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.

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.

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.

Quantitative PET and SPECT performance characteristics of the Albira Trimodal pre-clinical tomograph.

The Albira Trimodal pre-clinical scanner comprises PET, SPECT and CT sub-systems and thus provides a range of pre-clinical imaging options. The PET component consists of three rings of single-crystal LYSO detectors with axial/transverse fields-of-view (FOVs) of 148/80 mm. The SPECT component has two opposing CsI detectors (100 × 100 mm2) with single-pinhole (SPH) or multi(9)-pinhole (MPH) collimators; the detectors rotate in 6° increments and their spacing can be adjusted to provide different FOVs (25 to 120 mm). The CT sub-system provides 'low' (200 µA, 35 kVp) or 'high' (400 µA, 45 kVp) power x-rays onto a flat-panel CsI detector. This study examines the performance characteristics and quantitative accuracy of the PET and SPECT components. Using the NEMA NU 4-2008 specifications (22Na point source), the PET spatial resolution is 1.5 + 0.1 mm on axis and sensitivity 6.3% (axial centre) and 4.6% (central 70 mm). The usable activity range is ≤ 10 MBq (18F) over which good linearity (within 5%) is obtained for a uniform cylinder spanning the axial FOV; increasing deviation from linearity with activity is, however, observed for the NEMA (mouse) line source phantom. Image uniformity axially is within 5%. Spatial resolution (SPH/MPH) for the minimum SPECT FOV used for mouse imaging (50 mm) is 1.5/1.7 mm and point source sensitivity 69/750 cps MBq­1. Axial uniformity of SPECT images (%CV of regions-of-interest counts along the axis) is mostly within 8% although there is a range of 30­40% for the largest FOV. The variation is significantly smaller within the central 40 mm. Instances of count rate nonlinearity (PET) and axial non-uniformity (SPECT) were found to be reproducible and thus amenable to empirical correction.

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.

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.

Differentiated thyroid cancer presenting with thyrotoxicosis due to functioning metastases.

Thyrotoxicosis due to functioning metastases in differentiated thyroid cancer (DTC) is exceedingly rare. We report a case of follicular carcinoma in a 54-year-old manager, who presented with thyrotoxicosis, shortness of breath and lung metastases. Transbronchial biopsy of a pulmonary nodule demonstrated normal thyroid. This was interpreted as representing very well-differentiated thyroid cancer. CT, (131)I whole-body imaging and dosimetry is described following total thyroidectomy and repeated radioiodine administration (cumulative activity 34.6 GBq). The patient became asymptomatic with almost complete eradication of the pulmonary metastases. Potential complications of thyroid storm, bone marrow failure and pulmonary fibrosis following radioiodine are discussed, together with methods to minimise these risks.