Crister Ceberg

Boron Neutron Capture Therapy for Glioblastoma Multiforme: Clinical Studies in Sweden.

A boron neutron capture therapy (BNCT) facility has been constructed at Studsvik, Sweden. It includes two filter/moderator configurations. One of the resulting neutron beams has been optimized for clinical irradiations with a filter/moderator system that allows easy variation of the neutron spectrum from the thermal to the epithermal energy range. The other beam has been designed to produce a large uniform field of thermal neutrons for radiobiological research. Scientific operations of the Studsvik BNCT project are overseen by the Scientific Advisory Board comprised of representatives of major universities in Sweden. Furthermore, special task groups for clinical and preclinical studies have been formed to facilitate collaboration with academia. The clinical Phase II trials for glioblastoma are sponsored by the Swedish National Neuro-Oncology Group and, presently, involve a protocol for BNCT treatment of glioblastoma patients who have not received any therapy other than surgery. In this protocol, p-boronophenylalanine (BPA), administered as a 6-h intravenous infusion, is used as the boron delivery agent. As of January 2002, 17 patients were treated. The 6-h infusion of 900 mg BPA/kg body weight was shown to be safe and resulted in the average blood–boron concentration of 24 μg/g (range: 15–32 μg/g) at the time of irradiation (approximately 2–3 h post-infusion). Peak and average weighted radiation doses to the brain were in the ranges of 8.0–15.5 Gy(W) and 3.3–6.1 Gy(W), respectively. So far, no severe BNCT-related acute toxicities have been observed. Due to the short follow-up time, it is too early to evaluate the efficacy of these studies.

The dosimetric verification of a pencil beam based treatment planning system.

A new three-dimensional treatment planning system (TPS) based on convolution/superposition algorithms (TMS-Radix from HELAX AB, Uppsala, Sweden) was recently installed at the University Hospital in Lund. The purpose of the present study was to design a quality assurance and acceptance testing programme to meet the specific characteristics of this convolution model. The model is based on parametrization of a non-measurable quantity-the polyenergetic pencil beam. However, the verification of the treatment planning model is still dependent on numerous comparisons of measured depth-doses and dose profiles. The test programme was divided in two basic parts: (i) model implementation and beam data consistency and (ii) model performance and limitations in special situations. The first part was scheduled for all photon beam qualities available before they could be used for clinical treatment planning. The second part was performed for selected energies only. The results indicate clearly that the model is well suited for clinical three-dimensional dose planning and that the TPS handles data as expected. For example, calculated depth-doses for open and wedge beams at depths larger than the depth of dose maximum and profiles for open beams shows a very good agreement with measurements. However, depth-dose deviations at shallow depths, especially for high energies, were found. Monitor units calculated by the system were accurate for most fields except for very large fields, where deviations of several per cent were found.

The feasibility of using Pareto fronts for comparison of treatment planning systems and delivery techniques

Pareto optimality is a concept that formalises the trade-off between a given set of mutually contradicting objectives. A solution is said to be Pareto optimal when it is not possible to improve one objective without deteriorating at least one of the other. A set of Pareto optimal solutions constitute the Pareto front. The Pareto concept applies well to the inverse planning process, which involves inherently contradictory objectives, high and uniform target dose on one hand, and sparing of surrounding tissue and nearby organs at risk (OAR) on the other. Due to the specific characteristics of a treatment planning system (TPS), treatment strategy or delivery technique, Pareto fronts for a given case are likely to differ. The aim of this study was to investigate the feasibility of using Pareto fronts as a comparative tool for TPSs, treatment strategies and delivery techniques. In order to sample Pareto fronts, multiple treatment plans with varying target conformity and dose sparing of OAR were created for a number of prostate and head & neck IMRT cases. The DVHs of each plan were evaluated with respect to target coverage and dose to relevant OAR. Pareto fronts were successfully created for all studied cases. The results did indeed follow the definition of the Pareto concept, i.e. dose sparing of the OAR could not be improved without target coverage being impaired or vice versa. Furthermore, various treatment techniques resulted in distinguished and well separated Pareto fronts. Pareto fronts may be used to evaluate a number of parameters within radiotherapy. Examples are TPS optimization algorithms, the variation between accelerators or delivery techniques and the degradation of a plan during the treatment planning process. The issue of designing a model for unbiased comparison of parameters with such large inherent discrepancies, e.g. different TPSs, is problematic and should be carefully considered. fc

A Monte Carlo study of a flattening filter-free linear accelerator verified with measurements

A Monte Carlo model of an Elekta Precise linear accelerator has been built and verified by measured data for a 6 and 10 MV photon beam running with and without a flattening filter in the beam line. In this study the flattening filter was replaced with a 6 mm thick copper plate, provided by the linac vendor, in order to stabilize the beam. Several studies have shown that removal of the filter improves some properties of the photon beam, which could be beneficial for radiotherapy treatments. The investigated characteristics of this new beam included output, spectra, mean energy, half value layer and the origin of scattered photons. The results showed an increased dose output per initial electron at the central axis of 1.76 and 2.66 for the 6 and 10 MV beams, respectively. The number of scattered photons from the accelerator head was reduced by (31.7 ± 0.03)% (1 SD) for the 6 MV beam and (47.6 ± 0.02)% for the 10 MV beam. The photon energy spectrum of the unflattened beam was softer compared to a conventional beam and did not vary significantly with the off-axis distance, even for the largest field size (0-20 cm off-axis).

Pharmacokinetics of Na2B12H11SH (BSH) in patients with malignant brain tumours as prerequisite for a phase I clinical trial of boron neutron capture

SummaryThe disposition of Na2B12H11SH (BSH) in patients with malignant glioma has been investigated, in preparation for a Phase I clinical trial of boron neutron capture therapy. BSH was found to possess a linear disposition over the dosage interval investigated (up to 75 mg/kg). A bi-phasic blood pharmacokinetics was observed. Tumour-to-blood ratios showed variations between patients between 0.08 and 5.1. The data allow the definition of amount of BSH and timing of infusion for a Phase I clinical trial protocol.

Experimental determination of the dose kernel in high-energy x-ray beams.

A semiempirical method to characterize the pencil-beam dose kernel is presented. Results from measurements are described by mathematical models of the applicable physical processes. The measurements were made with 6 and 25 MV x-ray beams from a linear accelerator. Broad-beam notations were used consistently, and the pencil-beam quantities were obtained by differentiation. The results were compared to pencil-beam kernels calculated by Monte Carlo techniques. The analysis of the measured data included a number of approximations. It was assumed that all the constituent pencil beams in the field are parallel, i.e., the divergence is ignored. Furthermore, the lateral variations of the incident photon fluence and the energy spectrum were disregarded. Monte Carlo calculations, on the other hand, are based on an average energy spectrum over the field, and are free from divergence and variations in the incident photon fluence. Measured and Monte Carlo calculated pencil beams nevertheless agreed well, and the approximations mentioned caused at maximum 2.7% discrepancies for the largest field size at 6 MV.

Toward clinical application of prompt gamma spectroscopy for in vivo monitoring of boron uptake in boron neutron capture therapy

In boron neutron capture therapy (BNCT) the absorbed dose to the tumor cells and healthy tissues depends critically on the boron uptake. Pronounced individual variations in the uptake patterns have been observed for two boron compounds currently used in clinical trials. This implies a high uncertainty in the determination of the boron dose component. In the present work a technique known as prompt gamma spectroscopy (PGS) is studied that potentially can be used for in vivo and noninvasive boron concentration determination at the time of the treatment. The technique is based upon measurement of gamma rays promptly emitted in the 10B(n,alpha)7Li and 1H(n,gamma)2D reactions. The aim of this work is to prepare the present setup for clinical application as a monitor of boron uptake in BNCT patients. Therefore, a full calibration and a set of phantom experiments were performed in a clinical setting. Specifically, a nonuniform boron distribution was studied; a skin/ dura, a larger blood vessel, and tumor within a head phantom was simulated. The results show that it is possible to determine a homogeneous boron concentration of 5 microg/g within +/-3% (1 standard deviation). In the nonuniform case, this work shows that the boron concentration can be determined through a multistep measurement procedure, however, with a somewhat higher uncertainty (approximately 10%). The present work forms the basis for a subsequent clinical application of the PGS setup aimed at in vivo monitoring of boron uptake.

Quality control of measured x-ray beam data.

The purpose of this study was to examine whether the quality of measured x-ray beam data can be judged from how well the data agree with a semiempirical formula. Tissue-phantom ratios (TPR) and output factors for several accelerators in the energy range 4-25 MV were fitted to the formula, separating the dose contributions from primary and phantom-scattered photons. The former was described by exponential attenuation in water, with beam hardening, and the latter by the scatter-to-primary dose ratio using two parameters related to the probability and the directional distribution of the scattered photons. Electron disequilibrium was not considered. Two approaches were evaluated. In one, the attenuation and hardening coefficients were determined from measurements in a narrow-beam geometry; in the other, they were extracted by the fitting procedure. Measured and fitted data agreed within +/- 2% in both cases. The differences were randomly distributed and had a standard deviation of typically 0.7%. Singular points with errors were easily identified. Systematic errors were revealed by increased standard deviation. However, when the attenuation was derived by the fitting algorithm, the attenuation coefficient deviated significantly from the experimental value. It is concluded that the semiempirical formula can serve to evaluate and verify beam data measured in water and that the physically most accurate description requires that the attenuation and hardening coefficients be determined in a narrow-beam geometry. The attenuation coefficient is an excellent measure of both the primary and the scatter dose component, i.e., of beam quality.

Conversion of greyscale intensity values from CBCT images acquired on Elekta XVI to HU for treatment planning dose calculations

Purpose: To develop and evaluate a method to convert the greyscale intensity values from CBCT images acquired on an Elekta XVI into HU for treatment planning dose calculations.

Tissue-phantom ratios from percentage depth doses

When converting fractional (percentage) depth doses to tissue-phantom ratios, one must use a factor that accounts for the different source-to-point distances. Two minor correction factors are also involved. One is the ratio of total to primary dose at the two different distances from the source, for the same depth and field size. This factor is usually ignored. It was determined experimentally that this can introduce up to 1.5% error at 6 MV. The second correction factor reflects differences related to scattered photons and electrons at the depth of normalization in the two geometries. This correction is accounted for in published conversion procedures. It was found to be less than 1% provided the normalization depth is sufficient for electron equilibrium, which occurs first well beyond the depth of maximum dose. One may avoid electron-equilibrium problems by using an interim normalization depth that provides electron equilibrium with some margin, renormalizing to a shallower depth if desired. With this precaution, the accuracy when measured fractional depth doses were converted to tissue-phantom ratios was comparable to that of directly measured tissue-phantom ratios even when the correction factors were ignored.