critical structures. Thus, imaging techniques play an increasingly important role for treatment planning and in situ monitoring in ion beam therapy. At the Heidelberg Ion Beam Therapy (HIT) center, a prototype detector system based on a stack of 61 ionization chambers has been assembled for the purpose of radiographic and tomographic imaging of transmitted energetic ions. Its applicability to ion-based transmission imaging was investigated experimentally. An extensive characterization of the set-up in terms of beam parameters and settings of the read-out electronics was performed. Overall, the findings of this work support the potential of an efficient experimental set-up as the range telescope equipped with high sensitivity and fast electronics to perform heavy ion radiography and tomography at HIT.

Reliable treatment planning of highly conformal scanned ion beam therapy demands accurate tools for the determination and characterization of the individual pencil-like beams building up the integral dose delivery and related mixed radiation field. At present, clinically practicable inverse treatment planning systems (TPSs) can only rely on fast-performing analytical algorithms. However, the rapidly emerging though more computationally intensive Monte Carlo (MC) methods can be employed to complement analytical TPS, e.g., via accurate calculations of the input beam-model data, together with a considerable reduction of the measuring time. Here we present the work done for the application of the FLUKA MC code to support several aspects of scanned ion beam delivery and treatment planning at the Heidelberg Ion Beam Therapy Center (HIT). Emphasis is given to the generation of the accelerator library and of experimentally validated TPS input basic data which are now in clinical use for proton and carbon ion therapy. Additionally, MC dose calculations of planned treatments in water are shown to represent a valuable tool for supporting treatment plan verification in comparison to dosimetric measurements. This paper can thus provide useful information and guidelines for the start-up and clinical operation of forthcoming ion beam therapy facilities similar to HIT.

Purpose: To investigate the effect of carbon ion irradiation on glioma cell migration., Methods and Materials: U87 and Ln229 glioma cells were irradiated with photons and carbon ions. Migration was analyzed 24 h after irradiation. Fluorescence-activated cell sorting analysis was performed in order to quantify surface expression of integrins., Results: Single photon doses of 2 Gy and 10 Gy enhanced α(ν)β(3) and α(ν)β(5) integrin expression and caused tumor cell hypermigration on both vitronectin (Vn) and fibronectin (Fn). Compared to integrin expression in unirradiated cells, carbon ion irradiation caused decreased integrin expression and inhibited cell migration on both Vn and Fn., Conclusion: Photon radiotherapy (RT) enhances the risk of tumor cell migration and subsequently promotes locoregional spread via photon induction of integrin expression. In contrast to photon RT, carbon ion RT causes decreased integrin expression and suppresses glioma cell migration on both Vn and Fn, thus promising improved local control., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: To evaluate the cytotoxic effect of carbon ion radiotherapy and chemotherapy in glioblastoma cells in vitro., Methods and Materials: The human glioblastoma (GBM) cell line U87 was irradiated with photon radiotherapy (RT) doses of 2 Gy, 4 Gy and 6 Gy. Likewise, irradiation with carbon ions was performed with single carbon doses of 0.125, 0.5, 2 and 3 Gy. Four chemotherapeutic substances, camptothecin, gemcitabine, paclitaxel and cisplatinum, were used for single and combination experiments. The assessment of the effect of single and double treatment on cell viability was performed using the clonogenic growth assay representing the radiobiological gold standard., Results: The RBE of carbon ions ranges between 3.3 and 3.9 depending on survival level and dose. All chemotherapeutic substances showed a clear does-response relationhips. in their characteristic concentrations. For subsequent combination experiments, two dose levels leading to low and medium reduction of cell survival were chosen. Combination experiments showed additive effects independently of the drugs' mechanisms of action. Paclitaxel and campthothecin demonstrated the most prominent cytotoxic effect in combination with carbon ion radiotherapy., Conclusion: In conclusion, combination of carbon ion radiotherapy with chemotherapies of different mechanisms of action demonstrates additive effects. The most dominant effect was produced by paclitaxel, followed by camptothecin, as espected from previously published work. The present data serve as an important radiobiological basis for further combination experiments, as well as clinical studies on combination treatments.

Scanned ion pencil beams carry a low-dose envelope which can extend up to several centimeters from the individual beam central axis. Depending on the energy and species of the beam, this halo consists mainly of secondary particles produced by nuclear interactions in the target or of particles undergoing multiple Coulomb scattering in the beam line components. This halo is often neglected by single Gaussian beam modeling in current treatment planning systems. One possibility of improving the accuracy of treatment planning is to upgrade the used pencil beam models by adding a description of the low-dose envelope. But at the same time it is crucial to keep the calculation time and the complexity for treatment planning in reasonable limits. As a first approach we measured the lateral beam profiles of scanned proton and carbon ion pencil beams at different energies and depths in water and air at the Heidelberg Ion Beam Therapy Center. Then we tried to describe their beam halo by adding a supplementary Gaussian function to the standard single Gauss modeling which is used at the moment by our treatment planning systems. This analysis helped to identify trends in the parameters describing the lateral beam broadening to support its modeling. Finally, it is shown that the accuracy of treatment planning could be improved by the proposed upgrade of the pencil beam model. In particular, the presented experimental data can be either used directly as input for dose calculation or serve for representative comparison with the results of calculation models such as Monte Carlo simulations for the generation of lateral basic data to be input in upgraded beam models of treatment planning systems.

Purpose: To present the first direct experimental in vitro comparison of the biological effectiveness of range-equivalent protons and carbon ion beams for Chinese hamster ovary cells exposed in a three-dimensional phantom using a pencil beam scanning technique and to compare the experimental data with a novel biophysical model., Methods and Materials: Cell survival was measured in the phantom after irradiation with two opposing fields, thus mimicking the typical patient treatment scenario. The novel biophysical model represents a substantial extension of the local effect model, previously used for treatment planning in carbon ion therapy for more than 400 patients, and potentially can be used to predict effectiveness of all ion species relevant for radiotherapy. A key feature of the new approach is the more sophisticated consideration of spatially correlated damage induced by ion irradiation., Results: The experimental data obtained for Chinese hamster ovary cells clearly demonstrate that higher cell killing is achieved in the target region with carbon ions as compared with protons when the effects in the entrance channel are comparable. The model predictions demonstrate agreement with these experimental data and with data obtained with helium ions under similar conditions. Good agreement is also achieved with relative biological effectiveness values reported in the literature for other cell lines for monoenergetic proton, helium, and carbon ions., Conclusion: Both the experimental data and the new modeling approach are supportive of the advantages of carbon ions as compared with protons for treatment-like field configurations. Because the model predicts the effectiveness for several ion species with similar accuracy, it represents a powerful tool for further optimization and utilization of the potential of ion beams in tumor therapy., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Scanned ion beam delivery promises superior flexibility and accuracy for highly conformal tumour therapy in comparison to the usage of passive beam shaping systems. The attainable precision demands correct overlapping of the pencil-like beams which build up the entire dose distribution in the treatment field. In particular, improper dose application due to deviations of the lateral beam profiles from the nominal planning conditions must be prevented via appropriate beam monitoring in the beamline, prior to the entrance in the patient. To assess the necessary tolerance thresholds of the beam monitoring system at the Heidelberg Ion Beam Therapy Center, Germany, this study has investigated several worst-case scenarios for a sensitive treatment plan, namely scanned proton and carbon ion delivery to a small target volume at a shallow depth. Deviations from the nominal lateral beam profiles were simulated, which may occur because of misaligned elements or changes of the beam optic in the beamline. Data have been analysed with respect to the lateral penumbra, homogeneity and coverage of the dose deposition in the target volume. The results indicate that homogeneity is not seriously compromised by extremely narrow profiles for the standard planning choices of the lateral raster scan stepping and dose grid. Differently, broad beam distributions can significantly deteriorate the conformality of the dose delivery and too large increases (above approximately 150-200% of the nominal spotsize) must be prevented.

Clinical Monte Carlo (MC) calculations for carbon ion therapy have to provide absorbed and RBE-weighted dose. The latter is defined as the product of the dose and the relative biological effectiveness (RBE). At the GSI Helmholtzzentrum für Schwerionenforschung as well as at the Heidelberg Ion Therapy Center (HIT), the RBE values are calculated according to the local effect model (LEM). In this paper, we describe the approach followed for coupling the FLUKA MC code with the LEM and its application to dose and RBE-weighted dose calculations for a superimposition of two opposed (12)C ion fields as applied in therapeutic irradiations. The obtained results are compared with the available experimental data of CHO (Chinese hamster ovary) cell survival and the outcomes of the GSI analytical treatment planning code TRiP98. Some discrepancies have been observed between the analytical and MC calculations of absorbed physical dose profiles, which can be explained by the differences between the laterally integrated depth-dose distributions in water used as input basic data in TRiP98 and the FLUKA recalculated ones. On the other hand, taking into account the differences in the physical beam modeling, the FLUKA-based biological calculations of the CHO cell survival profiles are found in good agreement with the experimental data as well with the TRiP98 predictions. The developed approach that combines the MC transport/interaction capability with the same biological model as in the treatment planning system (TPS) will be used at HIT to support validation/improvement of both dose and RBE-weighted dose calculations performed by the analytical TPS.

We present a comprehensive study of the inclusive production of V0V0 pairs (V0=Λ, Λ̄ or KS ) by Σ- and π- of 340 GeV/ c momentum and neutrons of 260 GeV/ c mean momentum in copper and carbon targets. In particular, the dependence of the xF spectra on the combination of beam-particle and produced V0V0 pair is investigated and compared to predictions obtained from PYTHIA and QSGM calculations. The data and these predictions differ in many details, the agreement can at best be termed as qualitative. A signal from decays of the tensor meson f’2(1525) was observed in the KS KS mass distribution and inclusive production cross sections were measured. No signal was found from the double-strange H-dibaryon decaying to ΛΛ. [ABSTRACT FROM AUTHOR]

We report on a measurement of the inclusive cross sections of Λ, Λ, KS0 and Ω- production by ∑- and π- of 345 GeV/c momentum and by neutrons of 260 GeV/c mean momentum in copper and carbon. The differential cross sections as function of pt² show a distinct non-gaussian behavior above 1.2 (GeV/e)². A comparison of the xF-dependence of ΛΛ, A and K0 production with calculations using PYTFHA and the QGSM model is discussed. [ABSTRACT FROM AUTHOR]

Poster Highlights: Poster highlights 15: Particles and microbeams PH-0477: Effectiveness of fractionated carbon ion treatments in three rat prostate tumors C. Glowa, P. Peschke, S. Brons, J. Debus, C.P. Karger. [Extracted from the article]