Rapid effective dose calculation for raster-scanning 4He ion therapy with the modified microdosimetric kinetic model (mMKM).

PURPOSE: To develop and verify effective dose (DRBE) calculation in 4He ion beam therapy based on the modified microdosimetric kinetic model (mMKM) and evaluate the bio-sensitivity of mMKM-based plans to clinical parameters using a fast analytical dose engine. METHODS: Mixed radiation field particle spectra (MRFS) databases have been generated with Monte-Carlo (MC) simulations for 4He-ion beams. Relative biological effectiveness (RBE) and DRBE calculation using MRFS were established within a fast analytical engine. Spread-out Bragg-Peaks (SOBPs) in water were optimized for two dose levels and two tissue types with photon linear-quadratic model parameters αph, ßph, and (α/ß)ph to verify MRFS-derived database implementation against computations with MC-generated mixed-field α and ß databases. Bio-sensitivity of the SOBPs was investigated by varying absolute values of ßph, while keeping (α/ß)ph constant. Additionally, dose, dose-averaged linear energy transfer, and bio-sensitivity were investigated for two patient cases. RESULTS: Using MRFS-derived databases, dose differences ≲2% in the plateau and SOBP are observed compared to computations with MC-generated databases. Bio-sensitivity studies show larger deviations when altering the absolute ßph value, with maximum D50% changes of ~5%, with similar results for patient cases. Bio-sensitivity analysis indicates a greater impact on DRBE varying (α/ß)ph than ßph in mMKM. CONCLUSIONS: The MRSF approach yielded negligible differences in the target and small differences in the plateau compared to MC-generated databases. The presented analyses provide guidance for proper implementation of RBE-weighted 4He ion dose prescription and planning with mMKM. The MRFS-DRBE calculation approach using mMKM will be implemented in a clinical treatment planning system.

Helium ions at the heidelberg ion beam therapy center: comparisons between FLUKA Monte Carlo code predictions and dosimetric measurements.

In the field of particle therapy helium ion beams could offer an alternative for radiotherapy treatments, owing to their interesting physical and biological properties intermediate between protons and carbon ions. We present in this work the comparisons and validations of the Monte Carlo FLUKA code against in-depth dosimetric measurements acquired at the Heidelberg Ion Beam Therapy Center (HIT). Depth dose distributions in water with and without ripple filter, lateral profiles at different depths in water and a spread-out Bragg peak were investigated. After experimentally-driven tuning of the less known initial beam characteristics in vacuum (beam lateral size and momentum spread) and simulation parameters (water ionization potential), comparisons of depth dose distributions were performed between simulations and measurements, which showed overall good agreement with range differences below 0.1 mm and dose-weighted average dose-differences below 2.3% throughout the entire energy range. Comparisons of lateral dose profiles showed differences in full-width-half-maximum lower than 0.7 mm. Measurements of the spread-out Bragg peak indicated differences with simulations below 1% in the high dose regions and 3% in all other regions, with a range difference less than 0.5 mm. Despite the promising results, some discrepancies between simulations and measurements were observed, particularly at high energies. These differences were attributed to an underestimation of dose contributions from secondary particles at large angles, as seen in a triple Gaussian parametrization of the lateral profiles along the depth. However, the results allowed us to validate FLUKA simulations against measurements, confirming its suitability for 4He ion beam modeling in preparation of clinical establishment at HIT. Future activities building on this work will include treatment plan comparisons using validated biological models between proton and helium ions, either within a Monte Carlo treatment planning engine based on the same FLUKA code, or an independent analytical planning system fed with a validated database of inputs calculated with FLUKA.

Dosimetric verification in water of a Monte Carlo treatment planning tool for proton, helium, carbon and oxygen ion beams at the Heidelberg Ion Beam Therapy Center.

The introduction of 'new' ion species in particle therapy needs to be supported by a thorough assessment of their dosimetric properties and by treatment planning comparisons with clinically used proton and carbon ion beams. In addition to the latter two ions, helium and oxygen ion beams are foreseen at the Heidelberg Ion Beam Therapy Center (HIT) as potential assets for improving clinical outcomes in the near future. We present in this study a dosimetric validation of a FLUKA-based Monte Carlo treatment planning tool (MCTP) for protons, helium, carbon and oxygen ions for spread-out Bragg peaks in water. The comparisons between the ions show the dosimetric advantages of helium and heavier ion beams in terms of their distal and lateral fall-offs with respect to protons, reducing the lateral size of the region receiving 50% of the planned dose up to 12 mm. However, carbon and oxygen ions showed significant doses beyond the target due to the higher fragmentation tail compared to lighter ions (p and He), up to 25%. The Monte Carlo predictions were found to be in excellent geometrical agreement with the measurements, with deviations below 1 mm for all parameters investigated such as target and lateral size as well as distal fall-offs. Measured and simulated absolute dose values agreed within about 2.5% on the overall dose distributions. The MCTP tool, which supports the usage of multiple state-of-the-art relative biological effectiveness models, will provide a solid engine for treatment planning comparisons at HIT.

Optimizing the modified microdosimetric kinetic model input parameters for proton and 4He ion beam therapy application.

Models able to predict relative biological effectiveness (RBE) values are necessary for an accurate determination of the biological effect with proton and 4He ion beams. This is particularly important when including RBE calculations in treatment planning studies comparing biologically optimized proton and 4He ion beam plans. In this work, we have tailored the predictions of the modified microdosimetric kinetic model (MKM), which is clinically applied for carbon ion beam therapy in Japan, to reproduce RBE with proton and 4He ion beams. We have tuned the input parameters of the MKM, i.e. the domain and nucleus radii, reproducing an experimental database of initial RBE data for proton and He ion beams. The modified MKM, with the best fit parameters obtained, has been used to reproduce in vitro cell survival data in clinically-relevant scenarios. A satisfactory agreement has been found for the studied cell lines, A549 and RENCA, with the mean absolute survival variation between the data and predictions within 2% and 5% for proton and 4He ion beams, respectively. Moreover, a sensitivity study has been performed varying the domain and nucleus radii and the quadratic parameter of the photon response curve. The promising agreement found in this work for the studied clinical-like scenarios supports the usage of the modified MKM for treatment planning studies in proton and 4He ion beam therapy.

Experimental dosimetric comparison of 1H, 4He, 12C and 16O scanned ion beams.

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.

A phenomenological relative biological effectiveness approach for proton therapy based on an improved description of the mixed radiation field.

Proton therapy treatment planning systems (TPSs) are based on the assumption of a constant relative biological effectiveness (RBE) of 1.1 without taking into account the found in vitro experimental variations of the RBE as a function of tissue type, linear energy transfer (LET) and dose. The phenomenological RBE models available in literature are based on the dose-averaged LET (LET D ) as an indicator of the physical properties of the proton radiation field. The LET D values are typically calculated taking into account primary and secondary protons, neglecting the biological effect of heavier secondaries. In this work, we have introduced a phenomenological RBE approach which considers the biological effect of primary protons, and of secondary protons, deuterons, tritons (Z = 1) and He fragments (3He and 4He, Z = 2). The calculation framework, coupled with a Monte Carlo (MC) code, has been successfully benchmarked against clonogenic in vitro data measured in this work for two cell lines and then applied to determine biological quantities for spread-out Bragg peaks and a prostate and a head case. The introduced RBE formalism, which depends on the mixed radiation field, the dose and the ratio of the linear-quadratic model parameters for the reference radiation [Formula: see text], predicts, when integrated in an MC code, higher RBE values in comparison to LET D -based parameterizations. This effect is particular enhanced in the entrance channel of the proton field and for low [Formula: see text] tissues. For the prostate and the head case, we found higher RBE-weighted dose values up to about 5% in the entrance channel when including or neglecting the Z = 2 secondaries in the RBE calculation. TPSs able to proper account for the mixed radiation field in proton therapy are thus recommended for an accurate determination of the RBE in the whole treatment field.

Dosimetric advantages of proton therapy over conventional radiotherapy with photons in young patients and adults with low-grade glioma.

BACKGROUND AND PURPOSE: Low-grade glioma (LGG) is a very common brain tumor in pediatric patients typically associated with a very good prognosis. This prognosis makes it imperative that the risk of long-term treatment-related side effects be kept at an absolute minimum. Proton therapy (PRT) provides a radiation technique that has the potential to further reduce the genesis of radiogenic impairment. MATERIALS AND METHODS: We retrospectively assessed 74 patients with LGG who underwent PRT. Conventional three-dimensional photon and PRT plans were generated after contouring structures of neurogenesis, crucial neuronal structures, and areas susceptible to secondary malignancies. Target volume coverage was evaluated using the homogeneity index (HI) and inhomogeneity coefficient (IC). Results were compared using the Wilcoxon-signed rank test, with p < 0.05 being statistically significant. RESULTS: Target volume coverage was comparable for the photon and proton plans. Overall, we could show an essential reduction in maximal, mean, and integral doses in critical neurologic structures, areas of neurogenesis, and structures of neurocognitive function. The study indicated specifically how contralaterally located structures could be spared with PRT. CONCLUSION: PRT is a highly conformal radiation technique offering superior dosimetric advantages over conventional radiotherapy by allowing significant dose reduction for organs at risk (OAR) that are essential for neurologic function, neurocognition, and quality of life, thus demonstrating the potential of this technique for minimizing long-term sequelae.

Intensity-modulated proton therapy, volumetric-modulated arc therapy, and 3D conformal radiotherapy in anaplastic astrocytoma and glioblastoma : A dosimetric comparison.

PURPOSE: The prognosis for high-grade glioma (HGG) patients is poor; thus, treatment-related side effects need to be minimized to conserve quality of life and functionality. Advanced techniques such as proton radiation therapy (PRT) and volumetric-modulated arc therapy (VMAT) may potentially further reduce the frequency and severity of radiogenic impairment. MATERIALS AND METHODS: We retrospectively assessed 12 HGG patients who had undergone postoperative intensity-modulated proton therapy (IMPT). VMAT and 3D conformal radiotherapy (3D-CRT) plans were generated and optimized for comparison after contouring crucial neuronal structures important for neurogenesis and neurocognitive function. Integral dose (ID), homogeneity index (HI), and inhomogeneity coefficient (IC) were calculated from dose statistics. Toxicity data were evaluated. RESULTS: Target volume coverage was comparable for all three modalities. Compared to 3D-CRT and VMAT, PRT showed statistically significant reductions (p < 0.05) in mean dose to whole brain (-20.2 %, -22.7 %); supratentorial (-14.2 %, -20,8 %) and infratentorial (-91.0 %, -77.0 %) regions; brainstem (-67.6 %, -28.1 %); pituitary gland (-52.9 %, -52.5 %); contralateral hippocampus (-98.9 %, -98.7 %); and contralateral subventricular zone (-62.7 %, -66.7 %, respectively). Fatigue (91.7 %), radiation dermatitis (75.0 %), focal alopecia (100.0 %), nausea (41.7 %), cephalgia (58.3 %), and transient cerebral edema (16.7 %) were the most common acute toxicities. CONCLUSION: Essential dose reduction while maintaining equal target volume coverage was observed using PRT, particularly in contralaterally located critical neuronal structures, areas of neurogenesis, and structures of neurocognitive functions. These findings were supported by preliminary clinical results confirming the safety and feasibility of PRT in HGG.

Biologically optimized helium ion plans: calculation approach and its in vitro validation.

Treatment planning studies on the biological effect of raster-scanned helium ion beams should be performed, together with their experimental verification, before their clinical application at the Heidelberg Ion Beam Therapy Center (HIT). For this purpose, we introduce a novel calculation approach based on integrating data-driven biological models in our Monte Carlo treatment planning (MCTP) tool. Dealing with a mixed radiation field, the biological effect of the primary (4)He ion beams, of the secondary (3)He and (4)He (Z = 2) fragments and of the produced protons, deuterons and tritons (Z = 1) has to be taken into account. A spread-out Bragg peak (SOBP) in water, representative of a clinically-relevant scenario, has been biologically optimized with the MCTP and then delivered at HIT. Predictions of cell survival and RBE for a tumor cell line, characterized by [Formula: see text] Gy, have been successfully compared against measured clonogenic survival data. The mean absolute survival variation ([Formula: see text]) between model predictions and experimental data was 5.3% ± 0.9%. A sensitivity study, i.e. quantifying the variation of the estimations for the studied plan as a function of the applied phenomenological modelling approach, has been performed. The feasibility of a simpler biological modelling based on dose-averaged LET (linear energy transfer) has been tested. Moreover, comparisons with biophysical models such as the local effect model (LEM) and the repair-misrepair-fixation (RMF) model were performed. [Formula: see text] values for the LEM and the RMF model were, respectively, 4.5% ± 0.8% and 5.8% ± 1.1%. The satisfactorily agreement found in this work for the studied SOBP, representative of clinically-relevant scenario, suggests that the introduced approach could be applied for an accurate estimation of the biological effect for helium ion radiotherapy.

Data-driven RBE parameterization for helium ion beams.

Helium ion beams are expected to be available again in the near future for clinical use. A suitable formalism to obtain relative biological effectiveness (RBE) values for treatment planning (TP) studies is needed. In this work we developed a data-driven RBE parameterization based on published in vitro experimental values. The RBE parameterization has been developed within the framework of the linear-quadratic (LQ) model as a function of the helium linear energy transfer (LET), dose and the tissue specific parameter (α/ß)ph of the LQ model for the reference radiation. Analytic expressions are provided, derived from the collected database, describing the RBEα = αHe/αph and Rß = ßHe/ßph ratios as a function of LET. Calculated RBE values at 2 Gy photon dose and at 10% survival (RBE10) are compared with the experimental ones. Pearson's correlation coefficients were, respectively, 0.85 and 0.84 confirming the soundness of the introduced approach. Moreover, due to the lack of experimental data at low LET, clonogenic experiments have been performed irradiating A549 cell line with (α/ß)ph = 5.4 Gy at the entrance of a 56.4 MeV u(-1)He beam at the Heidelberg Ion Beam Therapy Center. The proposed parameterization reproduces the measured cell survival within the experimental uncertainties. A RBE formula, which depends only on dose, LET and (α/ß)ph as input parameters is proposed, allowing a straightforward implementation in a TP system.

Gating delays for two respiratory motion sensors in scanned particle radiation therapy.

Gating is one option for radiotherapy of tumours that move intrafractionally due to respiration. Delays of the motion monitoring system can lead to a shift of the gating window and thus slightly shifted dose distributions. We studied the delay of two motion monitoring systems which use the motion of the chest wall as surrogate for tumour motion. Delays and their dosimetric influence were determined against a precise motion acquisition system in a phantom study. The measurement data were supplemented by dedicated simulations of the experimental setup. Finally, the dosimetric influence for patient treatments was estimated for a lung tumour case using the extreme situation of a radiosurgery setting with a single field. We determined delays of 132 ± 18 ms and 103 ± 22 ms for the two systems. There was no significant difference between beam start and beam stop delay. Even for delays of 200 ms the dosimetric influence in a single-field radiosurgery setting is moderate (V95 = 96.5%, V107 = 8.5%, D5-D95 = 13%). We conclude, that the delay of the motion monitoring system should be part of the commissioning process for gated treatments. The dosimetric impact should be studied in detail prior treatments with a scanned ion beam.

A Monte Carlo-based treatment-planning tool for ion beam therapy.

Ion beam therapy, as an emerging radiation therapy modality, requires continuous efforts to develop and improve tools for patient treatment planning (TP) and research applications. Dose and fluence computation algorithms using the Monte Carlo (MC) technique have served for decades as reference tools for accurate dose computations for radiotherapy. In this work, a novel MC-based treatment-planning (MCTP) tool for ion beam therapy using the pencil beam scanning technique is presented. It allows single-field and simultaneous multiple-fields optimization for realistic patient treatment conditions and for dosimetric quality assurance for irradiation conditions at state-of-the-art ion beam therapy facilities. It employs iterative procedures that allow for the optimization of absorbed dose and relative biological effectiveness (RBE)-weighted dose using radiobiological input tables generated by external RBE models. Using a re-implementation of the local effect model (LEM), the MCTP tool is able to perform TP studies using ions with atomic numbers Z ≤ 8. Example treatment plans created with the MCTP tool are presented for carbon ions in comparison with a certified analytical treatment-planning system. Furthermore, the usage of the tool to compute and optimize mixed-ion treatment plans, i.e. plans including pencil beams of ions with different atomic numbers, is demonstrated. The tool is aimed for future use in research applications and to support treatment planning at ion beam facilities.

Investigating the robustness of ion beam therapy treatment plans to uncertainties in biological treatment parameters.

Uncertainties in determining clinically used relative biological effectiveness (RBE) values for ion beam therapy carry the risk of absolute and relative misestimations of RBE-weighted doses for clinical scenarios. This study assesses the consequences of hypothetical misestimations of input parameters to the RBE modelling for carbon ion treatment plans by a variational approach. The impact of the variations on resulting cell survival and RBE values is evaluated as a function of the remaining ion range. In addition, the sensitivity to misestimations in RBE modelling is compared for single fields and two opposed fields using differing optimization criteria. It is demonstrated for single treatment fields that moderate variations (up to ±50%) of representative nominal input parameters for four tumours result mainly in a misestimation of the RBE-weighted dose in the planning target volume (PTV) by a constant factor and only smaller RBE-weighted dose gradients. Ensuring a more uniform radiation quality in the PTV eases the clinical importance of uncertainties in the radiobiological treatment parameters, as for such a condition uncertainties tend to result only in a systematic misestimation of RBE-weighted dose in the PTV by a constant factor. Two opposed carbon ion fields with a constant RBE in the PTV are found to result in rather robust conditions. Treatments using two ion species may be used to achieve a constant RBE in the PTV irrespective of the size and depth of the spread-out Bragg peak.

Monte Carlo simulations to support start-up and treatment planning of scanned proton and carbon ion therapy at a synchrotron-based facility.

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.

Test bench to commission a third ion source beam line and a newly designed extraction system.

The HIT (Heidelberg Ion Beam Therapy Center) is the first hospital-based treatment facility in Europe where patients can be irradiated with protons and carbon ions. Since the commissioning starting in 2006 two 14.5 GHz electron cyclotron resonance ion sources are routinely used to produce a variety of ion beams from protons up to oxygen. In the future a helium beam for regular patient treatment is requested, therefore a third ion source (Supernanogan source from PANTECHNIK S.A.) will be integrated. This third ECR source with a newly designed extraction system and a spectrometer line is installed at a test bench at HIT to commission and validate this section. Measurements with different extraction system setups will be presented to show the improvement of beam quality for helium, proton, and carbon beams. An outlook to the possible integration scheme of the new ion source into the production facility will be discussed.

The influence of lateral beam profile modifications in scanned proton and carbon ion therapy: a Monte Carlo study.

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.

Progress in ion source injector development at the ion beam therapy center (Heidelberg Ion Beam Therapy Center).

Radiotherapy with heavy ions is an upcoming cancer treatment method with to date unachieved precision. It associates higher control rates particularly for radio-resistant tumor species with reduced adverse effects compared to conventional photon therapy. At Heidelberg Ion Beam Therapy Center two 14.5 GHz electron cyclotron resonance ion sources are routinely used to produce a variety of ion beams from protons up to oxygen. The operating time is 330 days per year; our experience after 3 yr of continuous operation will be presented, with special emphasis on stability and breakdowns of components. In addition, the latest enhancement and the results for the operation will be shown.

Electron cyclotron resonance ion source experience at the Heidelberg Ion Beam Therapy Center.

Radiotherapy with heavy ions is an upcoming cancer treatment method with to date unparalleled precision. It associates higher control rates particularly for radiation resistant tumor species with reduced adverse effects compared to conventional photon therapy. The accelerator beam lines and structures of the Heidelberg Ion Beam Therapy Center (HIT) have been designed under the leadership of GSI, Darmstadt with contributions of the IAP Frankfurt. Currently, the accelerator is under commissioning, while the injector linac has been completed. When the patient treatment begins in 2008, HIT will be the first medical heavy ion accelerator in Europe. This presentation will provide an overview about the project, with special attention given to the 14.5 GHz electron cyclotron resonance (ECR) ion sources in operation with carbon, hydrogen, helium, and oxygen, and the experience of one year of continuous operation. It also displays examples for beam emittances, measured in the low energy beam transport. In addition to the outlook of further developments at the ECR ion sources for a continuously stable operation, this paper focuses on some of the technical processings of the past year.

Treatment planning for scanned ion beams.

Since 1997 a radiotherapy unit using fast carbon ions is operational at GSI. An intensity-controlled magnetic raster scanner together with a synchrotron allowing fast energy variation enable a unique method of purely active dose shaping in three dimensions. This contribution describes the necessary steps to establish a treatment planning system for this novel modality. We discuss the requirements for the physical beam model and the radiobiological model. Based on these we chose to implement a home-grown pencil beam model to describe the ion-tissue interaction and the Local Effect Model to calculate the RBE voxel-by-voxel. Given the large number of degrees of freedom biological dose optimization must be achieved by means of inverse treatment planning. All ion-related aspects are collected in our TRiP98 software. Biological dosimetry measuring cell survival in two dimensions turns out to be a good way to verify the model predictions as well as the actual irradiation procedure. We show a patient example and outline the future steps towards a dedicated clinic facility for all light ions.