Phase I/II study of iodine 131 metaiodobenzylguanidine in chemoresistant neuroblastoma: a United Kingdom Children's Cancer Study Group investigation.

PURPOSE: The goal of this study was to evaluate the toxicity of iodine 131 metaiodobenzylguanidine (mIBG) in metastatic neuroblastoma. PATIENTS AND METHODS: A multicenter phase I study of 131I mIBG has been undertaken by the United Kingdom Children's Cancer Study Group (UKCCSG) in children with advanced chemoresistant neuroblastoma. Activity prescription was based on a prescribed whole-body radiation dose, which was established for individual patients by performing an initial tracer investigation with 75 MBq of 131I mIBG. An activity was derived from this pharmacokinetic study that would deliver an initial whole-body-absorbed radiation dose of 1 Gy. Subsequent dose escalations were based on observed toxicity. RESULTS: Twenty-five patients, aged 1 to 10 years, were treated with prescribed whole-body dose levels of 1.0 Gy (n = 2), 2.0 Gy (n = 13), and 2.5 Gy (n = 10). This necessitated administration of 2.4 to 12.1 GBq of activity. Hematologic, hepatic, kidney, and adrenal toxicity were observed, with bone marrow suppression being the principal dose-limiting toxicity. Bone marrow toxicity increased with prescribed whole-body-absorbed radiation dose, with 80% of patients developing grade 3 or 4 thrombocytopenia at a prescribed whole-body radiation dose of 2.5 Gy. Objective evidence of tumor response was seen in soft tissue (primary or nodal disease), bone, and bone marrow, with an overall response rate of 33% (partial response, n = 8; static disease, n = 9; progressive disease, n = 7). CONCLUSIONS: This study has established an effective method of activity prescription that predicts subsequent toxicity, with the maximally tolerated dose being sufficient activity to deliver a whole-body-absorbed radiation dose of 2.5 Gy. The objective response rate is comparable to other single agents in chemoresistant neuroblastoma and suggests that 131I mIBG may be a useful method for targeting radiotherapy in metastatic neuroblastoma.

The PETRRA positron camera: design, characterization and results of a physical evaluation.

The PETRRA positron camera is a large-area (600 mm x 400 mm sensitive area) prototype system that has been developed through a collaboration between the Rutherford Appleton Laboratory and the Institute of Cancer Research/Royal Marsden Hospital. The camera uses novel technology involving the coupling of 10 mm thick barium fluoride scintillating crystals to multi-wire proportional chambers filled with a photosensitive gas. The performance of the camera is reported here and shows that the present system has a 3D spatial resolution of approximately 7.5 mm full-width-half-maximum (FWHM), a timing resolution of approximately 3.5 ns (FWHM), a total coincidence count-rate performance of at least 80-90 kcps and a randoms-corrected sensitivity of approximately 8-10 kcps kBq(-1) ml. For an average concentration of 3 kBq ml(-1) as expected in a patient it is shown that, for the present prototype, approximately 20% of the data would be true events. The count-rate performance is presently limited by the obsolete off-camera read-out electronics and computer system and the sensitivity by the use of thin (10 mm thick) crystals. The prototype camera has limited scatter rejection and no intrinsic shielding and is, therefore, susceptible to high levels of scatter and out-of-field activity when imaging patients. All these factors are being addressed to improve the performance of the camera. The large axial field-of-view of 400 mm makes the camera ideally suited to whole-body PET imaging. We present examples of preliminary clinical images taken with the prototype camera. Overall, the results show the potential for this alternative technology justifying further development.

Measurements of blood-brain barrier permeability in patients undergoing radiotherapy and chemotherapy for primary cerebral lymphoma.

Positron emission tomography (PET) has been used to measure changes in regional blood-brain barrier (BBB) permeability in patients with primary cerebral lymphoma undergoing radiotherapy and chemotherapy. The method employed is to measure the rate of wash-out of a radioactive tracer (68Ga-EDTA) from blood into brain tissue using time-sequence PET imaging. Preliminary studies carried out on patients with more common primary cerebral tumours show that time-activity data are reproducible to approximately 10%. Measurements made in 2 patients with primary cerebral lymphoma treated with initial chemotherapy showed significant changes in permeability in the region of the tumour. Within 5 weeks of the start of treatment, permeability values reached the levels of normal brain. No changes in BBB permeability in normal brain were seen immediately after radiotherapy.

Radiation dose assessments in radioiodine (131I) therapy. 1. The necessity for in vivo quantitation and dosimetry in the treatment of carcinoma of the thyroid.

In order to destroy thyroid cancer metastases by radioiodine an average tissue dose of 80-300 Gy is needed. Such high doses can be expected, following the administration of the conventional 5.5 GBq of 131I, only if both the percentage uptake per gram in the target tissue and the effective half life of the radioiodine in it are higher than well-defined threshold values, and if every dimension of the tissue exceeds several millimeters. The fulfillment of such favourable conditions in actual clinical cases can only be confirmed by in vivo quantitation of the absorbed dose achieved as a result of the administration of radioiodine.

Radiation dose assessment in radioiodine therapy. Dose-response relationships in differentiated thyroid carcinoma using quantitative scanning and PET.

Dose-response charts have been constructed to determine the tumouricidal dose for differentiated thyroid carcinoma metastases and thus enable precise activities of radioiodine to be prescribed in order to maximise tumour kill and minimise morbidity. Tumour and normal residual thyroid absorbed doses from radioiodine-131 have been determined with increased precision using a dual-headed whole-body rectilinear scanner with special high-resolution low-sensitivity collimators. Improved accuracy in the estimation of functioning tumour mass has been achieved using positron emission tomography (PET) with a low-cost large area PET camera. Dose-response data have been obtained for 33 patients. Following near-total thyroidectomy and 3.0 GBq 131I, a mean absorbed dose of 410 Gy achieved complete ablation of thyroid remnants in 75% of patients. Patients who had persistent uptake in the thyroid region on subsequent radioiodine scanning had received a mean dose of only 83 Gy. Cumulative absorbed doses in excess of 100 Gy were found to eradicate cervical node metastases. Patients with bone metastases, who generally have a poor prognosis, were found to have received doses of the order of only 20 Gy to the tumour deposits. The dose-response data explain the spectrum of clinical responses to fixed activities of radioiodine. In future, they will enable precise prescription of radioiodine to achieve tumouricidal doses whilst avoiding the morbidity and expense of ineffective therapy.

The effects of single dose oral hydralazine on blood flow through human lung tumours.

Hydralazine has been shown to reduce tumour blood flow and to potentiate the cytotoxicity of melphalan and bioreductive agents in mice. In order to determine whether such a strategy might have clinical potential, a study was undertaken to investigate the effects of hydralazine on blood flow through human tumours. Twenty-two patients with carcinoma of the bronchus received a single oral dose of hydralazine in the range 25 to 150 mg (0.37-2.86 mg/kg) according to age and acetylator status. Tumour blood flow was assessed by single photon emission computed tomography (SPECT) performed 10 min following intravenous 99Tcm-HMPAO on two occasions 2-8 days apart, the second being performed 60 min after hydralazine administration. In 20 evaluable patients, hydralazine caused a 38% increase in blood flow through the whole tumour (p = 0.007) and a 28% increase in flow through the tumour centre (p = 0.03) with greater increases occurring in patients sustaining greater falls in peripheral resistance. Tumour vascular resistance fell indicating active vasodilation in arterioles supplying tumours. Side-effects due to hydralazine were reported by eight patients.

Radiation dose assessment in radioiodine therapy. 2. Practical implementation using quantitative scanning and PET, with initial results on thyroid carcinoma.

We have designed special high-resolution, low-sensitivity collimators for a dual-headed whole-body scanner for imaging and quantifying therapy levels of iodine-131. In addition, we have used positron emission tomography (PET) with a low-cost large-area PET camera to achieve improved accuracy in the estimate to tumor mass. The physical performance of these two imaging systems is described. In order to illustrate the practical implementation of these systems for the assessment of radiation dose to normal and tumour tissue during radioiodine therapy, three clinical examples are reported, and a summary of the initial clinical results obtained from 16 patients with carcinoma of the thyroid is presented. The dose to normal thyroid remnants for patients undergoing ablation ranged from 16 to 400 Gy, while the dose to involved neck nodes ranged from 2.5 to 33 Gy for patients undergoing post-ablation radioiodine therapy. In one patient with distant metastasis in the spine, a dose of 100 Gy was achieved. The techniques described in this paper can be used to determine if sufficient activity can be accumulated in tumours to provide a therapeutic effect while minimising irradiation of normal tissues by avoiding administrations which do not provide tumouricidal radiation doses.

The treatment of resistant neuroblastoma with 131I-mIBG: alternative methods of dose prescription.

A UK multi-centre study has been carried out to collect medical and dosimetry data from treatments with 131I-metaiodobenzylguanidine (mIBG) for patients suffering from resistant neuroblastoma. All data have been acquired in a standardised way, following strict physics and clinical protocols. The accuracy of three different methods of dose prescription was studied. The results show that the most accurate method involved the use of an initial tracer study to determine the therapeutic activity required to deliver a predetermined absorbed whole-body (WB) dose.

Improved quantification of radionuclide uptake using deconvolution and windowed subtraction techniques for scatter compensation in single photon emission computed tomography.

A comparison of two methods of scatter compensation in single photon emission computed tomography (SPECT) imaging is made on the basis of improvements in quantification. The methods, scatter-window subtraction and constrained deconvolution of an average point source response function (PSRF), are described; the theoretical basis of each method is also briefly assessed. Improvements in relative quantification offered by each method are measured by examining ratios of counts in hot cylinders to counts in a slightly radioactive background. The cylinder/background concentration ratio was varied by a factor of five; the sizes of the cylinders remained constant. Keeping the diameter of the cylinders constant allowed for an assessment of the effect of concentration differences, without the conflicting effect of variation in the size of the hot source. Results showed that while both scatter-window subtraction and constrained deconvolution offer quantification improvements in the final image, the method of prereconstruction deconvolution of a planar PSRF from each planar projection is substantially more successful than either scatter-window subtraction or other methods of implementing the deconvolution procedure.

Constrained deconvolution of SPECT liver tomograms by direct digital image restoration.

Several techniques for performing digital image restoration are reviewed and the problems associated with evaluating image processing are discussed. An application of constrained deconvulution to images of the liver produced by single-photon emission computed tomography is presented. Specific evaluation criteria are suggested and based on these, the choice of conditions best suited for processing liver images is proposed. Typically cold tumor contrast can be improved by a factor of greater than 2 whilst image mottle increases negligibly.

A comparison of deconvolution and windowed subtraction techniques for scatter compensation in SPECT.

Three procedures for the removal of Compton-scattered data in SPECT by constrained deconvolution are presented. The first is a deconvolution of a 2-D measured PSRF containing scatter from a single reconstructed transaxial image; the second is a deconvolution of a 2-D measured point-source response function (PSRF) from each frame of projection data prior to reconstruction; the third involves deconvolution of a 3-D measured PSRF from a stack of reconstructed slices. Results of applying these procedures to data obtained from a phantom containing cold cylinders and to data from a cold spot-resolution phantom are presented and are shown to be superior to the results of correcting for scatter by scatter-window substraction. Both 3-D deconvolution from reconstructed images and 2-D deconvolution from projection data show major improvements in image contrast, resolution, and quantitation. Improvements are especially marked for small (1.0-3.0 cm) cold sources.

A prototype rotating slat collimator for single photon emission computed tomography.

A collimator consisting of a series of highly attenuating parallel slats has been constructed and used in conjunction with a gamma-camera to approximately measure planar projections of a given radionuclide distribution. The enlarged solid angle of acceptance afforded by the slat collimator gave rise to an increased geometric efficiency of between 12 and 28 times that observed with a low-energy high-resolution (LEHR) parallel-hole collimator. When the slats rotated over the face of the detector and the camera gantry turned about the object, sufficient projections were acquired to reconstruct a three-dimensional (3-D) image using the inversion of the 3-D radon transform. The noise behavior of an algorithm for implementing this inversion was studied analytically and the resulting relationship has been verified by computer simulation. The substantially improved geometric efficiency of the slat collimator translated to improvements in reconstructed signal-to-noise ratio (SNR) by, at best, up to a factor of 2.0 with respect to standard parallel-hole collimation. The spatial resolution achieved with the slat collimator was comparable to that obtained with a LEHR collimator and no significant differences were observed in terms of scatter response. Accurate image quantification was hindered by the spatially variant response of the slat collimator.

Radiation dosimetry for 131I-mIBG therapy of neuroblastoma.

This paper describes the methodology which can be used to determine whole-body, red marrow, blood, bladder, liver, and tumour doses delivered during 131I-mIBG therapy of neuroblastoma. The methodology is based on the Physics Protocol used in a multi-centre study undertaken by the United Kingdom Children's Cancer Study Group (UKCCSG). In this study, the estimates of the doses delivered, using 2.4-12.1 GBq 131I-mIBG, were in the following ranges: whole body, 0.14-0.65 mGy MBq-1; red marrow, 0.17-0.63 mGy MBq-1; blood, 0.04-0.17 mGy MBq-1; bladder, 2.2-5.3 mGy MBq-1; liver, 0.3-1.9 mGy MBq-1; and tumour, 0.2-16.6 mGy MBq-1.

The experimental evaluation of a prototype rotating slat collimator for planar gamma camera imaging.

A collimator consisting of a series of parallel slats has been constructed and used in conjunction with a conventional gamma camera to collect one-dimensional projections of the radioisotope distribution being imaged. With the camera remaining stationary, the collimator was made to rotate continuously over the face of the detector and the projections acquired were used to reconstruct a planar image by the theory of computed tomography. The propagation of noise on image reconstruction was largely offset by the increased geometric efficiency that resulted from the enlarged solid angle of acceptance afforded by the slat collimator. For a uniform disc of activity the signal to noise ratio (SNR) at a point in an image reconstructed by convolution and backprojection is shown to be given by [formula:see text] and Q1(xi) is the one-dimensional filter function in Fourier space. Improved noise behaviour was observed for images acquired with the slat collimator compared to those acquired with a low-energy high-resolution (LEHR) collimator for small distributions of activity. Spatial resolution with the slat collimator was approximately equal to that obtained with an LEHR collimator and improved contrast was observed in images of small hot regions.

Monte Carlo modelling of the performance of a rotating slit-collimator for improved planar gamma-camera imaging.

Planar imaging with a gamma camera is currently limited by the performance of the collimator. Spatial resolution and sensitivity trade off against each other; it is not possible with conventional parallel-hole collimation to have high geometric sensitivity and at the same time excellent spatial resolution unless field-of-view is sacrificed by using fan- or cone-beam collimators. We propose a rotating slit-collimator which collects one-dimensional projections from which the planar image may be reconstructed by the theory of computed tomography. The performance of such a collimator is modelled by Monte Carlo methods and images are reconstructed by a convolution and backprojection technique. The performance is compared with that of a conventional parallel-hole collimator and it is shown that higher spatial resolution with increased sensitivity is possible with the slit-collimator. For a point source a spatial resolution of some 6 mm at a distance of 100 mm from the collimator with a x7 sensitivity compared with a parallel-hole collimator was achieved. Applications to bone scintigraphy are modelled and an improved performance in hot-spot imaging is demonstrated. The expected performance in cold-spot imaging is analytically investigated. The slit-collimator is not expected to improve cold-spot imaging. Practical design considerations are discussed.

A comparison of attenuation correction methods for quantitative single photon emission computed tomography.

Transverse section tomograms of experimental phantoms and patients have been obtained using a GE 400T camera and a filtered back-projection reconstruction technique. These tomograms have been compared with the corresponding sections reconstructed from the same tomographic projection data, but using iterative algorithms with correction for photon attenuation. The comparison assesses the importance of including a correction for attenuation as well as demonstrating how closely a simple geometric attenuation correction, applied to the filtered back-projection reconstruction method, approximates to a more accurate correction incorporated in the computation of line integrals during iterative reconstruction. A comparison is also made between the behaviour of reconstruction algorithms with simulated projection data and real data in terms of convergence properties, and some shortcomings arising from simulation are noted.

A comparison of three systems for performing single-photon emission tomography.

A comparison is made between the performance of three transverse axial single-photon emission tomographic machines, namely a rotating gamma-camera and two different scanning systems. Each system has been evaluation in terms of the spatial resolution, sensitivity and efficiency. The functional dependence of the volume sensitivity on the size of the emitting object has been derived using a theoretical model of the photon emission, attenuation and detection. The model is shown to predict this size dependence well and is consistent with the experimental observations.

Effects of cellular repair and proliferation on targeted radionuclide therapy: a modelling study.

A previous targeted radionuclide therapy modelling study has been extended to include the radiobiological effects of cellular repair and proliferation. Dose distributions have been converted into biologically effective dose (BED) distributions using a previously published formulation. With suitable estimated parameters, corrected tumour control probability (TCP) values were derived. The dependence of BED on the physical half-life of the radionuclide was also modelled. Results indicate that the TCP is greater when a shorter physical half-life is employed.

Fast accurate iterative reconstruction for low-statistics positron volume imaging.

A fast accurate iterative reconstruction (FAIR) method suitable for low-statistics positron volume imaging has been developed. The method, based on the expectation maximization-maximum likelihood (EM-ML) technique, operates on list-mode data rather than histogrammed projection data and can, in just one pass through the data, generate images with the same characteristics as several ML iterations. Use of list-mode data preserves maximum sampling accuracy and implicitly ignores lines of response (LORs) in which no counts were recorded. The method is particularly suited to systems where sampling accuracy can be lost by histogramming events into coarse LOR bins, and also to sparse data situations such as fast whole-body and dynamic imaging where sampling accuracy may be compromised by storage requirements and where reconstruction time can be wasted by including LORs with no counts. The technique can be accelerated by operating on subsets of list-mode data which also allows scope for simultaneous data acquisition and iterative reconstruction. The method is compared with a standard implementation of the EM-ML technique and is shown to offer improved resolution, contrast and noise properties as a direct result of using improved spatial sampling, limited only by hardware specifications.

An automated technique for SPECT marker-based image registration in radionuclide therapy.

An automated technique for marker-based image registration in radionuclide therapy is described. This technique is based on localization of the centroids of external markers and on establishing correspondence between the individual markers of the two studies to be registered. Localization of the centroids of markers relies on segmenting the markers using iterative thresholding. Thresholding is locally adaptive in order to account for study-dependent conditions (e.g. crossover between adjacent markers and markers with varying radioactive concentrations). Following marker segmentation, the centroids of the markers are computed based on an intensity-weighted method. Finally, prior to the least-squares fit registration, the markers of the two sets are matched to achieve one-to-one correspondence. The technique was applied to both simulated and patient studies resulting in mean residual three-dimensional registration errors (+/- 1SD) of 1.7 +/- 0.1 mm and 3.5 +/- 0.3 mm respectively. The technique was compared with a semi-automated approach and no significant difference was found between the mean residual three-dimensional registration errors (t = 0.281. p = 0.8). This automated marker-based image registration technique provides robust and accurate registration. Although it was developed as part of a programme to generate three-dimensional dose distributions for radionuclide therapy, it could be useful for other clinical applications.