[Gross tumor volume (GTV) : Basics, methods, registration, limitations]. / "Gross tumor volume" (GTV) : Grundsätze, Methoden, Registrierung, Grenzen.

CLINICAL ISSUE: Gross tumor volume (GTV) denotes the macroscopic tumor which as the central target volume needs to be correctly identified for successful radiotherapy. STANDARD RADIOLOGICAL METHODS AND METHODICAL INNOVATIONS: In precision radiotherapy, GTV is outlined on 3D tomographic images. The basis is computed tomography (CT), which is often supplemented by additional diagnostic information, e. g. magnetic resonance imaging (MRI) and positron emission tomography (PET). New developments like dual-energy CT, functional MRI and specific PET tracers facilitate a continuously better differentiation between tumor and surrounding normal tissue. ACHIEVEMENTS: The concept of GTV is a central part of radiotherapy and the basis of radiation treatment planning. Studies regarding the interobserver variability are performed in order to analyze the impact of different imaging modalities, interventions and observer qualifications, and to deduce steps to constantly improve the practical realization. Each tumor entity presents specific challenges which are demonstrated here using examples.

Monte Carlo study on the sensitivity of prompt gamma imaging to proton range variations due to interfractional changes in prostate cancer patients.

Proton range verification based on prompt gamma imaging is increasingly considered in proton therapy. Tissue heterogeneity normal to the beam direction or near the end of range may considerably degrade the ability of prompt gamma imaging to detect proton range shifts. The goal of this study was to systematically investigate the accuracy and precision of range detection from prompt gamma emission profiles for various fractions for intensity modulated proton therapy of prostate cancer, using a comprehensive clinical dataset of 15 different CT scans for 5 patients. Monte Carlo simulations using Geant4 were performed to generate spot-by-spot dose distributions and prompt gamma emission profiles for prostate treatment plans. The prompt gammas were scored at their point of emission. Three CT scans of the same patient were used to evaluate the impact of inter-fractional changes on proton range. The range shifts deduced from the comparison of prompt gamma emission profiles in the planning CT and subsequent CTs were then correlated to the corresponding range shifts deduced from the dose distributions for individual pencil beams. The distributions of range shift differences between prompt gamma and dose were evaluated in terms of precision (defined as half the 95% inter-percentile range IPR) and accuracy (median). In total about 1700 individual proton pencil beams were investigated. The IPR of the relative range shift differences between the dose profiles and the prompt gamma profiles varied between ±1.4 mm and ±2.9 mm when using the more robust profile shifting analysis. The median was found smaller than 1 mm. Methods to identify and reject unreliable spots for range verification due to range mixing were derived and resulted in an average 10% spot rejection, clearly improving the prompt gamma-dose correlation. This work supports that prompt gamma imaging can offer a reliable indicator of range changes due to anatomical variations and tissue heterogeneity in scanning proton treatment of prostate cancer patients when considering prompt gamma emission profiles.

Comparative analysis of Pareto surfaces in multi-criteria IMRT planning.

In the multi-criteria optimization approach to IMRT planning, a given dose distribution is evaluated by a number of convex objective functions that measure tumor coverage and sparing of the different organs at risk. Within this context optimizing the intensity profiles for any fixed set of beams yields a convex Pareto set in the objective space. However, if the number of beam directions and irradiation angles are included as free parameters in the formulation of the optimization problem, the resulting Pareto set becomes more intricate. In this work, a method is presented that allows for the comparison of two convex Pareto sets emerging from two distinct beam configuration choices. For the two competing beam settings, the non-dominated and the dominated points of the corresponding Pareto sets are identified and the distance between the two sets in the objective space is calculated and subsequently plotted. The obtained information enables the planner to decide if, for a given compromise, the current beam setup is optimal. He may then re-adjust his choice accordingly during navigation. The method is applied to an artificial case and two clinical head neck cases. In all cases no configuration is dominating its competitor over the whole Pareto set. For example, in one of the head neck cases a seven-beam configuration turns out to be superior to a nine-beam configuration if the highest priority is the sparing of the spinal cord. The presented method of comparing Pareto sets is not restricted to comparing different beam angle configurations, but will allow for more comprehensive comparisons of competing treatment techniques (e.g., photons versus protons) than with the classical method of comparing single treatment plans.

Trade-off bounds for the Pareto surface approximation in multi-criteria IMRT planning.

One approach to multi-criteria IMRT planning is to automatically calculate a data set of Pareto-optimal plans for a given planning problem in a first phase, and then interactively explore the solution space and decide on the clinically best treatment plan in a second phase. The challenge of computing the plan data set is to ensure that all clinically meaningful plans are covered and that as many clinically irrelevant plans as possible are excluded to keep computation times within reasonable limits. In this work, we focus on the approximation of the clinically relevant part of the Pareto surface, the process that constitutes the first phase. It is possible that two plans on the Pareto surface have a small, clinically insignificant difference in one criterion and a significant difference in another criterion. For such cases, only the plan that is clinically clearly superior should be included into the data set. To achieve this during the Pareto surface approximation, we propose to introduce bounds that restrict the relative quality between plans, the so-called trade-off bounds. We show how to integrate these trade-off bounds into the approximation scheme and study their effects. The proposed scheme is applied to two artificial cases and one clinical case of a paraspinal tumor. For all cases, the quality of the Pareto surface approximation is measured with respect to the number of computed plans, and the range of values occurring in the approximation for different criteria is compared. Through enforcing trade-off bounds, the scheme disregards clinically irrelevant plans during the approximation. Thereby, the number of plans necessary to achieve a good approximation quality can be significantly reduced. Thus, trade-off bounds are an effective tool to focus the planning and to reduce computation time.

[Computed tomography of the lungs. A step into the fourth dimension]. / Computertomographie der Lunge. Ein Schritt in die vierte Dimension.

PURPOSE: To discuss the techniques for four dimensional computed tomography of the lungs in tumour patients. METHOD: The image acquisition in CT can be done using respiratory gating in two different ways: the helical or cine mode. In the helical mode, the couch moves continuously during image and respiratory signal acquisition. In the cine mode, the couch remains in the same position during at least one complete respiratory cycle and then moves to next position. The 4D images are either acquired prospectively or reconstructed retrospectively with dedicated algorithms in a freely selectable respiratory phase. RESULTS: The time information required for motion depiction in 4D imaging can be obtained with tolerable motion artefacts. Partial projection and stepladder-artifacts are occurring predominantly close to the diaphragm, where the displacement is most prominent. Due to the long exposure times, radiation exposure is significantly higher compared to a simple breathhold helical acquisition. Therefore, the use of 4D-CT is restricted to only specific indications (i.e. radiotherapy planning). CONCLUSION: 4D-CT of the lung allows evaluating the respiration-correlated displacement of lungs and tumours in space for radiotherapy planning.

Pareto navigation: algorithmic foundation of interactive multi-criteria IMRT planning.

Inherently, IMRT treatment planning involves compromising between different planning goals. Multi-criteria IMRT planning directly addresses this compromising and thus makes it more systematic. Usually, several plans are computed from which the planner selects the most promising following a certain procedure. Applying Pareto navigation for this selection step simultaneously increases the variety of planning options and eases the identification of the most promising plan. Pareto navigation is an interactive multi-criteria optimization method that consists of the two navigation mechanisms 'selection' and 'restriction'. The former allows the formulation of wishes whereas the latter allows the exclusion of unwanted plans. They are realized as optimization problems on the so-called plan bundle -- a set constructed from pre-computed plans. They can be approximately reformulated so that their solution time is a small fraction of a second. Thus, the user can be provided with immediate feedback regarding his or her decisions. Pareto navigation was implemented in the MIRA navigator software and allows real-time manipulation of the current plan and the set of considered plans. The changes are triggered by simple mouse operations on the so-called navigation star and lead to real-time updates of the navigation star and the dose visualizations. Since any Pareto-optimal plan in the plan bundle can be found with just a few navigation operations the MIRA navigator allows a fast and directed plan determination. Besides, the concept allows for a refinement of the plan bundle, thus offering a middle course between single plan computation and multi-criteria optimization. Pareto navigation offers so far unmatched real-time interactions, ease of use and plan variety, setting it apart from the multi-criteria IMRT planning methods proposed so far.

Improved stratification algorithms for step-and-shoot MLC delivery in intensity-modulated radiation therapy.

In inverse planning for intensity-modulated radiotherapy (IMRT), the fluence distribution of each treatment beam is usually calculated in an optimization process. The delivery of the resulting treatment plan using multileaf collimators (MLCs) is performed either in the step-and-shoot or sliding window technique. For step-and-shoot delivery, the arbitrary beam fluence distributions have to be transformed into an applicable sequence of subsegments. In a stratification step the complexity of the fluence maps is reduced by assigning each beamlet to discrete intensity values, followed by the sequencing step that generates the subsegments. In this work, we concentrate on the stratification for step-and-shoot delivery. Different concepts of stratification are formally introduced. In addition to already used strategies that minimize the difference between original and stratified beam intensities, we propose an original stratification principle that minimizes the error of the resulting dose distribution. It could be shown that for a comparable total number of subsegments the dose-oriented stratification results in a better approximation of the original, unsequenced plan. The presented algorithm can replace the stratification routine in existing sequencer programs and can also be applied to interpolated plans that are generated in an interactive decision making process of multicriteria inverse planning programs.

Kilovoltage CT using a linac-CT scanner combination.

Modern radiotherapy techniques such as intensity modulation are capable of generating complex dose distributions whose high dose areas tightly conform to the tumour target volume, sparing critical organs even when they are located in close proximity. This potential can only be exploited to its full extent when the accumulated dose actually delivered over the complete treatment course is sufficiently close to the dose computed on the initial CT scan used for treatment planning. Exact patient repositioning is mandatory, but also other sources of error, e.g. changes of the patient's anatomy under therapy, should be taken into account. At the German Cancer Research Center, we use a combination of a linear accelerator and a CT scanner installed in one room and sharing the same couch. It allows the quantification and correction of interfractional variations between planning and treatment delivery. In this paper, we describe treatments of prostate, paraspinal and head and neck tumours. All patients were immobilized by customized fixation devices and treated in a stereotactic setup. For each patient, frequent CT scans were taken during the treatment course. Each scan was compared with the original planning CT using manual checks and automatic rigid matching algorithms. Depending on the individual case, the adaptation to variations was carried out offline after several fractions or in real-time between the CT scan and linac irradiation. We discuss the techniques for detecting and correcting interfractional errors and outline the procedural steps of a linac-CT scanner-supported radiation treatment course.

An enhanced block matching algorithm for fast elastic registration in adaptive radiotherapy.

Image registration has many medical applications in diagnosis, therapy planning and therapy. Especially for time-adaptive radiotherapy, an efficient and accurate elastic registration of images acquired for treatment planning, and at the time of the actual treatment, is highly desirable. Therefore, we developed a fully automatic and fast block matching algorithm which identifies a set of anatomical landmarks in a 3D CT dataset and relocates them in another CT dataset by maximization of local correlation coefficients in the frequency domain. To transform the complete dataset, a smooth interpolation between the landmarks is calculated by modified thin-plate splines with local impact. The concept of the algorithm allows separate processing of image discontinuities like temporally changing air cavities in the intestinal track or rectum. The result is a fully transformed 3D planning dataset (planning CT as well as delineations of tumour and organs at risk) to a verification CT, allowing evaluation and, if necessary, changes of the treatment plan based on the current patient anatomy without time-consuming manual re-contouring. Typically the total calculation time is less than 5 min, which allows the use of the registration tool between acquiring the verification images and delivering the dose fraction for online corrections. We present verifications of the algorithm for five different patient datasets with different tumour locations (prostate, paraspinal and head-and-neck) by comparing the results with manually selected landmarks, visual assessment and consistency testing. It turns out that the mean error of the registration is better than the voxel resolution (2 x 2 x 3 mm(3)). In conclusion, we present an algorithm for fully automatic elastic image registration that is precise and fast enough for online corrections in an adaptive fractionated radiation treatment course.

DAVID--a translucent multi-wire transmission ionization chamber for in vivo verification of IMRT and conformal irradiation techniques.

Permanent in vivo verification of IMRT photon beam profiles by a radiation detector with spatial resolution, positioned on the radiation entrance side of the patient, has not been clinically available so far. In this work we present the DAVID system, which is able to perform this quality assurance measurement while the patient is treated. The DAVID system is a flat, multi-wire transmission-type ionization chamber, placed in the accessory holder of the linear accelerator and constructed from translucent materials in order not to interfere with the light field. Each detection wire of the chamber is positioned exactly in the projection line of a MLC leaf pair, and the signal of each wire is proportional to the line integral of the ionization density along this wire. Thereby, each measurement channel essentially presents the line integral of the ionization density over the opening width of the associated leaf pair. The sum of all wire signals is a measure of the dose-area product of the transmitted photon beam and of the total radiant energy administered to the patient. After the dosimetric verification of an IMRT plan, the values measured by the DAVID system are stored as reference values. During daily treatment the signals are re-measured and compared to the reference values. A warning is output if there is a deviation beyond a threshold. The error detection capability is a leaf position error of less than 1 mm for an isocentric 1 cm x 1 cm field, and of 1 mm for an isocentric 20 cm x 20 cm field.

Chromosome aberrations induced in human lymphocytes by 3.45 MeV alpha particles analyzed by premature chromosome condensation.

Premature chromosome condensation (PCC) experiments using human lymphocytes with centromere staining have shown that after exposure to 3.45 MeV alpha-particle radiation, the full number of dicentric chromosomes appears when the cell fusion protocol is applied immediately after irradiation. In this case, the time available for repair and misrepair of DNA damage is only about 30 min. The number of dicentrics does not change with a further increase in the time available for chromatin rearrangement. This fast response confirms the expectation based on our previous experiments using PCC with 150 kV X rays in which the alpha component of the yield of dicentrics was found to appear when the cell fusion protocol was applied immediately after irradiation, whereas the beta component was delayed by several hours. The time constant for rejoining of the excess acentric chromosome fragments is found to be donor-specific and not to differ for alpha particles and X rays, but alpha-particle radiation leaves a larger fraction of the excess acentric fragments unrejoined. The RBEs of the 3.45 MeV alpha-particle radiation compared to 150 kV X rays, evaluated for the alpha component for the yield of dicentrics and for the yield of unrepaired acentric fragments, have almost equal values of about 4. This is consistent with data in the literature on chromosome aberrations observed in metaphase that show the equality of the RBE values for production of dicentrics and acentric fragments. Our experimental results concerning the fast kinetics of the alpha component of the yield of exchange-type chromosome aberrations are not consistent with Lea's pairwise lesion interaction model, and they support the proposed alternative mechanism of lesion-nonlesion interaction between chromatin regions carrying clustered DNA damage and intact chromatin regions.

[Heart wall rupture in acute myocardial infarct. An autopsy study in comparison with infarcts without rupture]. / Herzwandruptur beim akuten Myokardinfarkt. Eine Autopsiestudie im Vergleich mit Infarkten ohne Ruptur.

Among 237 patients who died of acute myocardial infarction (4% of the 5,390 autopsies from 1975 to 1979) 43 cases (18%) with a rupture of the cardiac wall were found. These 43 cases of rupture were compared with 43 non-rupture cases of the same period. In difference to the non-rupture cases the average weight of the heart was smaller. Myocardial scars, additional basic diseases and a lung oedema were rarer; an extended region of the infarction and an anamnestically known chronic ischemic heart disease were observed significantly more frequently. In what respect these and other analysed factors are responsible for the rupture mechanism, cannot be clearly estimated. Apart from a continuing hypertension as well as a relatively smaller weight of the heart and the absence of myocardial scars the extension of the area of the infarction as well as the possible effect of granulocytic enzymes in the area of the infarction appear significant for the origin of a heart rupture.