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Biomedical subjects

A Brahme

Publications and source records attributed to A Brahme.

At least 73 records · Page 4Linked to original sources
PubMed1994

Microdosimetric description of beam quality and biological effectiveness in radiation therapy.

Modern radiation therapy includes dosimetric and biological optimization methods aiming to improve the tumour control probability and reduce the unwanted reactions in healthy tissues. From this point of view the quality of the radiation beam is an important parameter that is not generally taken into account in clinical practice. The beam quality depends largely on the macroscopic absorption and scatter of the incident radiation but also on the microscopic fluctuations in the specific energy imparted within the cell nuclei in the patient. The radiation effect depends also on the complexity of the induced damage, the ability of the cells to control cell cycle progress and the efficiency and fidelity of the repair system. Therefore the conventional macrodosimetric quantities have to be complemented with microdosimetric quantities for an accurate description of the quality properties of the radiation beam. It is demonstrated that the DNA damage produced by sub keV electrons and high LET particles has a high probability to be lethal for the cell. These electrons may generate closely spaced double strand breaks or more general 'multiply damaged sites'. Such severely damaged sites may partly be due to the geometrical arrangement of double coiled DNA on the nucleosomes or triple coiled DNA in the cromatin fibre. This kind of damage has a large probability to be misrepaired when the DNA is opened up for repair and may therefore later result in cell death. Furthermore, it is shown that the reduced biological effect at ultra high LETs (> 200 eV/nm) and at ultra short pulses of high dose rate low LET radiation most likely is due to increased radical-radical recombination in the 10 nm-10 ns domain. Based on microdosimetric measurements, significant quality variations in conventional therapeutic beams are detected particularly close to inhomogeneities, in the build-up region or in the presence of high LET contamination. These variations influence the biological effectiveness of the radiation beam and the steepness of the dose-effect relation, thus affecting in some cases the clinical radiotherapeutic outcome. It is shown that such effects may also explain the limited success of most trials with high LET radiations. A serious consideration of beam quality variations in treatment planning algorithms combined with dosimetric and radiobiological optimization of the treatment techniques may increase the probability of tumour control and minimize the unwanted acute and late reactions in healthy normal tissues.

DNA↗
PubMed1993

The clinical value of different treatment objectives and degrees of freedom in radiation therapy optimization.

With inverse radiation therapy planning methods, both biological and physical objective functions can be used to perform the optimization. A biological objective function, namely the probability of achieving tumor control without causing severe complications in normal tissues, P+, has been used to evaluate six different optimization methods. All six methods have been tested on two different clinically relevant treatment geometries. The results show that optimization with a physical objective function which gives the best possible agreement with the desired dose distribution in the least squares sense, may result in severe loss of complication-free tumor control due to insufficient consideration of the organs at risk. It is generally better to use a physical objective function which minimizes the over-dosage when the desired dose distribution can not be exactly reproduced. In all cases the use of physical objective functions results in a lower probability of controlling the tumor without causing severe normal tissue reactions than if the biological objective function, P+, is used. However, the results also show the importance of accurately accounting for beam divergence, dose build-up, beam attenuation, and lateral scatter during the optimization procedure, particularly when the biological objective function is used. The loss in P+ by assuming that all energy deposition kernels are identical and that all the constituent beams have fixed relative weights can be 15% or more. When lateral scatter is not accounted for during the optimization, serious injury to organs at risk may result. This problem is specially severe for organs that are partly or totally encapsulated by the target volume. For superficial target volumes accurate consideration of the dose build-up of the incident pencil beams is fundamental.

Humans↗
PubMed1993

Optimal radiation beam profiles considering uncertainties in beam patient alignment.

The often large uncertainties that exist in beam patient alignment during radiation therapy may require modification of the incident beams to ensure an optimal delivered dose distribution to the target volume. This problem becomes increasingly severe when the required dose distribution of the incident beams becomes more heterogeneous. A simple analytical formula is derived for the case when the fraction number is high, and the desired relative dose variations are small. This formula adjusts the fluence distribution of the incident beam so that the resultant dose distribution will be as close as possible to the desired one considering the uncertainties in beam patient alignment. When sharp dose gradients are important, for instance at the border of the target volume, the problem is much more difficult. It is shown here that, if the tumor is surrounded by organs at risk, it is generally best to open up the field by about one standard deviation of the positional uncertainty--that is sigma/2 on each side of the target volume. In principle it is simultaneously desirable to increase the prescribed dose by a few per cent compared to the case where the positional uncertainty is negligible, in order to compensate for the rounded shoulders of the delivered dose distribution. When the tissues surrounding the tumor no longer are dose limiting even larger increases in field size may be advantageous. For more critical clinical situations the positional uncertainty may even limit the success of radiotherapy. In such cases one generally wants to create a steeper dose distribution than the underlying random Gaussian displacement process allows. The problem is then best handled by quantifying the treatment outcome under the influence of the stochastic process of patient misalignment. Either the coincidence with the desired dose distribution, or the expectation value of the probability of achieving complication-free tumor control is maximized under the influence of this stochastic process. It is shown that the most advantageous treatment is to apply beams that are either considerably widened or slightly widened and over flattened near the field edges for small and large fraction numbers respectively.

Dose-Response Relationship, Radiation↗
PubMed1992

Tumour and normal tissue responses to fractionated non-uniform dose delivery.

The dose-volume response of tumours and normal tissues is discussed in terms of 'parallelity' and 'seriality'. The volume dependence of the radiation response of a tumour depends primarily on the eradication of all its clonogenic cells and the tumour has a parallel organization. The response of heterogeneous tumours is examined, and it is shown that a small resistant clonogen population may cause a low dose-response gradient, gamma. Injury to normal tissue is a much more complex and gradual process. It depends on earlier effects induced long before depletion of stem cells or differentiated cells that in addition may have a complex structural and functional organization. The volume dependence of the dose-response relation of normal tissues is therefore described here by a new parameter, the 'relative seriality', s, of the infrastructure of the organ. The model is compared with clinical and experimental data on normal tissue response, and shows good agreement both with regard to the shape of dose-response relation and the volume dependence of the isoeffect dose. For example, the spinal cord has a high and the lung a low 'relative seriality', which is reasonable with regard to the organization of these tissues. The response of tumours and normal tissues to non-uniform dose delivery is quantified for fractionated therapy using the linear quadratic cell survival parameters alpha and beta. The steepness, gamma, and the 50% response dose, D50, of the dose-response relationship are derived both for a constant dose per fraction and a constant number of dose fractions.

Dose-Response Relationship, Radiation↗
PubMed1992

An algorithm for maximizing the probability of complication-free tumour control in radiation therapy.

New radiobiological models are used to describe tumour and normal tissue reactions and to account for their dependence on the irradiated volume and inhomogeneities of the delivered dose distribution and cell sensitivity. The probability of accomplishing complication-free tumour control is maximized by an iterative algorithm. The algorithm is demonstrated by applying it to a one-dimensional (1D) tumour model but also to a more clinically relevant 2D case. The new algorithm is n-dimensional so it could simultaneously optimize the dose delivery in a 3D volume and in principle also select the ideal beam orientations, beam modalities (photons, electrons, neutrons, etc) and optimal spectral distributions of the corresponding modalities. To make calculation time reasonable, 2D-3D problems are most practical, and suitable beam orientations are preselected by the choice of irradiation kernel. The energy deposition kernel should therefore be selected in order to avoid irradiation through organs at risk. Clinically established dose response parameters for the tissues of interest are used to make the optimization as relevant as possible to the clinical problems at hand. The algorithm can be used even with a poorly selected kernel because it will always, as far as possible, avoid irradiating organs at risk. The generated dose distribution will be optimal with respect to the spatial distribution and assumed radiobiological properties of the tumour and normal tissues at risk for the kernel chosen. More specifically the probability of achieving tumour control without fatal complications in normal tissues is maximized. In the clinical examples a reduced tumour dose is seen at the border to sensitive organs at risk, but instead an increased dose just inside the tumour border is generated. The increased tumour dose has the effect that the dose fall-off is as steep as possible at the border to organs at risk.

Algorithms↗
PubMed1992

Photon field quantities and units for kernel based radiation therapy planning and treatment optimization.

The problem of choosing radiation quantities and units for energy deposition kernels and their associated kernel densities is treated with the aim of making them consistent with related classical radiation quantities and units such as restricted mass stopping powers and mass attenuation coefficients. It is shown that it is very useful to define the kernels h(r), in terms of the quotient of the mean specific energy imparted to the medium by the radiant energy incident on a volume element centred at the origin of the kernel. The basic building block used to generate these kernels is the point energy deposition kernel, h(p), describing the spatial distribution of the energy imparted by a photon interacting at a point in a medium. This will allow the kernels to be regarded as generalizations of the traditional mass stopping and attenuation coefficients, which in detail describe the spatial distribution of the mean energy deposition around an interaction site. As a consequence, the irradiation or kernel density, f(r) should be expressed in terms of the radiant energy incident per unit volume of the medium. It is shown that the kernel density is equal to minus the divergence of the incident unattenuated vectorial energy fluence, and it therefore acts as an irradiation density for the incident vectorial energy fluence. The microscopic kernels or the irradiation density may thus be viewed as a perfect 'sink' distribution to the required incident photon energy fluence which is totally absorbed at f(r), and instead replaced by the kernels which describe the detailed energy deposition in the medium in coordinates centred at the sinks. From these definitions the required incident energy fluence from an external radiation source used for treatment realization can be determined directly by projecting the irradiation density on the relevant positions of the radiation source. This procedure has the valuable property that maximal calculational accuracy is achieved in the tumour because the irradiation density has non-zero values only in the tumour, and the accuracy of the kernel is highest at its origin.

Humans↗
PubMed1991

The narrow proton beam therapy unit at the the Svedberg Laboratory in Uppsala.

The synchrocyclotron at the The Svedberg Laboratory (TSL) in Uppsala is now reconstructed and can presently operate with fixed frequency and proton energies up to 100 MeV. A first treatment room with a narrow proton beam unit for therapy of eye tumours is now in operation. Therapy of eye melanomas started in April, 1989 and during 1989 and 1990, 19 patients were treated with 72 MeV protons. The narrow beam unit provides a fixed horizontal beam and the patient is treated in a seated position. The present paper describes mainly the technical aspects of the unit which so far has been used only for eye melanomas. In the future, modifications of the unit will allow therapy of intracranial targets when higher proton energies are available. In its final form, the proton therapy facility at TSL will harbour a second treatment unit. Here a rotating gantry for 200 MeV protons will provide a broad beam, which will enable treatment of tumours located anywhere in the body.

Eye Neoplasms↗
PubMed1990

Optimization of uncomplicated control for head and neck tumors.

Almost 200 patients have been treated for head and neck tumors at two different dose levels. Based on the clinically observed probabilities for tumor control and fatal normal tissue complications at the two dose levels, the dose giving maximum uncomplicated control has retrospectively been calculated and compared with the clinical data. A Poisson statistical model for control and complications has been used including a correlation parameter, delta, to describe the fraction of patients where control and complications are statistically independent. The clinically observed probability of uncomplicated tumor control, P+, is consistent with only a small fraction of the patients treated being statistically independent (delta = 0.2 or 20%). Customarily, 100% of the patients are assumed to be statistically independent with regard to tumor control and normal tissue complications. More precisely, the clinical data are consistent, with almost 20% of the patients being significantly more sensitive to radiation since they gain local tumor control but simultaneously suffer fatal complications. An even larger fraction of the patients (almost 30%) seemed to be more resistant to radiation, showing neither serious treatment complications nor control of the local tumor growth. It is suggested that if these patient groups could be identified by a predictive assay for the radiation sensitivity of their normal tissues and preferably also for their tumors, the uncomplicated tumor control could be increased by about 20%. This figure is based on the actuarial survival of the patients and has been corrected for the inevitable uncertainty in dose delivery. It is also pointed out that about 20% of the patients can never be saved by a predictive assay because of the considerable statistical variance associated with the Poisson process and the eradication of the last clonogenic tumor cell. Finally, note that the possible existence of radiation sensitive and resistant patient groups is consistent with known genetic deficiencies such as ataxia telangiectasia for the sensitive patients and the existence of repair efficient head and neck tumors that are unusually efficient in repairing double strand breaks. If such sensitive and resistant patient groups do exist, it should be sufficient to perform a predictive assay on normal tissues alone avoiding the often impossible task of sampling the most radiation resistant tumor cell line.

Carcinoma, Squamous Cell↗
PubMed1990

Photon beam energy deposition kernels for inverse radiotherapy planning.

A method for calculating energy deposition kernels for planar convergent isotropic irradiations of a point target has been developed. A geometric overlap algorithm is applied to pencil beam energy deposition kernels calculated by convolution of Monte Carlo generated point spread functions with the energy released by a point monodirectional photon beam. The geometric overlap interpolation technique is energy conservative and hence, for dosimetric purposes, more precise than interpolations based on smoothing techniques. Furthermore, due to the integration processes involved, most of the statistical noise in the original Monte Carlo data is eliminated. The resulting kernels have a precision and noise level corresponding to 10(9) - 10(10) Monte Carlo simulated photons. The kernels are useful for inverse conformation therapy planning, and for dose planning with small target volumes.

Humans↗
PubMed1990

Influence of microdosimetric quantities on observed dose-response relationships in radiation therapy.

The steepness of dose-response curves in radiation therapy depends to a large extent on the statistics of cell killing. This is so if the last few clonogenic tumor cells have to be hit or eradicated by other means to cure the patient. The steepness is dependent on the number of clonogenic cells in the tumor and the possible variation in their sensitivity. However, the uniformity of the dose distribution is also important and a decreased slope may result when the delivery of the dose is nonuniform or statistically uncertain. The variance in the energy imparted at the microdosimetric level to individual cell nuclei constitutes the ultimate limit of the variance in delivered dose at a given mean tumor dose. Considering all dosimetric variances it is shown that for low-LET beams the conventional microdosimetric variance will dominate, while in neutron and high-LET beams in general the microdosimetric variance may contribute significantly to the observed dose-response relationship. As a result the normalized slope of the dose-response curve for tumor control and normal tissue complications with neutrons and other high-LET beams will be reduced compared to that with photons. This conclusion is found to be in quantitative agreement with available data from clinical trials with neutron therapy. Finally, it is pointed out that for beams with a very high RBE and LET it may be favorable to deliver a fraction of the total dose in the form of conventional low-LET radiation. This addition of low-LET radiation may be desirable to ensure a dose to all clonogenic tumor cell nuclei that is sufficiently high and uniform to achieve a high probability of tumor control.

Dose-Response Relationship, Radiation↗
PubMed1988

Optimization of stationary and moving beam radiation therapy techniques.

A new approach is suggested for the optimization of stationary and more general moving beam type of irradiations. The method reverses the order of conventional treatment planning as it derives the optimum incident beam dose distributions from the desired dose distribution in the target volume. It is therefore deterministic and largely avoids the trial and error approach often applied in treatment planning of today. Based on the approximate spatial invariance of the convergent beam point irradiation dose distribution, the desired dose distribution in the target volume is analyzed in terms of the optimum density of such point irradiations. Since each point irradiation distribution is optimal for the irradiation of a given point and due to the linearity of individual energy depositions or absorbed dose contributions, the resultant point irradiation density will also generate the best possible irradiation of an extended target volume when the maximum absorbed dose at a certain distance from the target should be minimized. The optimum shape of the incident beam for each position of the gantry is obtained simply by inverse back projection of the point irradiation density on the position of the radiation source for that orientation of the incident beam.

Humans↗
PubMed1988

Shaping of arbitrary dose distributions by dynamic multileaf collimation.

Traditionally, the shaping of non-uniform dose distributions has been performed by using wedges or compensating filters. The advent of high resolution multileaf collimators may largely eliminate the need for material attenuators for modification of the beam. This is achieved by a new technique for the shaping of arbitrary dose distributions by dynamic motion of the collimator leaves. By employing narrow elementary slit beams that correspond to the smallest possible opening of the multileaf collimator, the optimal density of such slit beams, i.e. opening density, can be determined automatically using a newly developed inversion algorithm. The present method has two major advantages (1) internal structures in the field can be created, controlled solely by steering the collimator leaves, (2) the opening density determined by the algorithm never gives rise to underdosage: this is important from a radiobiological point of view.

Humans↗
PubMed1988

Optimal setting of multileaf collimators in stationary beam radiation therapy.

The new generation of high resolution double focused multileaf collimators is an important step towards true three-dimensional radiation treatment techniques. The principal advantages include increased flexibility in beam shaping and dose delivery using static radiation fields as well as the possibility to do conformation therapy employing dynamic computer controlled patient individual collimation in each CT slice and lateral dose plan. Beside the increased efficiency and flexibility and reduced set-up time, it is shown that multileaf collimation will often reduce the treated volume by as much as 20% or more in single fields and more than 30% when multiple fields are used instead of ordinary rectangular fields. When compared to conventional beam blocks the greater simplicity and flexibility will probably increase the use of individualized blockings by about the same percentages. The optimal rotation and setting of a multileaf collimator for static radiation fields is derived both for convex and for convex concave target volumes. Generally, the smallest cross-section or diameter of the target should be aligned with the direction of motion of the leaves.

Humans↗
PubMed1987

Radiotherapeutic computed tomography with scanned photon beams.

Radiotherapeutic computed tomography is a powerful technique to generate anatomical transversal tomograms of the patient in treatment position by using the therapy beam from the treatment unit. For this purpose the treatment unit has to be equipped with a detector array that can detect the beam transmitted through the patient and a computer that analyzes the data and performs the back projection. When the treatment unit uses scanned elementary photon beams, the only practical technique available for generating high quality high energy photon beams, the operation principle and, to some extent, the image quality is similar to that of a 3rd generation CT-scanner. The optimum choice of detection geometry and type of radiation detectors for radiotherapeutic computed tomography particularly at high photon energies are discussed indicating the merits of BGO (bismuthgermanate) or CWO (cadmiumtungstate) photodiod arrays. The first tomographic images of a thorax phantom at an acceleration potential of 50 MV using such detectors are presented. The image contrast is similar to that for 300 kV X rays mainly because the considerable influence of pair production at 50 MV. Line spread and modulation transfer functions are presented indicating a resolution of the order of two millimeters using a crystal thickness of 5 mm. The advantages with radiotherapeutic computed tomography, beside forming a new general communication channel between different diagnostic techniques, dose planning, and radiation delivery, are the elimination of position errors and the provision of exact attenuation data for dose planning.

Humans↗
PubMed1987

Optimal dose distribution for eradication of heterogeneous tumours.

The traditional single hit multitarget theory has been applied on the probability of eradication of an organ or a tumor and the probability for causing complications in normal tissue. This simple theory predicts a decreasing possibility to achieve uncomplicated tumor control with increasing tumor size and maintained irradiation technique, because the control curve moves to higher doses and the complication curve to lower doses as the tumor size increases. This simple result is shown to be consistent with clinically observed dose response relations for small and large tumors. The optimal dose distribution for eradication of a heterogeneous tumor is derived on the assumption that a uniform minimal recurrence probability is most advantageous for the patient. The optimal dose distribution is proportional to the spatial variation of the local D0 value and the logarithm of the tumor cell density. Various techniques to measure the density of tumor cells and the different possibilities to deliver non-uniform dose distributions to the target volume are also discussed.

Dose-Response Relationship, Radiation↗