[en] Purpose: A stereotactic fixation and localization device developed for small animal stereotactic radiosurgery is described. Methods and Materials: Irradiated volumes of spherical shape down to 1.7 mm in diameter at the 80% isodose level are attainable. The fixation device can also be used for magnetic resonance imaging (MRI) and allows target localization during magnetic resonance (MR) image content measurement. The capabilities of the entire system were investigated using a phantom that permitted measurement and localization of the three-dimensional dose distribution. Localization of target isocenter coordinates in MR images was also checked with the phantom. Results: An overall spatial error of about 1 mm for subsequent stereotactic irradiation was obtained. Conclusions: The accuracy of the fixation and localization techniques is adequate to investigate radiation-induced changes in the rat brain

[en] Purpose: Conformal radiotherapy in the head and neck region requires precise and reproducible patient setup. The definition of safety margins around the clinical target volume has to take into account uncertainties of fixation and positioning. Data are presented to quantify the involved uncertainties for the system used. Methods and Materials: Interfractional reproducibility of fixation and positioning of a target point in the brain was evaluated by biplanar films. 118 film pairs obtained at 52 fractions in 4 patients were analyzed. The setup was verified at the actual treatment table position by diagnostic X-ray units aligned to the isocenter and by a stereotactic X-ray localization technique. The stereotactic coordinates of the treated isocenter, of fiducials on the mask, and of implanted internal markers within the patient were measured to determine systematic and random errors. The data are corrected for uncertainty of the localization method. Results: Displacements in target point positioning were 0.35±0.41 mm, 1.22±0.25 mm, and -0.74±0.32 mm in the x, y, and z direction, respectively. The reproducibility of the fixation of the patient's head within the mask was 0.48 mm (x), 0.67 mm (y), and 0.72 mm (z). Rotational uncertainties around an axis parallel to the x, y, and z axis were 0.72 deg., 0.43 deg., and 0.70 deg., respectively. A simulation, based on the acquired data, yields a typical radial overall uncertainty for positioning and fixation of 1.80±0.60 mm. Conclusions: The applied setup technique showed to be highly reproducible. The data suggest that for the applied technique, a safety margin between clinical and planning target volume of 1-2 mm along one axis is sufficient for a target at the base of skull

[en] Purpose: Only few quantitative data are available on late effects in the healthy brain after radiosurgery. An animal model would contribute to systematically investigate such late effects. For this reason a rat model applying radiosurgery at the rat brain was established. This investigation comprised several steps: (1) design for a special fixation- and localization device to perform linac based stereotactic radiosurgery at the rat; (2) feasibility and accuracy study of irradiation and MRI-evaluation in the rat brain; (3) a long term (1 (1(2)) year) follow up study with a group of animals. Materials and Methods: A localization technique was developed to irradiate a small target volume within the rat brain. A mean spatial uncertainty of 1 mm was verified by phantom measurements. At 60 animals, a small area of the brain was irradiated stereotactically (15 MV linac). Different doses doses of 20, 30, 40, 50, and 100 Gy with two field sizes using the 2 and 3 mm collimator were administered. These dose levels were selected to be equally distributed between 0 and 100% effect probability according to the Flickinger model assuming comparable radiosensitivity between rat and human brain. The diameter of the spherical dose distribution (80%-isodose) was 3.9 and 5.8 mm, respectively. The alteration of the permeability of the blood brain barrier was investigated, using magnetic resonance imaging and Gd-DTPA contrast agent. An intracranial contrast enhancement was interpreted as a first indication for brain necrosis. Half of the animals were killed for histology after 9 and 18 months, respectively. Results: A first intracranial signal enhancement was observed 160 days after irradiation. Within one year, all animal in the two 100 Gy groups showed contrast enhancement, but none of the other groups. The incident rates were (6(6)) for the 2 mm collimator and(5(5)) for the 3 mm collimator. Contrast enhancement volume and signal intensity were significantly different between these two groups. After 18 months, however, other animals also showed contrast enhancements. The incidence rate was (2(3)) for the 50 (Gy(3)) mm group and the 40(Gy(3)) mm group, and (1(3)) for the 30 (Gy(3)) mm group and the 50 (Gy(2)) mm group. All other animals did not show any contrast enhancement within 18 months. Conclusions: Linac based stereotactic radiosurgery can be successfully applied at the rat brain. The animal model is appropriate to study late normal brain tissue response. Contrast enhancement as an indication of late radionecrosis was found 1 (1(2)) year after even moderate doses of radiosurgery. The behaviour of radioresponse appeared to followed the prediction of the Flickinger model for human brain. The techniques used can also be applied to study modifications in the irradiation modality, i.e. fractionation, irregular volumes, or radiation quality

[en] Purpose: Only few quantitative data are available on late effects in the healthy brain after radiosurgery. An animal model can contribute to systematically investigate such late effects. Therefore, a model applying radiosurgery at the rat brain was established. A long-term (19 months) follow up study with 66 animals after radiosurgery was carried out. Methods and Materials: In 60 animals, an area in the frontal lobe of the brain was irradiated stereotactically with a 15 MV linac. Different doses of 20, 30, 40, 50, and 100 Gy with two field sizes (3.9 and 5.9 mm collimator) were selected, using the integrated logistic formula with input parameters from human brain. The induced alteration of the blood-brain barrier permeability was investigated by means of contrast enhanced magnetic resonance imaging. Results: A first intracranial signal enhancement was observed in one animal 160 days after irradiation with 100 Gy. Beginning at 5 months all animals in the two 100 Gy groups homogeneously showed contrast enhancement, but none of the other groups. This remained until 13 months after irradiation. The volume of contrast enhancement as well as the increase of signal intensity were different between the two 100 Gy groups. After 19 months, the animals irradiated with lower doses also showed contrast enhancements, although not uniformly throughout one group. A maximum likelihood fit of the logistic formula P(D) = 1/[1 + (D₅₀/D)^k] to the incidence of late effects for the 5.9 mm collimator at 19 months after irradiation results in the parameters D₅₀ = 37.4^+6.1_-5.2 Gy and k = 4.7 ± 2.4. Conclusions: An animal model was established to study late normal brain tissue response. The observed late effects appeared very similar to the estimation of the integrated logistic formula for human brain. Based on these radiosurgery techniques, future experiments will focus on modifications in the irradiation modalities, i.e., irregular volumes, radiation quality or fractionation

[en] Carbon ion therapy is a promising evolving modality in radiotherapy to treat tumors that are radioresistant against photon treatments. As carbon ions are more effective in normal and tumor tissue, the relative biological effectiveness (RBE) has to be calculated by bio-mathematical models and has to be considered in the dose prescription. This review (i) introduces the concept of the RBE and its most important determinants, (ii) describes the physical and biological causes of the increased RBE for carbon ions, (iii) summarizes available RBE measurements in vitro and in vivo, and (iv) describes the concepts of the clinically applied RBE models (mixed beam model, local effect model, and microdosimetric-kinetic model), and (v) the way they are introduced into clinical application as well as (vi) their status of experimental and clinical validation, and finally (vii) summarizes the current status of the use of the RBE concept in carbon ion therapy and points out clinically relevant conclusions as well as open questions. The RBE concept has proven to be a valuable concept for dose prescription in carbon ion radiotherapy, however, different centers use different RBE models and therefore care has to be taken when transferring results from one center to another. Experimental studies significantly improve the understanding of the dependencies and limitations of RBE models in clinical application. For the future, further studies investigating quantitatively the differential effects between normal tissues and tumors are needed accompanied by clinical studies on effectiveness and toxicity. (topical review)

[en] Background. Currently, optimisation of the dose distribution and clinical acceptance are almost entirely based on the physical dose distribution and tumour control probability modelling is far from being routinely used as objective in treatment planning. For future individualised radiotherapeutic strategies, a reliable patient specific simulation model, taking into account customised tumour features, is needed to predict and improve treatment outcome. Materials and methods. To approach these demands, a single cell and Monte-Carlo based model was developed, which enables three-dimensional tumour growth and radiation response simulation. Tumour cells were characterised by cell-associated features such as age, intrinsic radio-sensitivity, proliferation ability, and oxygenation status, while capillary cells were considered as sources of a radial-dependent oxygen profile. Response to radiation was simulated by the linear-quadratic model, taking into account the lower radio-sensitivity of poorly oxygenated tumour cells. Results. The present study shows the influence of the model components and demonstrates the impact of the intra- and inter-tumoural radio-sensitivity heterogeneity on the treatment response. Conclusion. The simulation model adequately delineates the importance of the above described selected parameters on tumour control probability, providing an insight into the interplay of different physical and biological parameters, and its relevance for an individual tumour response

[en] At an isocentric irradiation facility, the rotation axis of the treatment table has to be accurately aligned in vertical orientation to the isocentre, which is usually marked by three perpendicular laser planes. In particular, high precision radiotherapy techniques, such as radiosurgery or intensity modulated radiotherapy, require a higher alignment accuracy of the table axis than routinely specified by the manufacturers. A simple and efficient method is presented to measure the direction and the size of the displacement of the table axis from the isocentre as marked by the lasers. In addition, the inclination of the table axis against the vertical direction can be determined. The measured displacement and inclination provide the required data to correct for possible misalignments of the treatment table axis and to maintain its alignment. Measurements were performed over a period of two years for a treatment table located at the German heavy ion therapy facility. The mean radial distance between the table axis and the isocentre was found to be 0.25±0.25 mm. The mean inclination of the table axis in the XZ- and YZ-planes was measured to be -0.03±0.02 deg. and -0.04±0.01 deg., respectively. The measurements demonstrate the good alignment of the treatment table over the analysed time period. The described method can be applied to any isocentric irradiation facility, especially including isocentric linear accelerators used for radiosurgery or other high precision irradiation techniques. (author)

[en] Purpose: To evaluate the clinical suitability of a specific optical surface imaging system to detect setup errors in fractionated radiation therapy. Methods and Materials: The setup correction accuracy of a 3-dimensional laser imaging system was analyzed for 6 different tumor locations with 20 patients each. For each patient, the setup corrections of the megavoltage computed tomography (MVCT) images of a TomoTherapy unit (TomoTherapy, Madison, WI) were compared with those of the laser system for the first 10 fractions. For the laser system, the reference surface either was obtained from the DICOM (Digital Imaging and Communications in Medicine) surface structure delineated on the planning computed tomography images or was acquired with the system itself at the first fraction after the MVCT-based setup correction. Data analysis was performed for both reference types. Results: By use of the DICOM reference image, systematic shifts between 3 and 9 mm were found, depending on the tumor location. For the optical reference, no clinically relevant systematic shifts were found. MVCT-based setup corrections were detected with high accuracy, and only small movements were observed during treatment. Conclusions: Using a reference image acquired with the laser system itself after MVCT-based setup correction appears more reliable than importing the DICOM reference surface. After generation of the optical reference, the laser system may be used to derive setup corrections over a certain number of fractions, but additional radiologic imaging may still be necessary on a regular basis (eg, weekly) or if the corrections of the optical system appear implausibly large. Nevertheless, such a combined application may help to reduce the imaging dose for the patient

[en] Recently, ion beam radiotherapy (including protons as well as heavier ions) gained considerable interest. Although ion beam radiotherapy requires dose prescription in terms of iso-effective dose (referring to an iso-effective photon dose), absorbed dose is still required as an operative quantity to control beam delivery, to characterize the beam dosimetrically and to verify dose delivery. This paper reviews current methods and standards to determine absorbed dose to water in ion beam radiotherapy, including (i) the detectors used to measure absorbed dose, (ii) dosimetry under reference conditions and (iii) dosimetry under non-reference conditions. Due to the LET dependence of the response of films and solid-state detectors, dosimetric measurements are mostly based on ion chambers. While a primary standard for ion beam radiotherapy still remains to be established, ion chamber dosimetry under reference conditions is based on similar protocols as for photons and electrons although the involved uncertainty is larger than for photon beams. For non-reference conditions, dose measurements in tissue-equivalent materials may also be necessary. Regarding the atomic numbers of the composites of tissue-equivalent phantoms, special requirements have to be fulfilled for ion beams. Methods for calibrating the beam monitor depend on whether passive or active beam delivery techniques are used. QA measurements are comparable to conventional radiotherapy; however, dose verification is usually single field rather than treatment plan based. Dose verification for active beam delivery techniques requires the use of multi-channel dosimetry systems to check the compliance of measured and calculated dose for a representative sample of measurement points. Although methods for ion beam dosimetry have been established, there is still room for developments. This includes improvement of the dosimetric accuracy as well as development of more efficient measurement techniques. (topical review)

[en] Purpose: As hypoxic cells are more resistant to photon radiation, it is desirable to obtain information about the oxygen distribution in tumors prior to the radiation treatment. Noninvasive techniques are currently not able to provide reliable oxygenation maps with sufficient spatial resolution; therefore mathematical models may help to simulate microvascular architectures and the resulting oxygen distributions in the surrounding tissue. Here, the authors present a new computer model, which uses the vascular fraction of tumor voxels, in principle measurable noninvasively in vivo, as input parameter for simulating realistic PO2 histograms in tumors, assuming certain 3D vascular architectures.Methods: Oxygen distributions were calculated by solving a reaction-diffusion equation in a reference volume using the particle strength exchange method. Different types of vessel architectures as well as different degrees of vascular heterogeneities are considered. Two types of acute hypoxia (ischemic and hypoxemic) occurring additionally to diffusion-limited (chronic) hypoxia were implemented as well.Results: No statistically significant differences were observed when comparing 2D- and 3D-vessel architectures (p > 0.79 in all cases) and highly heterogeneously distributed linear vessels show good agreement, when comparing with published experimental intervessel distance distributions and PO2 histograms. It could be shown that, if information about additional acute hypoxia is available, its contribution to the hypoxic fraction (HF) can be simulated as well. Increases of 128% and 168% in the HF were obtained when representative cases of ischemic and hypoxemic acute hypoxia, respectively, were considered in the simulations.Conclusions: The presented model is able to simulate realistic microscopic oxygen distributions in tumors assuming reasonable vessel architectures and using the vascular fraction as macroscopic input parameter. The model may be used to generate PO2 histograms, which are needed as input in models predicting the radiation response of hypoxic tumors