Dosimetry of Bone Seeking Beta Emitters for Bone Pain Palliation Metastases.

Amongst cancer patients, bone pain due to skeletal metastases is a major cause of morbidity. A number of beta-emitting radiopharmaceuticals have been used to provide internal radiotherapy of bone metastases and provide palliative pain relief. In this article we describe the different physical characteristics of the various beta emitting radionuclides which have been used in this clinical setting and the potential impact of differences in dose-rate on radiobiological outcomes. A detailed review of the biodistribution of these treatments, based on both in-vivo clinical investigations and post mortem autoradiography assessments is provided. These treatments result in physiological delivery of radiation doses to the target disease as well as to critical healthy organs. Particular attention is paid to the radiation doses received by normal bone tissue, bone marrow as well as metastatic bone disease. The underlying models of radiation transport within bone and bone marrow are reviewed alongside the practical steps that must be taken to acquire and analyse the information require for clinical dosimetry assessments. The role of whole body measurements, blood and faecal assays as well as both planar and tomographic gamma camera imaging are considered. In addition we review the rationale for allocating measured bone uptake between trabecular and cortical bone tissue. The difference between bone volume and bone surface seeking radiopharmaceuticals are also discussed. This review also extends to the development of preclinical models of bone metastases which may inform future dosimetric calculations. Finally, we also present a comprehensive review of the dosimetry of the established treatments 89Strontium-chloride; 32Phosphorus; 188Rhenium-hydroxyethylidine disphosphonate; 186Rhenium-1,1-hydroxyethylidene disphosphonate (186Re-HEDP); 153Samarium-ethylenediaminetetramethylene phosphonate; as well as the emerging treatments 188Rhenium-zoledronic acid; 188Rhenium-ibedronat; 177Lutetium-zoledronic acid; and 177Lutetium ethylenediaminetetramethylene phosphonate. This review highlights not only the inter treatment differences in the radiation absorbed doses delivered to metastatic disease by different radiopharmaceuticals but also the intra treatment differences which result in a large range of observed doses between patients.

EANM Dosimetry Committee guidance document: good practice of clinical dosimetry reporting.

Many recent publications in nuclear medicine contain data on dosimetric findings for existing and new diagnostic and therapeutic agents. In many of these articles, however, a description of the methodology applied for dosimetry is lacking or important details are omitted. The intention of the EANM Dosimetry Committee is to guide the reader through a series of suggestions for reporting dosimetric approaches. The authors are aware of the large amount of data required to report the way a given clinical dosimetry procedure was implemented. Another aim of this guidance document is to provide comprehensive information for preparing and submitting publications and reports containing data on internal dosimetry. This guidance document also contains a checklist which could be useful for reviewers of manuscripts submitted to scientific journals or for grant applications. In addition, this document could be used to decide which data are useful for a documentation of dosimetry results in individual patient records. This may be of importance when the approval of a new radiopharmaceutical by official bodies such as EMA or FDA is envisaged.

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.

ICRP Publication 140: Radiological Protection in Therapy with Radiopharmaceuticals.

Radiopharmaceuticals are increasingly used for the treatment of various cancers with novel radionuclides, compounds, tracer molecules, and administration techniques. The goal of radiation therapy, including therapy with radiopharmaceuticals, is to optimise the relationship between tumour control probability and potential complications in normal organs and tissues. Essential to this optimisation is the ability to quantify the radiation doses delivered to both tumours and normal tissues. This publication provides an overview of therapeutic procedures and a framework for calculating radiation doses for various treatment approaches. In radiopharmaceutical therapy, the absorbed dose to an organ or tissue is governed by radiopharmaceutical uptake, retention in and clearance from the various organs and tissues of the body, together with radionuclide physical half-life. Biokinetic parameters are determined by direct measurements made using techniques that vary in complexity. For treatment planning, absorbed dose calculations are usually performed prior to therapy using a trace-labelled diagnostic administration, or retrospective dosimetry may be performed on the basis of the activity already administered following each therapeutic administration. Uncertainty analyses provide additional information about sources of bias and random variation and their magnitudes; these analyses show the reliability and quality of absorbed dose calculations. Effective dose can provide an approximate measure of lifetime risk of detriment attributable to the stochastic effects of radiation exposure, principally cancer, but effective dose does not predict future cancer incidence for an individual and does not apply to short-term deterministic effects associated with radiopharmaceutical therapy. Accident prevention in radiation therapy should be an integral part of the design of facilities, equipment, and administration procedures. Minimisation of staff exposures includes consideration of equipment design, proper shielding and handling of sources, and personal protective equipment and tools, as well as education and training to promote awareness and engagement in radiological protection. The decision to hold or release a patient after radiopharmaceutical therapy should account for potential radiation dose to members of the public and carers that may result from residual radioactivity in the patient. In these situations, specific radiological protection guidance should be provided to patients and carers.

Radioiodine for High Risk and Radioiodine Refractory Thyroid Cancer: Current Concepts in Management.

The management of early stage differentiated thyroid cancer (DTC) with low risk of recurrence has been the subject of much interest and investigation in the recent years. Locally advanced DTC and patients with a high risk of recurrent disease however needs further investigation. This short review will look at what constitutes high risk thyroid cancer, the definition of radioiodine refractory disease, the current management and areas of debate within this clinical setting.

Ten Year Experience of Radioiodine Dosimetry: is it Useful in the Management of Metastatic Differentiated Thyroid Cancer?

AIMS: When a fixed activity of radioiodine is given for differentiated thyroid cancer (DTC), absorbed doses of radioiodine can vary widely and are not usually measured. Leeds Cancer Centre has routinely used a form of lesion-specific dosimetry for radioiodine patients. This study investigated if the results of dosimetry influenced treatment decisions for patients with advanced DTC. MATERIALS AND METHODS: Since 2005, patients with regionally advanced/metastatic DTC, who underwent radioiodine treatment together with dosimetry, were included in this study. Patients were excluded if their radioiodine post-treatment scan showed no abnormal uptake. Dosimetry was calculated using images taken 2, 3 and 7 days post-radioiodine. Regions of interest were drawn around lesions that required dosimetry and a time-dose activity curve was created. The total cumulative activity was equal to the area under the curve. Each patient's results were prospectively assessed by their oncologist regarding the usefulness of dosimetry in making management decisions. RESULTS: Thirty patients were studied and underwent 102 admissions of radioiodine between them. Dosimetry was carried out during 83 of 102 admissions. An absorbed dose of >20 Gy was taken as significant from dosimetry calculations, following which further radioiodine was considered. In 80% of patients, dosimetry was found to be useful when making treatment decisions. Only on 1/19 admissions did dosimetry calculate a minimum dose above 20 Gy in patients who had a total of four or more admissions for radioiodine. Ten per cent (3/30) had a complete response to radioiodine, both biochemically and radiologically, with a median follow-up of 6.7 months. Thirty-three per cent had a partial response/stable disease to radioiodine. The remainder had progressive disease. The decision to discontinue radioiodine therapy was often based on dosimetry and thyroglobulin results. Dosimetry was very useful for patients with thyroglobulin antibodies. CONCLUSION: Only 10% had a complete response. Therefore, a significant number of patients became refractory to radioiodine during a course of repeat admissions for treatment. Dosimetry (often together with thyroglobulin and anatomical scans) helped to identify these patients to avoid further futile radioiodine therapy.

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.

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.

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.

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.

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.

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.

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.