Recommendations for Multicentre Clinical Trials Involving Dosimetry for Molecular Radiotherapy.

Multicentre clinical trials involving a dosimetry component are becoming more prevalent in molecular radiotherapy and are essential to generate the evidence to support individualised approaches to treatment planning and to ensure that sufficient patients are recruited to achieve the statistical significance required. Quality assurance programmes should be considered to support the standardisation required to achieve meaningful results. Trials should be designed to ensure that dosimetry results from image acquisition systems across centres are comparable by incorporating steps to standardise the methodologies used for the quantification of images and dosimetry. Furthermore, it is essential to assess the expertise and resources available at each participating site prior to trial commencement. A quality assurance plan should be drawn up and training provided if necessary. Standardisation of quantification and dosimetry methodologies used in a trial are essential to ensure that results from different centres may be collated. In addition, appropriate uncertainty analysis should be carried out to correct for differences in methodologies between centres. Recommendations are provided to support dosimetry studies based on the experience of several previous and ongoing multicentre trials.

Development of patient-specific molecular imaging phantoms using a 3D printer.

PURPOSE: The aim of the study was to investigate rapid prototyping technology for the production of patient-specific, cost-effective liquid fillable phantoms directly from patient CT data. METHODS: Liver, spleen, and kidney volumes were segmented from patient CT data. Each organ was converted to a shell and filling holes and leg supports were added using computer aided design software and prepared for printing. Additional fixtures were added to the liver to allow lesion inserts to be fixed within the structure. Phantoms were printed from an ultraviolet curable photopolymer using polyjet technology on an Objet EDEN 500V 3D printer. RESULTS: The final print material is a clear solid acrylic plastic which is watertight, rigid, and sufficiently durable to withstand multiple assembly and scanning protocols. Initial scans of the phantoms have been performed with Tc-99m SPECT and F-18 PET/CT. CONCLUSIONS: The organ geometry showed good correspondence with anatomical references. The methodology developed can be generally applied to other anatomical or geometrical phantoms for molecular imaging.

Dosimetry in 131I-mIBG therapy: moving toward personalized medicine.

Internal dosimetry was developed as a basis for 131I-mIBG treatment at an early stage and has continued to develop for over the last 20 years. Whole-body dosimetry was introduced to prevent hematological toxicity. It will be the basis for a forthcoming European multicentre trial, in which the activity of a second administration is determined according to the results calculated from the first. Lesion dosimetry has also been performed in a small number of centres. The major goal of dosimetry now is to establish dose-effect correlation studies, which will be the basis for individualized treatment planning. The aim of this paper is to analyse previously published studies and to consider the potential for improvement in order to obtain a stronger predictive power of dosimetry. The intrinsic radiobiological limits of dosimetry are also illustrated. Due to the development and dissemination of methods of internal dosimetry and radiobiology over the last two decades, and to the increasing availability of quantitative 124I PET imaging, dosimetry could provide in the near future a more systematic basis for standardization and individualization of mIBG therapy. This will however require a number of multicentre trials which are performed under good instrumental and scientific methodology.

Monte Carlo verification of polymer gel dosimetry applied to radionuclide therapy: a phantom study.

This study evaluates the dosimetric performance of the polymer gel dosimeter 'Methacrylic and Ascorbic acid in Gelatin, initiated by Copper' and its suitability for quality assurance and analysis of I-131-targeted radionuclide therapy dosimetry. Four batches of gel were manufactured in-house and sets of calibration vials and phantoms were created containing different concentrations of I-131-doped gel. Multiple dose measurements were made up to 700 h post preparation and compared to equivalent Monte Carlo simulations. In addition to uniformly filled phantoms the cross-dose distribution from a hot insert to a surrounding phantom was measured. In this example comparisons were made with both Monte Carlo and a clinical scintigraphic dosimetry method. Dose-response curves generated from the calibration data followed a sigmoid function. The gels appeared to be stable over many weeks of internal irradiation with a delay in gel response observed at 29 h post preparation. This was attributed to chemical inhibitors and slow reaction rates of long-chain radical species. For this reason, phantom measurements were only made after 190 h of irradiation. For uniformly filled phantoms of I-131 the accuracy of dose measurements agreed to within 10% when compared to Monte Carlo simulations. A radial cross-dose distribution measured using the gel dosimeter compared well to that calculated with Monte Carlo. Small inhomogeneities were observed in the dosimeter attributed to non-uniform mixing of monomer during preparation. However, they were not detrimental to this study where the quantitative accuracy and spatial resolution of polymer gel dosimetry were far superior to that calculated using scintigraphy. The difference between Monte Carlo and gel measurements was of the order of a few cGy, whilst with the scintigraphic method differences of up to 8 Gy were observed. A manipulation technique is also presented which allows 3D scintigraphic dosimetry measurements to be compared to polymer gel dosimetry measurements without generating misleading errors due to the limited spatial resolution.

Clinical applications of dosimetry for mIBG therapy.

Metaiodobenzylguanidine (mIBG), developed 30 years ago, is taken up by tumours expressing the noradrenaline transporter. Radiolabelled with I-123 or I-131, mIBG has become a gold standard for diagnostic imaging of pediatric and adult neuroendocrine cancer. Within a few years of its clinical introduction, I-131 mIBG was found to be an effective palliative treatment with minimal toxicity that in some cases could produce a complete response. The importance of internal dosimetry for I-131 mIBG therapy has been demonstrated by a number of studies showing that absorbed doses delivered to tumours and organs-at-risk from standard and weight-based activities can vary by an order of magnitude. However, significant correlations between the whole-body absorbed dose and myelotoxicity have been demonstrated and studies based on this relationship have enabled treatments to be tailored to the individual. Ongoing developments include patient-specific treatment planning based on tumour dosimetry and cocktails of radionuclides and radiosensitisers.

Clinical dosimetry in the treatment of bone tumors: old and new agents.

Treatment of multisite, sclerotic bone metastases is successfully performed by radionuclide therapy. Pain palliation is the most common aim for the treatment. Two radiopharmaceuticals are currently approved by the European Medicines Agency ((153)Sm-EDTMP and (89)Sr-Cl2) whilst other radiopharmaceuticals are at different stages of development, or are approved in some European countries ((186)Re-HEDP, (117)Snm-DTPA and (223)Ra-Cl2). The tissues at risk for the treatment are bone marrow and normal bone. A review of the methods applied for dosimetry for these tissues and for tumours is performed, including the calculation of S values (the absorbed dose per decay) and optimal procedures on how to obtain biodistribution data for each radiopharmaceutical. The dosimetry data can be used to individualise and further improve the treatment for each patient. Dosimetry for radionuclide therapy of bone metastases is feasible and can be performed in a routine clinical practice.

The application of polymer gel dosimeters to dosimetry for targeted radionuclide therapy.

There is a lack of standardized methodology to perform dose calculations for targeted radionuclide therapy and at present no method exists to objectively evaluate the various approaches employed. The aim of the work described here was to investigate the practicality and accuracy of calibrating polymer gel dosimeters such that dose measurements resulting from complex activity distributions can be verified. Twelve vials of the polymer gel dosimeter, 'MAGIC', were uniformly mixed with varying concentrations of P-32 such that absorbed doses ranged from 0 to 30 Gy after a period of 360 h before being imaged on a magnetic resonance scanner. In addition, nine vials were prepared and irradiated using an external 6 MV x-ray beam. Magnetic resonance transverse relaxation time, T2, maps were obtained using a multi-echo spin echo sequence and converted to R2 maps (where T2 = 1/R2). Absorbed doses for P-32 irradiated gel were calculated according to the medical internal radiation dose schema using EGSnrc Monte Carlo simulations. Here the energy deposited in cylinders representing the irradiated vials was scored. A relationship between dose and R(2) was determined. Effects from oxygen contamination were present in the internally irradiated vials. An increase in O2 sensitivity over those gels irradiated externally was thought to be a result of the longer irradiation period. However, below the region of contamination dose response appeared homogenous. Due do a drop-off of dose at the periphery of the internally irradiated vials, magnetic resonance ringing artefacts were observed. The ringing did not greatly affect the accuracy of calibration, which was comparable for both methods. The largest errors in calculated dose originated from the initial activity measurements, and were approximately 10%. Measured R2 values ranged from 5-35 s(-1) with an average standard deviation of 1%. A clear relationship between R2 and dose was observed, with up to 40% increased sensitivity for internally irradiated gels. Curve fits to the calibration data followed a single exponential function. The correlation coefficients for internally and externally irradiated gels were 0.991 and 0.985, respectively. With the ability to accurately calibrate internally dosed polymer gels, this technology shows promise as a means to evaluate dosimetry methods, particularly in cases of non-uniform uptake of a radionuclide.

Multicellular dosimetry in voxel geometry for targeted radionuclide therapy.

A software package to investigate absorbed doses and dose-rates at the cellular and multicellular scale has been developed that considers two- and three-dimensional activity distributions and makes use of analytical representations of the point-dose kernels for (131)I, (32)P, and (90)Y. This software allows cell assemblies to be simulated by definition of the number, size, and geometry of cells and their nuclei, and radionuclide uptake can be specified to occur within the nucleus, the cytoplasm, at the membrane, or within the extracellular space. The software has been validated at a cellular scale by comparison with results obtained using spherical geometry, as found in the literature. At a multicellular scale, comparisons were made with a Monte Carlo simulation in voxel geometry. The software has been designed to work within a user-defined voxel geometry. This geometry is useful not only to simulate complex cell assemblies and realistic heterogeneous radionuclide distributions, but will also allow the use of histological and autoradiographic data. Absorbed dose distributions for a single cell calculated using this code varied significantly with activity localization within the cell, and to a lesser extent, with the cellular geometry. At a multicellular level, a two-dimensional heterogeneous activity distribution inferred from a two-dimensional image of a slice throughout a spheroid was used to calculate a dose-rate distribution. This resulted in a heterogeneous dose-rate delivery even for longer-range radionuclides such as (90)Y and (32)P.

Combining dosimetry for targeted radionuclide and external beam therapies using the biologically effective dose.

It is not uncommon for a patient to receive both external beam and targeted radionuclide therapy during the course of a cancer treatment. The total dose received by the tumor and by normal tissues will therefore be subject to the contributions of both treatment modalities. However, the two treatments are generally applied independently of one another, with little attention paid to the combined effect. With the availability of patient-specific three-dimensional dosimetry for radionuclide therapies, it is pertinent now to consider the combined effect of the two treatments, and to investigate how dosimetry for this situation may be carried out. Methodology has been developed to allow a combination of dose information from the two types of therapy. The biologically effective dose (BED) has been employed to address the issue of inequivalence of biological effect of the two therapies. Dose distributions have been represented as distributions of BED, and the net effect resulting from the combination of these two therapies demonstrated through a combination of BED maps. Examples are presented of cases in which this analysis of a combined therapy provides a more favorable treatment than either therapy alone. For one patient the ratio of the mean spinal cord dose to the mean CTV dose was calculated for both an external beam therapy alone and for a combined therapy and was found to be 0.40 and 0.16, respectively.

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.

Value of protein-bound radioactive iodine measurements in the management of differentiated thyroid cancer treated with (131)I.

Measurement of the protein-bound radioactive iodine level (PBI(131)) in the plasma of patients following (131)I-iodide administration for thyroid cancer has been re-examined in a retrospective study of 171 patient episodes. It is shown that whereas the previously used threshold value for the measurement at 6 days does not correlate well with the 3-day whole body scan, there is good agreement between the scan and the temporal changes in PBI(131) from 1-6 days: an increasing PBI(131) correlates with a positive scan, and a decreasing PBI(131) with a negative scan. The area under the curve (AUC) for the PBI(131)-time curve is related to the absorbed dose for the tumour. For a small group of 11 patients, dosimetry estimates were made from serial scans, quantified with phantoms; these absorbed doses correlated with the AUC and the 6-day PBI(131). Therefore, it is suggested that these parameters may be useful in predicting absorbed radiation dose in these patients.

Automated CT marker segmentation for image registration in radionuclide therapy.

In this paper a novel, automated CT marker segmentation technique for image registration is described. The technique, which is based on analysing each CT slice contour individually, treats the cross sections of the external markers as protrusions of the slice contour. Knowledge-based criteria, using the shape and dimensions of the markers, are defined to enable marker identification and segmentation. Following segmentation, the three-dimensional (3D) markers' centroids are localized using an intensity-weighted algorithm. Finally, image registration is performed using a least-squares fit algorithm. The technique was applied to both simulated and patient studies. The patients were undergoing 131I-mIBG radionuclide therapy with each study comprising several 99mTc single photon emission computed tomography (SPECT) scans and one CT marker scan. The mean residual 3D registration errors (+/- 1 SD) computed for the simulated and patient studies were 1.8 +/- 0.3 mm and 4.3 +/- 0.5 mm respectively.

FDG-PET in the prediction of survival of patients with cancer of the pancreas: a pilot study.

Carcinoma of the pancreas is an aggressive tumour with an extremely poor prognosis. Recent studies have shown that chemotherapy can improve survival as well as quality of life. Since the prognosis is generally poor, the identification of early responders to chemotherapy is important to avoid unnecessary toxicity in patients who are not responding. Response assessment by conventional radiographic methods is problematical because treatment induces fibrosis and makes tumour measurements difficult. The aim of this pilot study was to assess 18-fluoro-deoxy-glucose positron emission tomography (FDG-PET) as an early marker of the benefit of chemotherapy. Eleven patients with histologically proven adenocarcinoma of the pancreas were treated with protracted venous infusional 5-fluorouracil (PVI 5-FU) alone or PVI 5-FU and mitomycin C (MMC). FDG-PET scans were performed prior to and at 1 month following the commencement of chemotherapy. FDG uptake was compared with the tumour dimensions measured on a computer tomographic (CT) scan. Patients were followed up for relapse, death and symptomatic response. Three of the 11 patients had no measurable FDG uptake prior to chemotherapy. Of the eight patients who had measurable uptake prior to treatment, seven had a reduction in uptake at 1 month. Six out of the 11 patients had no measurable FDG uptake at 1 month. The overall survival (OS) in these patients ranged from 124 to 1460 days, with a median of 318.5 days. This was superior in comparison to patients who had residual FDG uptake at 1 month (median survival 318.5 days vs 139 days; P = 0.034) and there was a trend to improved symptoms (84% [5/6] vs 20% [1/5]; P = 0.13). There was no statistically significant correlation between best CT response and FDG uptake at 1 month. These results suggest that the absence of FDG uptake at 1 month following chemotherapy for carcinoma of the pancreas is an indicator of improved overall survival. This suggests that FDG-PET may be superior to response assessment by conventional radiographic methods and FDG-PET may have the potential to help make difficult treatment decisions in the management of pancreatic cancer. Larger prospective studies are required to confirm this finding.

Are 18fluorodeoxyglucose positron emission tomography and magnetic resonance imaging useful in the prediction of relapse in lymphoma residual masses?

Treatment of both Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) frequently results in a residual mass visible radiologically. Such patients may receive radiotherapy unnecessarily because the residual mass may represent benign fibrotic tissue rather than residual active lymphoma. Radiotherapy has been shown to have significant short and more worrying long-term toxicity. Refining the criteria for its use would be a major advance. A number of clinical investigations have been evaluated to more accurately determine the nature of such lesions, including erythrocyte sedimentation rate (ESR), magnetic resonance imaging (MRI) and high-dose gallium-67 scanning (HDGS) but none has proven utility. 18[F]-fluorodeoxyglucose positron emission tomography (FDG-PET) is an imaging technique that has been shown to be useful in distinguishing fibrosis from residual active disease in solid tumours. The aim of this study was to compare FDG PET and MRI in the assessment of residual masses following treatment for lymphoma. Patients with NHL/HD who had a residual mass following chemotherapy were eligible for this study. Patients had a combination of MRI and/or PET. All scans were completed within 5 months of the end of treatment. Patients were followed-up for relapse. 56 patients had an MRI scan, 24 had a PET scan and 22 patients had both investigations. Overall sensitivity and specificity, respectively, were for MRI 45% and 74%, PET 50% and 69%, and PET/MRI concurring 50% and 67%. There was a trend for improved relapse-free survival (RFS) with a negative result of both MRI and PET, but this was not statistically significant. The predictive value for both tests failed to reach statistical significance. Subgroup analysis suggests that PET may be better at predicting relapse in patients with NHL, especially those with masses above the diaphragm. There is no convincing evidence that either MRI or PET or the combination can reliably predict relapse within residual masses after treatment for lymphoma. A negative PET scan however appears to be more informative than a positive result and may well aid clinical decision making. There are a number of factors that may produce false-positive results, including post-treatment inflammatory changes, the sensitivity of the test in the setting of minimal residual disease and the heterogeneity of the histological subtypes studied. A negative PET (or MRI) result in lymphoma residual masses following therapy may negate the necessity for further therapy such as chemotherapy or radiotherapy and their concomitant toxicities.

Three-dimensional dosimetry for intralesional radionuclide therapy using mathematical modeling and multimodality imaging.

UNLABELLED: A method of dosimetry is described that quantifies the three-dimensional absorbed-dose distribution resulting from an intralesional administration of a radiolabeled monoclonal antibody, allowing for both spatial and temporal heterogeneity of distribution of the radionuclide and without the need for a calibration scan. METHODS: A mathematical model was developed to describe the distribution of activity as a function of time resulting from infusion at a single point within the solid component of a tumor. The parameters required for this model are either known directly or may be obtained from SPECT image data registered to computed tomography. Convolution of this distribution with a point-source dose kernel enabled the three-dimensional absorbed-dose distribution to be obtained. RESULTS: This method was applied to a set of patient data acquired in the course of a clinical study performed at our center, and dose profiles and dose-volume histograms were produced. It was shown that the three-dimensional distribution of dose was significantly nonuniform. CONCLUSION: Initial results suggest that this method offers a means of determining the absorbed dose distribution within a tumor resulting from intralesional infusion. This method extends the Medical Internal Radiation Dose computation, which, in these circumstances, would make erroneous assumptions. Furthermore, it will enable individual patient treatment planning and optimization of the parameters that are within the clinician's control.