Final Report Summary - PEDDOSE.NET (Dosimetry and Health Effects of Diagnostic Applications of Radiopharmaceuticals with particular emphasis on the use in children and adolescents)
The project PEDDOSE.NET was a 22-month support action that started in April 2010. Coordinated by the European Institute for Biomedical Imaging Research (EIBIR, see http://www.eibir.org online), the project consisted of five partners from four countries (Austria, Belgium, France, and Germany) with leading expertise in nuclear medicine dosimetry. Scientific coordinator was Professor Michael Lassmann from the Department of Nuclear Medicine of the University of Würzburg, Germany.
PEDDOSE.NET (see http://www.peddose.net online) was fully supported by the European Association of Nuclear Medicine (EANM, see http://www.eanm.org online) which is the scientific body of nuclear medicine professionals in Europe. Three members of the consortium were also members of the EANM Dosimetry Committee, thus establishing a tight connection to nuclear medicine. The scientific advisory board of the project included representatives from scientific societies and industry associations in the field of nuclear medicine, thus ensuring that the results of the project were disseminated in a timely manner and at a broad level.
The specific objectives of the PEDDOSE.NET support action as requested by the European Commission (EC) were:
- to summarise and evaluate the current knowledge on the impact on patients' health of diagnostic radiopharmaceuticals as currently used in diagnostic imaging procedures;
- to develop recommendations and guidelines to drive scientific and technologic innovation to improve patient healthcare in medical imaging;
- to identify, if clinical studies are needed, and corresponding detailing of the studies;
- to involve people in legislative approval of these agents for human use.
The approach to meet these objectives was to review existing data on biokinetics, dosimetry models and corresponding dose related risks for diagnostic radiopharmaceuticals in children and adults. In addition, the consortium contacted international bodies such as the International Commission on Radiological Protection (ICRP), the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine and Member State radiation protection agencies in order to obtain up-to-date information on the developments in this field. Furthermore, data on imaging device-specific parameters were gathered in order to get information on potential dose reductions with emphasis on paediatric nuclear medicine procedures, and on computed tomography absorbed doses in hybrid scanners.
As a result of the project a set of recommendations were derived. These recommendations will aid the scientific community and the EC in identifying further research areas of research in the field of nuclear medicine dosimetry and patient radiation protection. It might also give guidance to radiopharmaceutical industry on how to improve the clinical trials and the corresponding documentation needed for obtaining marketing authorisation for new compounds.
The dissemination of results was coordinated by EIBIR. During two major European congresses (ECR 2011, EANM 2011) the results of the project were presented in separate pre-congress workshops, of which one (EANM 2011) was the best attended pre-congress event. In addition, one major publication (Eberlein et al, Eur J Nucl Med Mol Imag 2011) summarises the findings of the consortium on behalf of diagnostic nuclear medicine dosimetry. A second publication summarising the view of the consortium on the strong need for standardisation and optimisation of CT protocols for multimodality imaging in nuclear medicine will be submitted soon. Another manuscript on the use of phantoms and computer models in nuclear medicine dosimetry is currently under preparation.
Project context and objectives:
Nuclear medicine contributes significantly to the health, healthcare and quality of life of European citizens, particularly in major clinical areas such as cancer and cardiovascular disease. Every year in Europe over 6 million patients benefit from a nuclear medicine procedure, 95 % of which are diagnostic and 5 % therapeutic. The number of procedures will increase in the coming years, in particular with the increasing number of installed positron emission tomographs (PET) or PET/CT systems and the introduction of new molecules and radiopharmaceuticals through rapid developments in molecular biology and medicine.
In the EU Council Directive 97/43/EURATOM (June 1997), the establishment of a system of reference activities for the major diagnostic procedures has been included. Most of these nuclear medicine procedures, however, are done on an ad-hoc basis; the administered activities vary from country to country. This fact is reflected in the European Association of Nuclear Medicine (EANM) guidelines for diagnostic procedures, in which most of the administered activities vary within a certain range. These issues highlight the need for optimization of the administered activity in nuclear medicine diagnostics.
Diagnostic procedures imply the administration of activity levels that do not lead to the appearance of radiation deterministic effects. This means the stochastic risk associated to the exposure to ionizing radiation cannot be assessed for an individual patient. However, the concept of risk associated to a diagnostic procedure is valid for a population of patients, and requires as a prerequisite the determination of the absorbed dose, i.e. the energy absorbed per unit mass (in Gy) in all irradiated tissues or organs of interest. In a diagnostic context, the determination of the absorbed doses (i.e. a dosimetric study) is required before the introduction of a new radiopharmaceutical to the market (in order to obtain a marketing authorization by the corresponding agencies such as EMEA). This helps to determine the range of activity to inject for the procedure.
'Good practice' also implies to inject the minimum activity compatible with the diagnostic purpose, and to assess the radiation exposure delivered by that amount of activity.
As a summary, the evaluation of the impact on patients' health of small and non- or little repetitive doses (amounts) of radioactive substances, as currently used in diagnostic imaging procedures heavily relies on a precise determination of reference levels of irradiation, since that conditions the quality of data used further for routine diagnostic procedures.
A lot of the absorbed dose data for nuclear medicine diagnostic procedures are older than 20 years and are mainly based upon the ICRP53 tables and their respective addenda. The concepts and methodological advances within the field of internal dosimetry, however, now allow a better assessment of the absorbed doses delivered during nuclear medicine procedures. This is illustrated by the development of new, more representative patient models (in the following denoted as 'phantoms'): The very first phantom to be proposed in the literature for that purpose is the so-called 'reference man'). Since then, many phantoms have been proposed, including children phantoms, gender- or ethnic-specific phantoms.
The situation becomes even worse when considering paediatric nuclear medicine. In a recent publication by Treves et al., the authors identified n the US a broad range of administered doses directly leading to variability in radiation-absorbed doses to patients. The situation is somewhat better in Europe where the paediatrics and dosimetry committees of the EANM published a new dosage card for paediatric nuclear medicine with the aim of keeping the effective dose constant over the age. Uniform weight dependent administered activities are recommended for many procedures. Improvements, however, are needed for the incorporation of new tracers and with respect to technological advances.
Absorbed dose evaluation during routine use of radiopharmaceuticals, if ever performed, is relying on reference models or concepts that have evolved since the time they were established. In addition, the development of new radiopharmaceuticals is limited by the small number of clinical departments able to perform dosimetric studies according to the most recent scientific standards.
Since the introduction of hybrid imaging systems such as PET/CT and SPECT/CT in nuclear medicine departments, both functional and anatomical images can be acquired and merged together very accurately. Unfortunately, the use of these CT images may increase the patient dose considerably, especially if no CT dose optimisation is carried out. Systematic implementation of low-dose CT settings is of particular importance in paediatric nuclear medicine.
The specific objectives of the PEDDOSE.NET support action, as requested by the EC, were:
- to summarise and evaluate the current knowledge on the impact on patients' health of diagnostic radiopharmaceuticals, as currently used in diagnostic imaging procedures;
- to develop recommendations and guidelines to drive scientific and technologic innovation;
- to improve patient healthcare in medical imaging;
- to identify, if clinical studies are needed, and corresponding detailing of the studies; and
- to involve people in legislative approval of these agents for human use.
In order to meet these requirements, the project was divided into several work packages (WPs):
WP 1 dealt with literature reviews and an appraisal of the available dosimetry and epidemiology data for established and new radiopharmaceuticals.
The aim of this WP was to provide an overview of published data on the dosimetry of radiopharmaceuticals as a basis for subsequent recommendations to identify improvements, which are needed for the incorporation of new tracers and with respect to technological advances. This WP also provided an overview of epidemiologic results of the diagnostic administration of radiopharmaceuticals.
WP2 investigated and summarised the status, recommendations and future plans of other bodies regarding radiopharmaceutical dosimetry. ICRP was identified as the most important organisation and their recommendations were the basis for all other bodies. For some frequently used radiopharmaceuticals identified in WP 1 without ICRP recommendations, age-dependent doses were compiled from the literature and their underlying data and the models used to derive them were evaluated. The results of the project were reported to the bodies and may influence their work.
WP 3 summarised the properties of imaging systems with emphasis on potential dose reductions (including hybrid scanners). Data on technical innovations of nuclear medicine imaging systems was provided together with the possibility of reducing patient radiation doses. A critical review was conducted with respect to imaging system sensitivity in order to assess if the sensitivities of the newest generation of nuclear medicine diagnostic devices are such that the current recommendations for the reference activities could be lowered, particularly for children. In addition, it was investigated if a potential reduction of the CT dose in PET/CT and/or SPECT/CT systems could be considered, particularly for paediatric patients.
WP 4 dealt with phantoms and pharmacokinetic modeling for dose delivery.
This WP provided an assessment of existing phantoms and pharmacokinetics modeling for absorbed dose calculations and should lead to the determination of more relevant modeling processes to be used as reference for radiopharmaceutical development.
WP 5 identified the necessity of future clinical trials related to the dosage of radiopharmaceuticals. Within this WP further clinical research need in association with the administration of radiopharmaceuticals was identified and detailed.
WP 6 developed recommendations for patient-specific minimum and maximum activities with particular emphasis on paediatric nuclear medicine as the group of children and adolescents is the most radio-sensitive group of patients.
The objective of WP 7 was to disseminate project results to scientists within and outside the consortium, to healthcare providers and policy makers, and to the public and to establish an exploitation plan for the results obtained in the PEDDOSE.NET project.
Furthermore, general recommendations for the optimisation of reference activities to be approved and disseminated by EIBIR, its co-shareholder, the European association of nuclear medicine, as well as by national authorities should be provided. A final PEDDOSE.NET public workshop was to be organised in order to publicise the project results and to demonstrate and promote the importance and role of diagnostic nuclear medicine at political level, in particular in view of the recent shortage of diagnostic radionuclides.
Project results:
Introduction
The results of the scientific work within the PEDDOSE.NET project were achieved in three major areas:
- appraisal of the available dosimetry and epidemiology data for current and new radiopharmaceuticals
- properties of imaging systems with emphasis on potential dose reductions (including hybrid scanners)
- phantoms and pharmacokinetic modeling for dose delivery.
The latter results were based on a critical review of the scientific literature in each of these areas. Based on these findings, recommendations for future research and improvements in patient radiation protection in nuclear medicine were developed.
Appraisal of the available dosimetry and epidemiology data for current and new radiopharmaceuticals
Dosimetry data on current radiopharmaceuticals
The first part of the project provided an overview of published data on the dosimetry of diagnostic radiopharmaceuticals as a basis for subsequent recommendations.
The literature survey was mostly conducted through PubMed (see http://www.ncbi.nlm.nih.gov/PubMed online) and secondary literature contained in the PubMed references.
The inclusion criteria were:
- publications of official bodies such as the ICRP;
- peer-reviewed journals;
- special conference proceedings containing detailed descriptions on the methodologies on dosimetry.
The search was restricted to the publication date of ICRP 53 (1987) unless there were no other data available.
For presenting the results of our literature review of biokinetic and dosimetry data, we divided radiopharmaceuticals in three categories, namely:
- radiopharmaceuticals having a marketing authorization;
- radiopharmaceuticals well-established in clinical practice;
- radiopharmaceuticals not well-established in clinical practice.
We decided on preparing tables for each category that show the most crucial points with respect to dosimetry. Additionally, PET and non-PET radiopharmaceuticals were considered separately.
In principle, the criteria defined by the EANM dosimetry committee guidance document on good clinical reporting were used:
- Which quantitative imaging method was used, planar, SPECT or PET, and which corrections (e.g. attenuation correction) were applied?
- Are data on biokinetics given; especially detailed information on residence times (time-integrated activity coefficients)?
- When was the last data point of the image acquisition?
- Which bladder voiding intervals were used?
- Are the absorbed doses for the organs listed?
- Which tissue weighting factors were used? Is the effective dose (ED) or the effective dose equivalent listed (EDE)?
- How many volunteers/patients did take part in the dosimetry studies?
- Which computer code was used to calculate the absorbed doses and the effective dose?
- Is there a package insert, in which dosimetry data are given?
The results of this part were published in the European Journal of Nuclear Medicine and Molecular Imaging (Eberlein U., Bröer J. H., Vandevoorde C., Santos P., Bardiès M., Bacher K., Nosske D., Lassmann M. Biokinetics and dosimetry of commonly used radiopharmaceuticals in diagnostic nuclear medicine a review, European Journal of Nuclear Medicine and Molecular Imaging: Volume 38, Issue 12 (2011), Pages 2269 - 2281). In this open access publication the complete information on all radiopharmaceuticals is provided.
In summary it can be stated, that for most commonly used diagnostic radiopharmaceuticals dosimetry data are available, although the data collection and calculation methods are heterogeneous. As some of the data were acquired more than 20 years ago, it would be of interest to generate new data on biokinetics and dosimetry in diagnostic nuclear medicine using state-of-the art equipment and more uniform dosimetry protocols. As the concept of effective dose calculation has changed with ICRP 103 gender-specific dosimetry data will be needed (see sections 4.4 and 5.5). Data for paediatric nuclear medicine are missing in most cases. As some of the references collected for this review are not easily accessible a major conclusions of this work is that, for easier public access to dosimetry data of diagnostic radiopharmaceuticals, a database containing these data should be created and maintained.
New radiopharmaceuticals of potential importance
When considering new radiopharmaceuticals of potential interest one encounters the problem that it is not easy to search for substances with unknown names; therefore, the list of radiopharmaceuticals might be incomplete. However, there is a fast development of many new radiopharmaceuticals; for many of those, it is impossible to judge how important they will be in the near future. In addition, there are older radiopharmaceuticals not mentioned which are gaining importance. In order to find a compromise between new and of potential importance substances, they were included if they fulfilled at least one of the following criteria:
- There is a study about human dosimetry published in 2005 or more recently.
- The substance is on the to do list of the Radiation Dose to Patients from Radiopharmaceuticals Task Group of ICRP.
- The substance could come short term on the market.
- There was an application for a research project filed to the German Federal Office for Radiation Protection in 2011.
The reason for the first criterion was the idea that older substances had enough time to become well established or at least important enough for additional research. The other criteria were chosen to identify substances of potential importance.
To make comparisons easier, radiopharmaceuticals were sorted in one of the three categories neurology, oncology or cardiology and subsequently ordered according to the used radionuclide. As most of the new radiopharmaceuticals are experimental, many dosimetric studies include less than ten subjects. Besides this, the quality of the peer-reviewed studies improved as compared to the ones cited in the first report of this WP, e.g. the majority of studies with PET substances used attenuation correction just as the majority of studies including planar imaging used at least the conjugate view method for more precise measurements.
Unfortunately, for some radiopharmaceuticals developed by companies there are no peer-reviewed studies and therefore the quality of the underlying experimental data cannot be assessed. Also for some radiopharmaceuticals in phase I or phase II only in-vitro / animal data and press releases are available.
For new radiopharmaceuticals, there are no biokinetic or dosimetric studies with children. For an estimate with limited experimental evidence, it is always possible to combine adult residence times with paediatric phantoms or even vary the bladder voiding interval as proposed in ICRP 106, but uncertainties about the paediatric biokinetics remain.
The list of radiopharmaceuticals and further details are available upon request from the project coordinator.
Epidemiological data
A compilation of the existing epidemiological data of the administration of radiopharmaceuticals was undertaken. As very large sample sizes are needed to statistically distinguish radiation induced cancers from the baseline cancer incidence rate at very low absorbed doses, there exist only epidemiologic studies on the diagnostic use of I-131 sodium iodide, for which the thyroid absorbed dose is in the range of 1 Gy. Especially for children and adolescents only few data on I-131 with limited patient numbers can be found. Therefore, it is not possible to make a reliable risk assumption for children and adolescents.
According to these epidemiologic studies, there is no evidence that diagnostic exposure of I-131 causes excessive thyroid cancer cases. For other radiopharmaceuticals used in diagnostic nuclear medicine, the absorbed doses to the organs are too small and are therefore below the detection limit. In this case, theoretical assumptions have to be taken into account. The data for low doses are primarily based on the long-term follow-up of the atomic bomb cohort and are linear extrapolations from high dose exposure (linear no threshold model).
The following examples for theoretical risk assessments using the lifetime attributable risk according to the BEIR VII report were assessed:
- a general model, which takes a reduced life expectancy for special patient groups into account and estimates the reduction of the attributable risk due to the lower life expectancy of the patient compared to the non-patient group;
- cancer risks from breast imaging studies with x-rays and internal radiations;
- cancer risks from myocardial perfusion scans.
These examples provide a new approach to risk assessments in nuclear medicine diagnostics. The respective methodologies should be partly included in future studies describing the radiation risk of radiopharmaceuticals in nuclear medicine.
Properties of imaging systems with emphasis on potential dose reductions (including hybrid scanners)
The impact of new technological developments on image quality and patient doses in multimodality imaging
Technological innovations have led to the appearance of new generations of imaging systems in nuclear medicine. The latter innovations were linked with both improvements in detector architectures (such as solid state detectors, new scintillator materials with time-of-flight capabilities) and reconstruction techniques. This resulted in overall improved detector sensitivities and, as a consequence, in an improvement of the image quality. However, the higher sensitivities could also be used to lower the administered activities to patients.
The literature review on the recent developments in nuclear medicine imaging instrumentation showed that PET and SPECT innovations are mostly announced to be beneficial for the image quality. On the other hand, a lot of authors emphasise on the possibility to reduce the scanning time significantly, without affecting image quality. Only a few publications focused on the potential of these new techniques in reducing patient radiation doses. The latter is especially important for children, who are more sensitive to the adverse effects of radiation exposure compared to adults. Hence, further research in this area should be encouraged, to find an acceptable balance between scan time reduction, image quality improvement and patient radiation dose reduction.
It is important to remark, that most of the existing recommendations for administrated activity in diagnostic nuclear medicine (diagnostic reference levels, EANM paediatric dosage card and the North American consensus guidelines) do not take into account the opportunity to reduce the currently activity levels based on the higher sensitivity of the latest generations of nuclear medicine instrumentation. It should be recommended that, when updating these recommendations, these aspects are taken into account.
Next to the technological innovations in stand-alone nuclear medicine imaging, one of the major developments in the last decade was the introduction of hybrid imaging systems (PET/CT and SPECT/CT). The last years, they have gained wide acceptance in clinical practice and they became one of the fastest growing imaging modalities worldwide. The success of these combined systems is due to their possibility to fuse morphological (CT) and functional (PET or SPECT) information in one examination, to improve the sensitivity and specificity of the diagnostic examination. As the CT acquisition is mostly associated with large patient radiation doses, efforts should be made to reduce and optimize the CT radiation burden. Therefore, CT innovations play also an important role for nuclear medicine diagnostics. In contrast to nuclear medicine instrumentation, where most emphasis is on image quality improvement and scan time reduction, manufacturers are focusing strongly on dose reduction in new CT systems. Unfortunately, the state-of-the-art dose reduction tools are not (always) available on hybrid imaging systems.
Review of CT protocols currently used in hybrid imaging systems
The use of CT in hybrid imaging can be related to:
- attenuation correction;
- anatomic localisation and/or
- the acquisition of additional diagnostic examination.
Depending on the particular application, appropriate CT exposure settings and corresponding dose levels should be selected. An optimised CT scan for the purpose of attenuation correction of the emission data will contribute only for a fraction of the total patient exposure of the complete multimodality study. On the other hand, if CT settings are not optimized, a CT acquisition may contribute to more than 75 % of the total radiation exposure when diagnostic information is required.
The reported effective CT doses for children were similar to the effective doses for adults. Taken into account the higher sensitivity of these patients, an adjustment of the scanning parameters to the smaller size of these patients is necessary. In the case of serial PET/CT scans for follow-up in children, cumulative effective CT doses may amount to more than 300 mSv! Therefore, it is important that the nuclear medicine physician is aware of the radiation dose contribution of the CT examination within the complete examination.
In general, the range in published effective doses for hybrid imaging is very large, indicating a lack of standardisation in CT protocols. An appropriate optimisation of the CT protocols is necessary, taking into account the clinical need, the availability of previous diagnostic CT scans and the age of the patient. Efforts should be made to develop diagnostic reference levels for hybrid devices, in order to give nuclear medicine physicians guidelines to rely on. Such reference levels only exist for conventional diagnostic CT studies, but not for the typical setting of hybrid imaging.
Dose reduction techniques for CT
As CT doses in hybrid imaging may by high in comparison with the radiation dose attributed to the used radiopharmaceutical, appropriate optimization of CT protocols is necessary. Significant dose reductions are feasible by selecting relevant scan parameters corresponding with the requested image quality. In general, the use of low-dose CT protocols in hybrid imaging should be encouraged. Based on the available data, one can conclude that low-dose CT's with a tube current of 10 mA and acquired with a high helical pitch are sufficient for attenuation correction purposes. The latter CT acquisition result in a typical effective dose of less than 1 mSv for a whole body scan. Even then, these CT images may contain useful clinical information. Lowering the kVp-settings of the CT may be another option; however, a possible reduction of these values depends on the used transformation algorithm for constructing the attenuation maps.
The acquisition of diagnostic quality CT should be justified and should take into account the availability of previous CT exams.
In the new(er) CT instruments, dose reduction hardware / software options are available. The automatic tube current modulation will automatically select an appropriate tube current value taking into account the individual anatomy of the patient and taking into account the exact scan location within the patient. Iterative CT data reconstruction, will allow for low-dose scanning without compromising image quality, as the iterative reconstruction algorithm will significantly reduce the noise content in the CT image.
The latter options have proven their efficiency. A combination of automatic tube current modulation and iterative CT reconstruction can reduce the patient CT dose with more than 50 %. Therefore, the implementation and the use of dose reduction options should be strongly encouraged. Unfortunately, most CT systems of hybrid equipment currently in use do not have such state-of-the-art dose reduction tools. Still, patient doses can be optimised taking into account the weight of the individual patient and by scaling the mA-values accordingly.
In order to be able to optimise CT protocols, nuclear medicine physicians should be provided with appropriate educational material to understand the basics principles of CT dosimetry. A summary of these aspects is provided in an educational PowerPoint publication which can be used by the nuclear medicine community. In the latter presentation following issues are addressed:
- Is the CT radiation dose contribution important in multimodality imaging?
- Why are radiation doses from CT imaging high?
- Which quantities are used to describe the CT doses?
- How can we estimate the effective dose of a CT acquisition?
- Which parameters are influencing radiation dose and image quality?
- How can we optimise CT radiation doses for hybrid imaging?
- What are the recent developments with respect to CT dose reduction techniques?
Phantoms and pharmacokinetic modelling for absorbed dose delivery
Literature review on existing absorbed dose approaches that have been implemented
According to the MIRD formalism absorbed dose determination relies on:
- activity (A, in Bq) determination within the patient, at different time after radiopharmaceutical injection, mostly via quantitative scintigraphic imaging even though external counting can also be considered;
- cumulated activity (Ã, in Bq.s) or residence time (tau, in s) assessment from time activity curves;
- dose conversion factor (S, in Gy/Bq.s) for a given set of source-target configuration and for a given isotope.
The first two items are usually considered as a single step, even though they are in fact independent tasks: the most accurate activity determination is of little help when time sampling is wanting.
The last item relies on the definition of computational models (that define the geometry), and radiation transport codes that score the absorbed dose for any type of target defined in the computational model, for a given isotope and a given source-target configuration.
The analysis of a given dosimetric approach will consider the way activity, cumulated activity and S factors are determined, considering the fact that the least accurate parameter will directly impact on the final result.
The publications collected for this project were analysed to identify the method used for calculating absorbed doses. All the authors of the mentioned papers used the MIRD formalism. The dosimetric data used, in terms of specific absorbed fractions (SAF), S-values and dose conversion factors for absorbed dose per unit administered activity, was obtained from different sources, of which the most commonly used were the MIRD pamphlets and dose estimate reports, the ICRP publications and the RADAR website.
An analysis of experimental protocols used to measure cumulated activity from nuclear medicine images was performed. This allowed an assessment of the quality of data gathered on radiopharmaceutical fixation on patient organs, and consequently of biokinetics used for absorbed dose assessment.
Review of phantom characteristics and impact on dosimetric results
Dosimetric data used for absorbed dose calculation reported in ICRP reports 53, 80 and 106 are based on the following models:
- adult male from Snyder et al., 1974 (MIRD Pamphlet No 5 Revised)
- Cristy and Eckerman series of phantoms at various ages
- Stabin et al. computational models for the non-pregnant adult female and at the end of each trimester of pregnancy.
These models are all mathematical models, i.e. designed from equations, and therefore are made of a combination of simple geometric shapes that do not describe very accurately human geometry.
The evolution in the representation of human geometry led to the advent of voxel-based, and then hybrid models.
Computational models have seen a major evolution in the recent past. The transition is not yet finished (S factors tables for new adult models are still not available, and more reference voxel-based models are needed for paediatric or pregnant patients for example).
For adult models, a complete recalculation of S values for the numerous radioisotopes considered for nuclear medicine is important, in order to assess how the voxel-based definition of the anatomy impacts the absorbed dose. This certainly is relevant for overlapping organs, where local cross-irradiation is likely to be significant.
Impact of pharmacokinetics modelling assumptions on dosimetric results
Most available data for 'established' radiopharmaceuticals is old, obtained using sub-optimal methodology (as compared to what's available today). This is especially true for non-PET tracers (i.e. the oldest available data), and to a lesser extent for PET tracers. New tracers in nuclear medicine are mostly involving PET tracers, for which quantitative imaging is considered superior to conventional scintigraphic imaging.
Most published dosimetric data were obtained from a reduced number of patients, which limits the value of the absorbed dose / effective dose figures given.
New radiopharmaceuticals sometimes benefited from methodology improvements, even though the trend is not very strongly established. Hybrid imaging for example, is not as often used as one would hope given the acknowledged advantages introduced by that modality for scintigraphic quantitative imaging.
A careful assessment of acquisition times is required for any given pharmacokinetics study. As could be seen from the literature study, currently available results show variability in that respect. The definition of the last data point should be carefully discussed in the view of the biological behaviour of the tracer, and the physical half-life of the associated isotope.
Biokinetic modelling does impact the dosimetric result, even though this is more apparent for absorbed doses delivered to organs, and less marked for the effective dose. However, within the context of and organ-based risk assessment, absorbed doses delivered to individualised organs or tissues are of paramount importance.
Reporting is a major aspect of any dosimetric study. There may be no standardized reference regarding the way to implement a clinical dosimetry study, however, not carefully mentioning the various steps leading from data acquisition to activity and cumulated activity should be considered as bad practice. This limits the value of dosimetric results presented in most of the articles analysed in this project. There seem to be a trend to better document the way pharmacokinetics was assessed, even though a lot of work still has to be done in that area.
Definition of a list of radiopharmaceutical that would benefit from revised approaches
Absorbed dose calculation via anthropomorphic models has seen major evolutions in the recent past, some of which led to the presentation of new reference computing models for adult male and female (ICRP report 110). The obvious consequence is that of a more accurate representation of human anatomy, which on principle should lead to more accurate absorbed dose calculations.
The present moment is that of a transition phase, where only old dosimetric data are available that correspond to the dosimetric concepts presented in ICRP 60. New reference data to comply with ICRP 103 recommendations are not yet available. This explains why ICRP 106 (published after ICRP 103) presents dosimetric data for radiopharmaceuticals using the ICRP 60 formalism and concepts (computing models, etc.).
Voxel-based description of patient anatomy allows for absorbed dose gradients to be computed within a given organ (voxel-based). This is relevant as long as pharmacokinetics is also defined at the voxel level. Should this not be possible, it is strongly advised to keep expressing results as mean absorbed doses to organs and tissues, as deriving absorbed dose volume histograms from (assumed) homogeneous distributions of activity within a given organ would not provide for correct results, and give a false feeling of accuracy.
Is it realistic to ask for a global revision of available data? It may not be possible to reassess pharmacokinetics for all already available radiopharmaceuticals, even though the quality of past quantification studies may be debatable.
A common sense approach would be to try to increase the quality of pharmacokinetics assessment for new tracers. An obvious limitation is the absence of standardised procedure for activity and cumulated activity determination (both for PET and non-PET tracers). A minimum requirement would be to better document the way activity and cumulated activity was derived, as is proposed in the guidance document published by the EANM Dosimetry Committee.
For paediatric studies, a further point to consider is establishing a balance between the need to cover, as broadly as possible, a range of patients varying in morphology and physiology, and the ethical difficulty to set-up dosimetric studies for paediatric patients as these may induce extra irradiation (CT) with no benefit to the patient.
A last but major point to consider is related to the release of voxel-based computing models. In order to be able to fully account for the optimised spatial resolution of absorbed dose calculation, it is mandatory to be able to determine the activity at the same spatial sampling, i.e. at the voxel level. This certainly will require optimising the quantification procedures, both for PET and SPECT approaches.
Recommendations
Identification of future clinical trials related to the dosage of radiopharmaceuticals
Based on the analysis provided in the previous sections, urgent clinical research is recommended in the following areas:
- Ga-68-Dotatate as it is frequently used and there are no published dosimetry data;
- F-18-Fluoride as the biokinetics measured stopped at very early time-points (< 2 h) and/or are based on partial body measurements only. Some of the published absorbed dose data were taken from a biokinetic model that was not confirmed by a comparison to experimental data;
- confirmatory data on the biokinetics in children and adolescents as most of the dosimetry data in paediatric nuclear medicine assume the same biokinetics in children and in adults.
As there are few existing clinical trials with respect to dosimetry and the associated potential long-term risk of the application of radiopharmaceuticals, a basic template on dosimetry methodology is developed which can be used for setting up such a trial. Part of this template can be inserted into a study protocol of future clinical trials related to diagnostic radiopharmaceuticals and is available upon request.
Need of epidemiological research
As nuclear medicine involves ionising radiation with an associated stochastic risk of radiation damage, it would be of importance to obtain reliable data on the long term effects of the administration of radiopharmaceuticals.
In 2011, a retrospective study on the epidemiology of CT procedures in children started under FP7. It is called 'Epidemiological study to quantify risks for paediatric computerised tomography and to optimise doses' (EPI-CT).
This project will provide direct epidemiological evidence on the potential cancer risk due to low doses of ionising radiation exposure in a large multinational European cohort. It will be the largest and the most statistically powerful study of paediatric CT scans undertaken until to date. The results will contribute to the radiation protection, dose optimisation and low dose radiation research and are awaited for 2015.
However, such a study with the same statistically power would probably not be possible for nuclear medicine for several reasons:
- There are four times less nuclear medicine diagnostic procedures performed as compared to CT procedures (CT and nuclear medicine procedures in 2006 in the US).
- Furthermore, the effective doses of NM-procedures are lower as compared to CT. According to the NCRP Report No. 160 nuclear medicine contributes with 12 % to the collective effective dose compared to CT with 24 % (this applies for the US). However, the effective doses for nuclear medicine might become higher because of the increasing availability and use of hybrid imaging systems.
- The analysis of the existing epidemiological data provided in WPs 1 and 6 showed no evidence of an increased cancer risk associated with nuclear medicine diagnostics.
- Therefore, we cannot recommend performing epidemiological studies involving Nuclear Medicine diagnostics at the present stage. Should the EPI-CT study provide evidence for a radiation-related risk involving CT scans, however, this might need to be reconsidered in the future.
Patient-specific minimum and maximum activities
Many publications deal with the optimisation of diagnostic procedures, most of them on F-18-FDG PET/(CT) using a wide range of administered activities which hampers the comparison of these studies. Using the new technological developments such as hybrid systems, iterative reconstruction algorithms and detectors with higher efficiencies it could be shown that it is possible to reduce the administered activities.
However, the use of more sensitive instrumentation (e.g. 3D-PET, TOF PET) does not automatically result in lowering injected activity levels as these techniques allow for better image quality and reduced scanning times.
- It is recommended to establish standards for calculating the activity to be administered to a patient according to weight (better morphometry), camera systems, reconstruction algorithms and scanning time.
How this can be achieved is shown, for example for PET scanners, by Boellaard et al. and for paediatric nuclear medicine by Sgouros et al.
Imaging device sensitivities and the respective impact on paediatric nuclear medicine
Properties of imaging systems with emphasis on potential dose reduction have been investigated, based on a literature review on the possible impact of new technological innovations in nuclear medicine imaging on patient dose and image quality.
In hybrid imaging devices, the CT phase is contributing significantly to the total effective dose of the complete examination. The currently used CT protocols in hybrid imaging have been reviewed in order to formulate recommendations with respect to CT dose reduction techniques for the nuclear medicine community. In this context, we should keep in mind that every radiation exposure must be medically indicated and that the required image quality is not always the 'best' image quality. A trade-off should be made with respect to image quality improvement, scan time reduction and patient dose reduction.
- There is a severe lack of standardised guidelines on CT protocols for hybrid imaging. The nuclear medicine community should be encouraged to critically review the currently used CT parameters and the corresponding effective dose contribution for the patient.
- There is an urgent need for diagnostic reference levels and their respective justification for hybrid imaging, so that PET/CT and SPECT/CT acquisitions can be performed in a more standardised and unified way. Secondly, the existing recommendations on administered activities should be updated according to the more sensitive and efficient nuclear medicine equipment that exists today.
The new ICRP recommendations and their impact on paediatric nuclear medicine
In the new 2007 ICRP recommendations (ICRP 103), the basic definition of effective dose remains unchanged from the 1990 recommendations (ICRP 60). However, some of the tissue weighting factors have been changed on the basis of new epidemiological data for cancer induction. In fact, instead of taking cancer mortality as a basis for w, in the new recommendations one uses the incidence of radiation-induced cancer as well as the risk of heritable disease over the first two generations. The most significant changes in w are found for breast tissue, gonads and the remainder organs.
ICRP now clearly demands the use of male and female reference voxel phantoms which have been published in ICRP 110. The new concept demands a determination of the equivalent doses in the organs and tissues of the reference male and the reference female separately. In order to obtain the equivalent doses of the reference person, the gender-specific equivalent doses are averaged; hence the new tissue weighting factors can be applied. Moreover, according to ICRP 103, only the latest ICRP voxel phantoms have to be used for the calculations of effective dose. Applying the new weighting factors on a set of equivalent organ doses previously calculated with a mathematical phantom will therefore not result in a correct effective dose value due to ICRP 103. Presently, the modified tissue weighting factors and the subsequent calculation of the effective dose according to the formalism of ICRP 103 cannot be applied to nuclear medicine as the calculations of the S-values for the radiopharmaceuticals using the new recommendations of the ICRP are still missing but are currently performed.
As children of the same age do not necessarily have the same body weight or body morphometry it is not recommended to use only the age of a child as indicator for the activity to be administered.
Still, the current situation is that patients are administered standard levels of activity, although these standards themselves vary from country to country and even from centre to centre.
To avoid this situation for children, in 2007 a new EANM paediatric dosage card was published by Lassmann et al. superseding the old dosage card by Piepsz et al. In the Piepsz dosage card, the fraction of administered activity was calculated according to the body surface area (estimated from body weight) with respect to an adult of 70 kg. However, as the administered activity for adults is not the same within Europe the dosage table results in different and in some cases very high administered activities in children.
In 2011, Gelfand et al. published a North American consensus guideline to harmonise the administered activity in paediatric nuclear medicine in North America. Both cards (EANM and the North American) do not differ very much in terms of recommended amounts of administered activities. However, there are exceptions, for example a difference in the administered activity for I-123-MIBG for children below 10 kg. In this case, the recommended value of the North American consensus guideline is nearly half the value of the recommended EANM value.
Until more measurements or simulations on the influence of patient morphology and pharmacokinetics on image quality are available the use of the current weight-dependent EANM paediatric dosage card is recommended as, for Europe, the EANM dosage card is better adapted to the practice of European nuclear medicine. Should more data become available in the near future efforts should be undertaken to update the EANM dosage card.
Other recommendations
Based on the information provided in previous sections, other general recommendations for further study and research areas were derived:
- Dosimetry data of new radiopharmaceuticals should be published in peer-reviewed journals so that they are publicly available. The EANM dosimetry guidance document on good dosimetry reporting should be considered when publishing.
- An effort to harmonise the diagnostic reference levels for nuclear medicine within Europe should be undertaken. The large differences between European countries can only partially be explained by differences in equipment. Repetitions of national surveys for new national diagnostic reference levels are unlikely to change this situation. An update of the nuclear medicine section of the EU 1999 document RP109 'Guidance on diagnostic reference level for medical exposures' is urgently needed.
- For easier access of the general public to dosimetry and biokinetic data in nuclear medicine the establishment of a publicly available web-based database would overcome the difficulties in finding and accessing the data on radiopharmaceutical dosimetry.
- Urgent efforts should be undertaken to resolve the current situation of the use of ICPR 60 versus ICRP 103 as the data on the phantoms for nuclear medicine to be used in conjunction with the risk factors of ICRP 103 are not publicly available yet.
- There is a need to consider alternative means of assessing stochastic risk such as the use of organ doses and BEIR VII risk models.
- For hybrid imaging (PET/CT, SPECT/CT), the following action items are recommended:
- standardisation of CT-protocols for the different applications such as attenuation correction, localization and diagnostic CT;
- establishment of European CT diagnostic reference levels;
- mandatory use of dose reduction techniques such as iterative reconstruction;
- more studies on image quality for dose reduction techniques.
- More in-depth discussion on new instrumentation within the nuclear medicine community should be started with respect to finding a balance between:
- patient-dose reduction
- image quality improvement
- acquisition time reduction.
- As some of the radiopharmaceuticals applied in nuclear medicine show a very inhomogeneous distribution on a microscopic scale further research on the influence of absorbed dose distributions in this case should be encouraged.
- A standardised teaching and training program should be established for physicians and scientists in nuclear medicine with respect to the:
- need for improved understanding of stochastic risks from ionizing radiation;
- need for better understanding and consideration of CT doses in hybrid imaging;
- need for improved instrumentation and software based dose reduction strategies;
- need for better understanding the limitations of the effective dose concept in medical dosimetry of the patient.
An extension of the concept of this project to radionuclide therapy with their deterministic radiation effects is strongly recommended.
References
1. ICRP. Publication 53: Radiation Dose to Patients from Radiopharmaceuticals. Ann ICRP. 1987;18(1-4).
2. Lassmann M., Chiesa C., Flux G., Bardiès M. EANM Dosimetry Committee guidance document: Good practice of clinical dosimetry reporting. Eur J Nucl Med Mol Imaging. 2011;38(1):192200.
3. Bolch W. E., Eckerman K. F., Sgouros G., Thomas S. R. MIRD Pamphlet No. 21: A Generalized Schema for Radiopharmaceutical Dosimetry-Standardization of Nomenclature. J Nucl Med. 2009;50(3):477484.
4. Eberlein U., Bröer J. H., Vandevoorde C., Santos P., Bardiès M., Bacher K., et al. Biokinetics and dosimetry of commonly used radiopharmaceuticals in diagnostic nuclear medicine - a review. Eur J Nucl Med Mol Imaging. 2011;38(12):22692281.
5. ICRP. Publication 103: The 2007 recommendations of the International Commission of Radiological Protection. Ann ICRP. 2007;37 (2-4).
6. ICRP. Publication 106: Radiation dose to patients from radiopharmaceuticals: Addendum 3 to ICRP Publication 53. Ann ICRP. 2008;38 (1-2).
7. Dickman P. W., Holm L.-E. Lundell G., Boice J. D., Hall P. Thyroid cancer risk after thyroid examination with 131I: a population-based cohort study in Sweden. Int. J. Cancer. 2003;106(4):580587.
8. Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation, National Research Council. Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2. Washington, D.C.: The National Academies Press; 2006.
9. Eschner W., Schmidt M., Dietlein M., Schicha H. PROLARA: prognosis-based lifetime attributable risk approximation for cancer from diagnostic radiation exposure. Eur. J. Nucl. Med. Mol. Imaging. 2010;37(1):131135.
10. Hendrick R. E. Radiation doses and cancer risks from breast imaging studies. Radiology. 2010;257(1):246253.
11. Berrington de Gonzalez A., Kim K.-P. Smith-Bindman R., McAreavey D. Myocardial perfusion scans: projected population cancer risks from current levels of use in the United States. Circulation. 2010;122(23):24032410.
12. Lassmann M., Biassoni L., Monsieurs M., Franzius C., Jacobs F. The new EANM paediatric dosage card. Eur J Nucl Med Mol Imaging. 2007;34(5):796798.
13. Lassmann M., Biassoni L., Monsieurs M., Franzius C. The new EANM paediatric dosage card: additional notes with respect to F-18. Eur J Nucl Med Mol Imaging. 2008;35(9):16661668.
14. Gelfand M. J., Parisi M. T., Treves S. T. Pediatric Radiopharmaceutical Administered Doses: 2010 North American Consensus Guidelines. J Nucl Med. 2011;52(2):318322.
15. Huang B., Law M.W.-M. Khong P.-L. Whole-Body PET/CT Scanning: Estimation of Radiation Dose and Cancer Risk1. Radiology. 2009;251(1):166 174.
16. Chawla S. C., Federman N., Zhang D., Nagata K., Nuthakki S., McNitt-Gray M., et al. Estimated cumulative radiation dose from PET/CT in children with malignancies: a 5-year retrospective review. Pediatr Radiol. 2010;40(5):681686.
17. Loevinger R., Budinger T.F. Watson E.E. MIRD primer for absorbed dose calculations. Rev. ed. New York NY: Society of Nuclear Medicine; 1991.
18. ICRP. Publication 60: 1990 recommendations of the International Commission on Radiological Protection. Ann ICRP. 1991;21 (13).
19. Snyder W. S., Ford M. R., Warner G. G.. MIRD Pamphlet No. 5 revised: estimates of absorbed fractions for monoenergetic photon sources uniformly distributed in various organs of a heterogeneous phantoms. Society of Nuclear Medicine. 1978.
20. Cristy M., Eckerman K. F. Specific Absorbed Fractions of Energy at Various Ages from Internal Photon Sources. ORNL/TM-8381 V1-V7. Oak Ridge National Laboratory. 1987;
21. Stabin M. G., Watson E., Cristy M., Ryman J. C., Eckerman K. F., Davis J. L., et al. Mathematical models and specific absorbed fractions of photon energy in the nonpregnant adult female and at the end of each trimester of pregnancy. Oak Ridge, TN: Oak Ridge National Laboratory. 1995;ORNL/TM-12907:5354.
22. ICRP. Publication 110: Adult Reference Computational Phantoms. Ann ICRP. 2009;30(2).
23. Epidemiological study to quantify risks for paediatric computerized tomography and to optimise doses (EPI-CT). https://cordis.europa.eu/project/id/269912.
24. National Council on Radiation Protection and Measurements. NCRP Report No. 160, Ionizing Radiation Exposure of the Population of the United States. Bethesda, Md: National Council on Radiation Protection and Measurements. 2009.
25. Boellaard R., Oyen W. J. G., Hoekstra C. J., Hoekstra O. S., Visser E. P., Willemsen A. T., et al. The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials. Eur J Nucl Med Mol Imaging. 2008;35(12):23202333.
26. Boellaard R., O'Doherty M. J., Weber W. A., Mottaghy F. M., Lonsdale M. N., Stroobants S. G., et al. FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. Eur J Nucl Med Mol Imaging. 2010;37(1):181200.
27. Boellaard R. Standards for PET image acquisition and quantitative data analysis. J Nucl Med. 2009;50 Suppl 1:11S20S.
28. Sgouros G., Frey E. C., Bolch W. E., Wayson M. B., Abadia A. F., Treves S. T. An Approach for Balancing Diagnostic Image Quality with Cancer Risk: Application to Pediatric Diagnostic Imaging of 99mTc-Dimercaptosuccinic Acid. J Nucl Med. 2011;52(12):19231929.
29. Piepsz A., Hahn K., Roca I., Ciofetta G., Toth G., Gordon I., et al. A radiopharmaceuticals schedule for imaging in paediatrics. Eur J Nucl Med. 1990;17(3-4):127129.
30. European Commission. Guidance on diagnostic reference levels for medical exposures. Radiation Protection 109. 1999; http://ec.europa.eu/energy/nuclear/radiation_protection/doc/publication/109_en.pdf.
Potential impact:
As this Support Action is based mainly on a review of the available literature and its intention was not to perform research the potential impact of this project is restricted to recommendations to the EC based on the critical evaluation of the available data by applying scientific criteria.
Due to the fact that the MIRD-scheme is state of the art concerning dosimetry and ICRP publications are the de facto international standard there will probably no impact on those who rely on ICRP. The responsible task group of ICRP is aware of the results of this project and is planning to calculate revised absorbed doses for Rb-82 and other radiopharmaceuticals. The absorbed doses for radiopharmaceuticals besides Rb-82 relying on old measurements may be recalculated but without new measurements the data basis for biokinetic models will remain unchanged.
The German Federal Office for Radiation Protection - and possibly also other national bodies - is planning to determine new diagnostic reference levels and will consider the results of this project.
Main dissemination activities
In order to promote PEDDOSE.NET its objectives and research results, general and scientific information were disseminated to diverse recipients - within the relevant scientific groups (e.g. nuclear medicine) as well as in the general and scientific public.
Three public events are noteworthy regarding the dissemination of PEDDOSE.NET project results: project partners organised a final public workshop in the framework of the Annual EANM-Congress in Birmingham, UK in October 2011 under the title 'Do we apply too much radiation in diagnostic nuclear medicine?' and organised and chaired one thematic session under the title 'Practical aspects of CT during the International Conference on Clinical PET and Molecular Nuclear Medicine (IPET-II-2011) - Trends in Clinical PET and Radiopharmaceutical Development' organised by the IAEA in Vienna, AT in November 2011.
Further, a PEDDOSE.NET session on 'Multimodality Imaging: Do we apply too much radiation?' was held during the European Congress of Radiology (ECR) on 4 March 2011 in Vienna, Austria.
Other important dissemination activities undertaken during the project lifetime of PEDDOSE.NET were the distribution of print material at conferences, to devise articles and press releases on the project, to announce project outcomes and events in the quarterly EIBIR eNewsletter, the ESR eNewsletter and two EIBIR annual reports.
During the EANM Annual Congress 2011, which was held from 15 - 19 October 2011, the project PEDDOSE.NET was presented at the EIBIR booth.
Results of the PEDDOSE.NET project were published in scientific and peer reviewed publications:
2011: Biokinetics and dosimetry of commonly used radiopharmaceuticals in diagnostic nuclear medicine - a review, Uta Eberlein et al. in the European Journal of Nuclear Medicine and Molecular Imaging, online publication in August 2011.
Journal publication: December 2011, 38(12).
http://www.springerlink.com/content/j50177h5p8183p4v/
A particular highlight is the development of 'PedDose' in 2011, an iApp derived from the EANM Pediatric Dosage Card. 'PedDose' is considered as very easy to use in clinical practice, provides for an estimate of the effective dose delivered (according to ICRP references), and proposes a printout of the summary of the procedure (radiopharmaceutical, patient's weight, recommended injected activity and effective dose delivered for a reference patient) that can be appended to the patients file. This application is currently being evaluated for administrative approval by the Apple Store.
Further, an educational Power Point presentation on 'CT radiation exposure in multimodality imaging was developed in 2011, which can be downloaded free of charge from http://www.peddose.net.
Exploitation of results / foregrounds
As the results of the project are mainly reports based on literature surveys there is no potential for future economic exploitation. The results, however, can be exploited for defining future areas of research, for deriving EU-wide recommendations and for education and training.
Project website: http://www.peddose.net
PEDDOSE.NET (see http://www.peddose.net online) was fully supported by the European Association of Nuclear Medicine (EANM, see http://www.eanm.org online) which is the scientific body of nuclear medicine professionals in Europe. Three members of the consortium were also members of the EANM Dosimetry Committee, thus establishing a tight connection to nuclear medicine. The scientific advisory board of the project included representatives from scientific societies and industry associations in the field of nuclear medicine, thus ensuring that the results of the project were disseminated in a timely manner and at a broad level.
The specific objectives of the PEDDOSE.NET support action as requested by the European Commission (EC) were:
- to summarise and evaluate the current knowledge on the impact on patients' health of diagnostic radiopharmaceuticals as currently used in diagnostic imaging procedures;
- to develop recommendations and guidelines to drive scientific and technologic innovation to improve patient healthcare in medical imaging;
- to identify, if clinical studies are needed, and corresponding detailing of the studies;
- to involve people in legislative approval of these agents for human use.
The approach to meet these objectives was to review existing data on biokinetics, dosimetry models and corresponding dose related risks for diagnostic radiopharmaceuticals in children and adults. In addition, the consortium contacted international bodies such as the International Commission on Radiological Protection (ICRP), the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine and Member State radiation protection agencies in order to obtain up-to-date information on the developments in this field. Furthermore, data on imaging device-specific parameters were gathered in order to get information on potential dose reductions with emphasis on paediatric nuclear medicine procedures, and on computed tomography absorbed doses in hybrid scanners.
As a result of the project a set of recommendations were derived. These recommendations will aid the scientific community and the EC in identifying further research areas of research in the field of nuclear medicine dosimetry and patient radiation protection. It might also give guidance to radiopharmaceutical industry on how to improve the clinical trials and the corresponding documentation needed for obtaining marketing authorisation for new compounds.
The dissemination of results was coordinated by EIBIR. During two major European congresses (ECR 2011, EANM 2011) the results of the project were presented in separate pre-congress workshops, of which one (EANM 2011) was the best attended pre-congress event. In addition, one major publication (Eberlein et al, Eur J Nucl Med Mol Imag 2011) summarises the findings of the consortium on behalf of diagnostic nuclear medicine dosimetry. A second publication summarising the view of the consortium on the strong need for standardisation and optimisation of CT protocols for multimodality imaging in nuclear medicine will be submitted soon. Another manuscript on the use of phantoms and computer models in nuclear medicine dosimetry is currently under preparation.
Project context and objectives:
Nuclear medicine contributes significantly to the health, healthcare and quality of life of European citizens, particularly in major clinical areas such as cancer and cardiovascular disease. Every year in Europe over 6 million patients benefit from a nuclear medicine procedure, 95 % of which are diagnostic and 5 % therapeutic. The number of procedures will increase in the coming years, in particular with the increasing number of installed positron emission tomographs (PET) or PET/CT systems and the introduction of new molecules and radiopharmaceuticals through rapid developments in molecular biology and medicine.
In the EU Council Directive 97/43/EURATOM (June 1997), the establishment of a system of reference activities for the major diagnostic procedures has been included. Most of these nuclear medicine procedures, however, are done on an ad-hoc basis; the administered activities vary from country to country. This fact is reflected in the European Association of Nuclear Medicine (EANM) guidelines for diagnostic procedures, in which most of the administered activities vary within a certain range. These issues highlight the need for optimization of the administered activity in nuclear medicine diagnostics.
Diagnostic procedures imply the administration of activity levels that do not lead to the appearance of radiation deterministic effects. This means the stochastic risk associated to the exposure to ionizing radiation cannot be assessed for an individual patient. However, the concept of risk associated to a diagnostic procedure is valid for a population of patients, and requires as a prerequisite the determination of the absorbed dose, i.e. the energy absorbed per unit mass (in Gy) in all irradiated tissues or organs of interest. In a diagnostic context, the determination of the absorbed doses (i.e. a dosimetric study) is required before the introduction of a new radiopharmaceutical to the market (in order to obtain a marketing authorization by the corresponding agencies such as EMEA). This helps to determine the range of activity to inject for the procedure.
'Good practice' also implies to inject the minimum activity compatible with the diagnostic purpose, and to assess the radiation exposure delivered by that amount of activity.
As a summary, the evaluation of the impact on patients' health of small and non- or little repetitive doses (amounts) of radioactive substances, as currently used in diagnostic imaging procedures heavily relies on a precise determination of reference levels of irradiation, since that conditions the quality of data used further for routine diagnostic procedures.
A lot of the absorbed dose data for nuclear medicine diagnostic procedures are older than 20 years and are mainly based upon the ICRP53 tables and their respective addenda. The concepts and methodological advances within the field of internal dosimetry, however, now allow a better assessment of the absorbed doses delivered during nuclear medicine procedures. This is illustrated by the development of new, more representative patient models (in the following denoted as 'phantoms'): The very first phantom to be proposed in the literature for that purpose is the so-called 'reference man'). Since then, many phantoms have been proposed, including children phantoms, gender- or ethnic-specific phantoms.
The situation becomes even worse when considering paediatric nuclear medicine. In a recent publication by Treves et al., the authors identified n the US a broad range of administered doses directly leading to variability in radiation-absorbed doses to patients. The situation is somewhat better in Europe where the paediatrics and dosimetry committees of the EANM published a new dosage card for paediatric nuclear medicine with the aim of keeping the effective dose constant over the age. Uniform weight dependent administered activities are recommended for many procedures. Improvements, however, are needed for the incorporation of new tracers and with respect to technological advances.
Absorbed dose evaluation during routine use of radiopharmaceuticals, if ever performed, is relying on reference models or concepts that have evolved since the time they were established. In addition, the development of new radiopharmaceuticals is limited by the small number of clinical departments able to perform dosimetric studies according to the most recent scientific standards.
Since the introduction of hybrid imaging systems such as PET/CT and SPECT/CT in nuclear medicine departments, both functional and anatomical images can be acquired and merged together very accurately. Unfortunately, the use of these CT images may increase the patient dose considerably, especially if no CT dose optimisation is carried out. Systematic implementation of low-dose CT settings is of particular importance in paediatric nuclear medicine.
The specific objectives of the PEDDOSE.NET support action, as requested by the EC, were:
- to summarise and evaluate the current knowledge on the impact on patients' health of diagnostic radiopharmaceuticals, as currently used in diagnostic imaging procedures;
- to develop recommendations and guidelines to drive scientific and technologic innovation;
- to improve patient healthcare in medical imaging;
- to identify, if clinical studies are needed, and corresponding detailing of the studies; and
- to involve people in legislative approval of these agents for human use.
In order to meet these requirements, the project was divided into several work packages (WPs):
WP 1 dealt with literature reviews and an appraisal of the available dosimetry and epidemiology data for established and new radiopharmaceuticals.
The aim of this WP was to provide an overview of published data on the dosimetry of radiopharmaceuticals as a basis for subsequent recommendations to identify improvements, which are needed for the incorporation of new tracers and with respect to technological advances. This WP also provided an overview of epidemiologic results of the diagnostic administration of radiopharmaceuticals.
WP2 investigated and summarised the status, recommendations and future plans of other bodies regarding radiopharmaceutical dosimetry. ICRP was identified as the most important organisation and their recommendations were the basis for all other bodies. For some frequently used radiopharmaceuticals identified in WP 1 without ICRP recommendations, age-dependent doses were compiled from the literature and their underlying data and the models used to derive them were evaluated. The results of the project were reported to the bodies and may influence their work.
WP 3 summarised the properties of imaging systems with emphasis on potential dose reductions (including hybrid scanners). Data on technical innovations of nuclear medicine imaging systems was provided together with the possibility of reducing patient radiation doses. A critical review was conducted with respect to imaging system sensitivity in order to assess if the sensitivities of the newest generation of nuclear medicine diagnostic devices are such that the current recommendations for the reference activities could be lowered, particularly for children. In addition, it was investigated if a potential reduction of the CT dose in PET/CT and/or SPECT/CT systems could be considered, particularly for paediatric patients.
WP 4 dealt with phantoms and pharmacokinetic modeling for dose delivery.
This WP provided an assessment of existing phantoms and pharmacokinetics modeling for absorbed dose calculations and should lead to the determination of more relevant modeling processes to be used as reference for radiopharmaceutical development.
WP 5 identified the necessity of future clinical trials related to the dosage of radiopharmaceuticals. Within this WP further clinical research need in association with the administration of radiopharmaceuticals was identified and detailed.
WP 6 developed recommendations for patient-specific minimum and maximum activities with particular emphasis on paediatric nuclear medicine as the group of children and adolescents is the most radio-sensitive group of patients.
The objective of WP 7 was to disseminate project results to scientists within and outside the consortium, to healthcare providers and policy makers, and to the public and to establish an exploitation plan for the results obtained in the PEDDOSE.NET project.
Furthermore, general recommendations for the optimisation of reference activities to be approved and disseminated by EIBIR, its co-shareholder, the European association of nuclear medicine, as well as by national authorities should be provided. A final PEDDOSE.NET public workshop was to be organised in order to publicise the project results and to demonstrate and promote the importance and role of diagnostic nuclear medicine at political level, in particular in view of the recent shortage of diagnostic radionuclides.
Project results:
Introduction
The results of the scientific work within the PEDDOSE.NET project were achieved in three major areas:
- appraisal of the available dosimetry and epidemiology data for current and new radiopharmaceuticals
- properties of imaging systems with emphasis on potential dose reductions (including hybrid scanners)
- phantoms and pharmacokinetic modeling for dose delivery.
The latter results were based on a critical review of the scientific literature in each of these areas. Based on these findings, recommendations for future research and improvements in patient radiation protection in nuclear medicine were developed.
Appraisal of the available dosimetry and epidemiology data for current and new radiopharmaceuticals
Dosimetry data on current radiopharmaceuticals
The first part of the project provided an overview of published data on the dosimetry of diagnostic radiopharmaceuticals as a basis for subsequent recommendations.
The literature survey was mostly conducted through PubMed (see http://www.ncbi.nlm.nih.gov/PubMed online) and secondary literature contained in the PubMed references.
The inclusion criteria were:
- publications of official bodies such as the ICRP;
- peer-reviewed journals;
- special conference proceedings containing detailed descriptions on the methodologies on dosimetry.
The search was restricted to the publication date of ICRP 53 (1987) unless there were no other data available.
For presenting the results of our literature review of biokinetic and dosimetry data, we divided radiopharmaceuticals in three categories, namely:
- radiopharmaceuticals having a marketing authorization;
- radiopharmaceuticals well-established in clinical practice;
- radiopharmaceuticals not well-established in clinical practice.
We decided on preparing tables for each category that show the most crucial points with respect to dosimetry. Additionally, PET and non-PET radiopharmaceuticals were considered separately.
In principle, the criteria defined by the EANM dosimetry committee guidance document on good clinical reporting were used:
- Which quantitative imaging method was used, planar, SPECT or PET, and which corrections (e.g. attenuation correction) were applied?
- Are data on biokinetics given; especially detailed information on residence times (time-integrated activity coefficients)?
- When was the last data point of the image acquisition?
- Which bladder voiding intervals were used?
- Are the absorbed doses for the organs listed?
- Which tissue weighting factors were used? Is the effective dose (ED) or the effective dose equivalent listed (EDE)?
- How many volunteers/patients did take part in the dosimetry studies?
- Which computer code was used to calculate the absorbed doses and the effective dose?
- Is there a package insert, in which dosimetry data are given?
The results of this part were published in the European Journal of Nuclear Medicine and Molecular Imaging (Eberlein U., Bröer J. H., Vandevoorde C., Santos P., Bardiès M., Bacher K., Nosske D., Lassmann M. Biokinetics and dosimetry of commonly used radiopharmaceuticals in diagnostic nuclear medicine a review, European Journal of Nuclear Medicine and Molecular Imaging: Volume 38, Issue 12 (2011), Pages 2269 - 2281). In this open access publication the complete information on all radiopharmaceuticals is provided.
In summary it can be stated, that for most commonly used diagnostic radiopharmaceuticals dosimetry data are available, although the data collection and calculation methods are heterogeneous. As some of the data were acquired more than 20 years ago, it would be of interest to generate new data on biokinetics and dosimetry in diagnostic nuclear medicine using state-of-the art equipment and more uniform dosimetry protocols. As the concept of effective dose calculation has changed with ICRP 103 gender-specific dosimetry data will be needed (see sections 4.4 and 5.5). Data for paediatric nuclear medicine are missing in most cases. As some of the references collected for this review are not easily accessible a major conclusions of this work is that, for easier public access to dosimetry data of diagnostic radiopharmaceuticals, a database containing these data should be created and maintained.
New radiopharmaceuticals of potential importance
When considering new radiopharmaceuticals of potential interest one encounters the problem that it is not easy to search for substances with unknown names; therefore, the list of radiopharmaceuticals might be incomplete. However, there is a fast development of many new radiopharmaceuticals; for many of those, it is impossible to judge how important they will be in the near future. In addition, there are older radiopharmaceuticals not mentioned which are gaining importance. In order to find a compromise between new and of potential importance substances, they were included if they fulfilled at least one of the following criteria:
- There is a study about human dosimetry published in 2005 or more recently.
- The substance is on the to do list of the Radiation Dose to Patients from Radiopharmaceuticals Task Group of ICRP.
- The substance could come short term on the market.
- There was an application for a research project filed to the German Federal Office for Radiation Protection in 2011.
The reason for the first criterion was the idea that older substances had enough time to become well established or at least important enough for additional research. The other criteria were chosen to identify substances of potential importance.
To make comparisons easier, radiopharmaceuticals were sorted in one of the three categories neurology, oncology or cardiology and subsequently ordered according to the used radionuclide. As most of the new radiopharmaceuticals are experimental, many dosimetric studies include less than ten subjects. Besides this, the quality of the peer-reviewed studies improved as compared to the ones cited in the first report of this WP, e.g. the majority of studies with PET substances used attenuation correction just as the majority of studies including planar imaging used at least the conjugate view method for more precise measurements.
Unfortunately, for some radiopharmaceuticals developed by companies there are no peer-reviewed studies and therefore the quality of the underlying experimental data cannot be assessed. Also for some radiopharmaceuticals in phase I or phase II only in-vitro / animal data and press releases are available.
For new radiopharmaceuticals, there are no biokinetic or dosimetric studies with children. For an estimate with limited experimental evidence, it is always possible to combine adult residence times with paediatric phantoms or even vary the bladder voiding interval as proposed in ICRP 106, but uncertainties about the paediatric biokinetics remain.
The list of radiopharmaceuticals and further details are available upon request from the project coordinator.
Epidemiological data
A compilation of the existing epidemiological data of the administration of radiopharmaceuticals was undertaken. As very large sample sizes are needed to statistically distinguish radiation induced cancers from the baseline cancer incidence rate at very low absorbed doses, there exist only epidemiologic studies on the diagnostic use of I-131 sodium iodide, for which the thyroid absorbed dose is in the range of 1 Gy. Especially for children and adolescents only few data on I-131 with limited patient numbers can be found. Therefore, it is not possible to make a reliable risk assumption for children and adolescents.
According to these epidemiologic studies, there is no evidence that diagnostic exposure of I-131 causes excessive thyroid cancer cases. For other radiopharmaceuticals used in diagnostic nuclear medicine, the absorbed doses to the organs are too small and are therefore below the detection limit. In this case, theoretical assumptions have to be taken into account. The data for low doses are primarily based on the long-term follow-up of the atomic bomb cohort and are linear extrapolations from high dose exposure (linear no threshold model).
The following examples for theoretical risk assessments using the lifetime attributable risk according to the BEIR VII report were assessed:
- a general model, which takes a reduced life expectancy for special patient groups into account and estimates the reduction of the attributable risk due to the lower life expectancy of the patient compared to the non-patient group;
- cancer risks from breast imaging studies with x-rays and internal radiations;
- cancer risks from myocardial perfusion scans.
These examples provide a new approach to risk assessments in nuclear medicine diagnostics. The respective methodologies should be partly included in future studies describing the radiation risk of radiopharmaceuticals in nuclear medicine.
Properties of imaging systems with emphasis on potential dose reductions (including hybrid scanners)
The impact of new technological developments on image quality and patient doses in multimodality imaging
Technological innovations have led to the appearance of new generations of imaging systems in nuclear medicine. The latter innovations were linked with both improvements in detector architectures (such as solid state detectors, new scintillator materials with time-of-flight capabilities) and reconstruction techniques. This resulted in overall improved detector sensitivities and, as a consequence, in an improvement of the image quality. However, the higher sensitivities could also be used to lower the administered activities to patients.
The literature review on the recent developments in nuclear medicine imaging instrumentation showed that PET and SPECT innovations are mostly announced to be beneficial for the image quality. On the other hand, a lot of authors emphasise on the possibility to reduce the scanning time significantly, without affecting image quality. Only a few publications focused on the potential of these new techniques in reducing patient radiation doses. The latter is especially important for children, who are more sensitive to the adverse effects of radiation exposure compared to adults. Hence, further research in this area should be encouraged, to find an acceptable balance between scan time reduction, image quality improvement and patient radiation dose reduction.
It is important to remark, that most of the existing recommendations for administrated activity in diagnostic nuclear medicine (diagnostic reference levels, EANM paediatric dosage card and the North American consensus guidelines) do not take into account the opportunity to reduce the currently activity levels based on the higher sensitivity of the latest generations of nuclear medicine instrumentation. It should be recommended that, when updating these recommendations, these aspects are taken into account.
Next to the technological innovations in stand-alone nuclear medicine imaging, one of the major developments in the last decade was the introduction of hybrid imaging systems (PET/CT and SPECT/CT). The last years, they have gained wide acceptance in clinical practice and they became one of the fastest growing imaging modalities worldwide. The success of these combined systems is due to their possibility to fuse morphological (CT) and functional (PET or SPECT) information in one examination, to improve the sensitivity and specificity of the diagnostic examination. As the CT acquisition is mostly associated with large patient radiation doses, efforts should be made to reduce and optimize the CT radiation burden. Therefore, CT innovations play also an important role for nuclear medicine diagnostics. In contrast to nuclear medicine instrumentation, where most emphasis is on image quality improvement and scan time reduction, manufacturers are focusing strongly on dose reduction in new CT systems. Unfortunately, the state-of-the-art dose reduction tools are not (always) available on hybrid imaging systems.
Review of CT protocols currently used in hybrid imaging systems
The use of CT in hybrid imaging can be related to:
- attenuation correction;
- anatomic localisation and/or
- the acquisition of additional diagnostic examination.
Depending on the particular application, appropriate CT exposure settings and corresponding dose levels should be selected. An optimised CT scan for the purpose of attenuation correction of the emission data will contribute only for a fraction of the total patient exposure of the complete multimodality study. On the other hand, if CT settings are not optimized, a CT acquisition may contribute to more than 75 % of the total radiation exposure when diagnostic information is required.
The reported effective CT doses for children were similar to the effective doses for adults. Taken into account the higher sensitivity of these patients, an adjustment of the scanning parameters to the smaller size of these patients is necessary. In the case of serial PET/CT scans for follow-up in children, cumulative effective CT doses may amount to more than 300 mSv! Therefore, it is important that the nuclear medicine physician is aware of the radiation dose contribution of the CT examination within the complete examination.
In general, the range in published effective doses for hybrid imaging is very large, indicating a lack of standardisation in CT protocols. An appropriate optimisation of the CT protocols is necessary, taking into account the clinical need, the availability of previous diagnostic CT scans and the age of the patient. Efforts should be made to develop diagnostic reference levels for hybrid devices, in order to give nuclear medicine physicians guidelines to rely on. Such reference levels only exist for conventional diagnostic CT studies, but not for the typical setting of hybrid imaging.
Dose reduction techniques for CT
As CT doses in hybrid imaging may by high in comparison with the radiation dose attributed to the used radiopharmaceutical, appropriate optimization of CT protocols is necessary. Significant dose reductions are feasible by selecting relevant scan parameters corresponding with the requested image quality. In general, the use of low-dose CT protocols in hybrid imaging should be encouraged. Based on the available data, one can conclude that low-dose CT's with a tube current of 10 mA and acquired with a high helical pitch are sufficient for attenuation correction purposes. The latter CT acquisition result in a typical effective dose of less than 1 mSv for a whole body scan. Even then, these CT images may contain useful clinical information. Lowering the kVp-settings of the CT may be another option; however, a possible reduction of these values depends on the used transformation algorithm for constructing the attenuation maps.
The acquisition of diagnostic quality CT should be justified and should take into account the availability of previous CT exams.
In the new(er) CT instruments, dose reduction hardware / software options are available. The automatic tube current modulation will automatically select an appropriate tube current value taking into account the individual anatomy of the patient and taking into account the exact scan location within the patient. Iterative CT data reconstruction, will allow for low-dose scanning without compromising image quality, as the iterative reconstruction algorithm will significantly reduce the noise content in the CT image.
The latter options have proven their efficiency. A combination of automatic tube current modulation and iterative CT reconstruction can reduce the patient CT dose with more than 50 %. Therefore, the implementation and the use of dose reduction options should be strongly encouraged. Unfortunately, most CT systems of hybrid equipment currently in use do not have such state-of-the-art dose reduction tools. Still, patient doses can be optimised taking into account the weight of the individual patient and by scaling the mA-values accordingly.
In order to be able to optimise CT protocols, nuclear medicine physicians should be provided with appropriate educational material to understand the basics principles of CT dosimetry. A summary of these aspects is provided in an educational PowerPoint publication which can be used by the nuclear medicine community. In the latter presentation following issues are addressed:
- Is the CT radiation dose contribution important in multimodality imaging?
- Why are radiation doses from CT imaging high?
- Which quantities are used to describe the CT doses?
- How can we estimate the effective dose of a CT acquisition?
- Which parameters are influencing radiation dose and image quality?
- How can we optimise CT radiation doses for hybrid imaging?
- What are the recent developments with respect to CT dose reduction techniques?
Phantoms and pharmacokinetic modelling for absorbed dose delivery
Literature review on existing absorbed dose approaches that have been implemented
According to the MIRD formalism absorbed dose determination relies on:
- activity (A, in Bq) determination within the patient, at different time after radiopharmaceutical injection, mostly via quantitative scintigraphic imaging even though external counting can also be considered;
- cumulated activity (Ã, in Bq.s) or residence time (tau, in s) assessment from time activity curves;
- dose conversion factor (S, in Gy/Bq.s) for a given set of source-target configuration and for a given isotope.
The first two items are usually considered as a single step, even though they are in fact independent tasks: the most accurate activity determination is of little help when time sampling is wanting.
The last item relies on the definition of computational models (that define the geometry), and radiation transport codes that score the absorbed dose for any type of target defined in the computational model, for a given isotope and a given source-target configuration.
The analysis of a given dosimetric approach will consider the way activity, cumulated activity and S factors are determined, considering the fact that the least accurate parameter will directly impact on the final result.
The publications collected for this project were analysed to identify the method used for calculating absorbed doses. All the authors of the mentioned papers used the MIRD formalism. The dosimetric data used, in terms of specific absorbed fractions (SAF), S-values and dose conversion factors for absorbed dose per unit administered activity, was obtained from different sources, of which the most commonly used were the MIRD pamphlets and dose estimate reports, the ICRP publications and the RADAR website.
An analysis of experimental protocols used to measure cumulated activity from nuclear medicine images was performed. This allowed an assessment of the quality of data gathered on radiopharmaceutical fixation on patient organs, and consequently of biokinetics used for absorbed dose assessment.
Review of phantom characteristics and impact on dosimetric results
Dosimetric data used for absorbed dose calculation reported in ICRP reports 53, 80 and 106 are based on the following models:
- adult male from Snyder et al., 1974 (MIRD Pamphlet No 5 Revised)
- Cristy and Eckerman series of phantoms at various ages
- Stabin et al. computational models for the non-pregnant adult female and at the end of each trimester of pregnancy.
These models are all mathematical models, i.e. designed from equations, and therefore are made of a combination of simple geometric shapes that do not describe very accurately human geometry.
The evolution in the representation of human geometry led to the advent of voxel-based, and then hybrid models.
Computational models have seen a major evolution in the recent past. The transition is not yet finished (S factors tables for new adult models are still not available, and more reference voxel-based models are needed for paediatric or pregnant patients for example).
For adult models, a complete recalculation of S values for the numerous radioisotopes considered for nuclear medicine is important, in order to assess how the voxel-based definition of the anatomy impacts the absorbed dose. This certainly is relevant for overlapping organs, where local cross-irradiation is likely to be significant.
Impact of pharmacokinetics modelling assumptions on dosimetric results
Most available data for 'established' radiopharmaceuticals is old, obtained using sub-optimal methodology (as compared to what's available today). This is especially true for non-PET tracers (i.e. the oldest available data), and to a lesser extent for PET tracers. New tracers in nuclear medicine are mostly involving PET tracers, for which quantitative imaging is considered superior to conventional scintigraphic imaging.
Most published dosimetric data were obtained from a reduced number of patients, which limits the value of the absorbed dose / effective dose figures given.
New radiopharmaceuticals sometimes benefited from methodology improvements, even though the trend is not very strongly established. Hybrid imaging for example, is not as often used as one would hope given the acknowledged advantages introduced by that modality for scintigraphic quantitative imaging.
A careful assessment of acquisition times is required for any given pharmacokinetics study. As could be seen from the literature study, currently available results show variability in that respect. The definition of the last data point should be carefully discussed in the view of the biological behaviour of the tracer, and the physical half-life of the associated isotope.
Biokinetic modelling does impact the dosimetric result, even though this is more apparent for absorbed doses delivered to organs, and less marked for the effective dose. However, within the context of and organ-based risk assessment, absorbed doses delivered to individualised organs or tissues are of paramount importance.
Reporting is a major aspect of any dosimetric study. There may be no standardized reference regarding the way to implement a clinical dosimetry study, however, not carefully mentioning the various steps leading from data acquisition to activity and cumulated activity should be considered as bad practice. This limits the value of dosimetric results presented in most of the articles analysed in this project. There seem to be a trend to better document the way pharmacokinetics was assessed, even though a lot of work still has to be done in that area.
Definition of a list of radiopharmaceutical that would benefit from revised approaches
Absorbed dose calculation via anthropomorphic models has seen major evolutions in the recent past, some of which led to the presentation of new reference computing models for adult male and female (ICRP report 110). The obvious consequence is that of a more accurate representation of human anatomy, which on principle should lead to more accurate absorbed dose calculations.
The present moment is that of a transition phase, where only old dosimetric data are available that correspond to the dosimetric concepts presented in ICRP 60. New reference data to comply with ICRP 103 recommendations are not yet available. This explains why ICRP 106 (published after ICRP 103) presents dosimetric data for radiopharmaceuticals using the ICRP 60 formalism and concepts (computing models, etc.).
Voxel-based description of patient anatomy allows for absorbed dose gradients to be computed within a given organ (voxel-based). This is relevant as long as pharmacokinetics is also defined at the voxel level. Should this not be possible, it is strongly advised to keep expressing results as mean absorbed doses to organs and tissues, as deriving absorbed dose volume histograms from (assumed) homogeneous distributions of activity within a given organ would not provide for correct results, and give a false feeling of accuracy.
Is it realistic to ask for a global revision of available data? It may not be possible to reassess pharmacokinetics for all already available radiopharmaceuticals, even though the quality of past quantification studies may be debatable.
A common sense approach would be to try to increase the quality of pharmacokinetics assessment for new tracers. An obvious limitation is the absence of standardised procedure for activity and cumulated activity determination (both for PET and non-PET tracers). A minimum requirement would be to better document the way activity and cumulated activity was derived, as is proposed in the guidance document published by the EANM Dosimetry Committee.
For paediatric studies, a further point to consider is establishing a balance between the need to cover, as broadly as possible, a range of patients varying in morphology and physiology, and the ethical difficulty to set-up dosimetric studies for paediatric patients as these may induce extra irradiation (CT) with no benefit to the patient.
A last but major point to consider is related to the release of voxel-based computing models. In order to be able to fully account for the optimised spatial resolution of absorbed dose calculation, it is mandatory to be able to determine the activity at the same spatial sampling, i.e. at the voxel level. This certainly will require optimising the quantification procedures, both for PET and SPECT approaches.
Recommendations
Identification of future clinical trials related to the dosage of radiopharmaceuticals
Based on the analysis provided in the previous sections, urgent clinical research is recommended in the following areas:
- Ga-68-Dotatate as it is frequently used and there are no published dosimetry data;
- F-18-Fluoride as the biokinetics measured stopped at very early time-points (< 2 h) and/or are based on partial body measurements only. Some of the published absorbed dose data were taken from a biokinetic model that was not confirmed by a comparison to experimental data;
- confirmatory data on the biokinetics in children and adolescents as most of the dosimetry data in paediatric nuclear medicine assume the same biokinetics in children and in adults.
As there are few existing clinical trials with respect to dosimetry and the associated potential long-term risk of the application of radiopharmaceuticals, a basic template on dosimetry methodology is developed which can be used for setting up such a trial. Part of this template can be inserted into a study protocol of future clinical trials related to diagnostic radiopharmaceuticals and is available upon request.
Need of epidemiological research
As nuclear medicine involves ionising radiation with an associated stochastic risk of radiation damage, it would be of importance to obtain reliable data on the long term effects of the administration of radiopharmaceuticals.
In 2011, a retrospective study on the epidemiology of CT procedures in children started under FP7. It is called 'Epidemiological study to quantify risks for paediatric computerised tomography and to optimise doses' (EPI-CT).
This project will provide direct epidemiological evidence on the potential cancer risk due to low doses of ionising radiation exposure in a large multinational European cohort. It will be the largest and the most statistically powerful study of paediatric CT scans undertaken until to date. The results will contribute to the radiation protection, dose optimisation and low dose radiation research and are awaited for 2015.
However, such a study with the same statistically power would probably not be possible for nuclear medicine for several reasons:
- There are four times less nuclear medicine diagnostic procedures performed as compared to CT procedures (CT and nuclear medicine procedures in 2006 in the US).
- Furthermore, the effective doses of NM-procedures are lower as compared to CT. According to the NCRP Report No. 160 nuclear medicine contributes with 12 % to the collective effective dose compared to CT with 24 % (this applies for the US). However, the effective doses for nuclear medicine might become higher because of the increasing availability and use of hybrid imaging systems.
- The analysis of the existing epidemiological data provided in WPs 1 and 6 showed no evidence of an increased cancer risk associated with nuclear medicine diagnostics.
- Therefore, we cannot recommend performing epidemiological studies involving Nuclear Medicine diagnostics at the present stage. Should the EPI-CT study provide evidence for a radiation-related risk involving CT scans, however, this might need to be reconsidered in the future.
Patient-specific minimum and maximum activities
Many publications deal with the optimisation of diagnostic procedures, most of them on F-18-FDG PET/(CT) using a wide range of administered activities which hampers the comparison of these studies. Using the new technological developments such as hybrid systems, iterative reconstruction algorithms and detectors with higher efficiencies it could be shown that it is possible to reduce the administered activities.
However, the use of more sensitive instrumentation (e.g. 3D-PET, TOF PET) does not automatically result in lowering injected activity levels as these techniques allow for better image quality and reduced scanning times.
- It is recommended to establish standards for calculating the activity to be administered to a patient according to weight (better morphometry), camera systems, reconstruction algorithms and scanning time.
How this can be achieved is shown, for example for PET scanners, by Boellaard et al. and for paediatric nuclear medicine by Sgouros et al.
Imaging device sensitivities and the respective impact on paediatric nuclear medicine
Properties of imaging systems with emphasis on potential dose reduction have been investigated, based on a literature review on the possible impact of new technological innovations in nuclear medicine imaging on patient dose and image quality.
In hybrid imaging devices, the CT phase is contributing significantly to the total effective dose of the complete examination. The currently used CT protocols in hybrid imaging have been reviewed in order to formulate recommendations with respect to CT dose reduction techniques for the nuclear medicine community. In this context, we should keep in mind that every radiation exposure must be medically indicated and that the required image quality is not always the 'best' image quality. A trade-off should be made with respect to image quality improvement, scan time reduction and patient dose reduction.
- There is a severe lack of standardised guidelines on CT protocols for hybrid imaging. The nuclear medicine community should be encouraged to critically review the currently used CT parameters and the corresponding effective dose contribution for the patient.
- There is an urgent need for diagnostic reference levels and their respective justification for hybrid imaging, so that PET/CT and SPECT/CT acquisitions can be performed in a more standardised and unified way. Secondly, the existing recommendations on administered activities should be updated according to the more sensitive and efficient nuclear medicine equipment that exists today.
The new ICRP recommendations and their impact on paediatric nuclear medicine
In the new 2007 ICRP recommendations (ICRP 103), the basic definition of effective dose remains unchanged from the 1990 recommendations (ICRP 60). However, some of the tissue weighting factors have been changed on the basis of new epidemiological data for cancer induction. In fact, instead of taking cancer mortality as a basis for w, in the new recommendations one uses the incidence of radiation-induced cancer as well as the risk of heritable disease over the first two generations. The most significant changes in w are found for breast tissue, gonads and the remainder organs.
ICRP now clearly demands the use of male and female reference voxel phantoms which have been published in ICRP 110. The new concept demands a determination of the equivalent doses in the organs and tissues of the reference male and the reference female separately. In order to obtain the equivalent doses of the reference person, the gender-specific equivalent doses are averaged; hence the new tissue weighting factors can be applied. Moreover, according to ICRP 103, only the latest ICRP voxel phantoms have to be used for the calculations of effective dose. Applying the new weighting factors on a set of equivalent organ doses previously calculated with a mathematical phantom will therefore not result in a correct effective dose value due to ICRP 103. Presently, the modified tissue weighting factors and the subsequent calculation of the effective dose according to the formalism of ICRP 103 cannot be applied to nuclear medicine as the calculations of the S-values for the radiopharmaceuticals using the new recommendations of the ICRP are still missing but are currently performed.
As children of the same age do not necessarily have the same body weight or body morphometry it is not recommended to use only the age of a child as indicator for the activity to be administered.
Still, the current situation is that patients are administered standard levels of activity, although these standards themselves vary from country to country and even from centre to centre.
To avoid this situation for children, in 2007 a new EANM paediatric dosage card was published by Lassmann et al. superseding the old dosage card by Piepsz et al. In the Piepsz dosage card, the fraction of administered activity was calculated according to the body surface area (estimated from body weight) with respect to an adult of 70 kg. However, as the administered activity for adults is not the same within Europe the dosage table results in different and in some cases very high administered activities in children.
In 2011, Gelfand et al. published a North American consensus guideline to harmonise the administered activity in paediatric nuclear medicine in North America. Both cards (EANM and the North American) do not differ very much in terms of recommended amounts of administered activities. However, there are exceptions, for example a difference in the administered activity for I-123-MIBG for children below 10 kg. In this case, the recommended value of the North American consensus guideline is nearly half the value of the recommended EANM value.
Until more measurements or simulations on the influence of patient morphology and pharmacokinetics on image quality are available the use of the current weight-dependent EANM paediatric dosage card is recommended as, for Europe, the EANM dosage card is better adapted to the practice of European nuclear medicine. Should more data become available in the near future efforts should be undertaken to update the EANM dosage card.
Other recommendations
Based on the information provided in previous sections, other general recommendations for further study and research areas were derived:
- Dosimetry data of new radiopharmaceuticals should be published in peer-reviewed journals so that they are publicly available. The EANM dosimetry guidance document on good dosimetry reporting should be considered when publishing.
- An effort to harmonise the diagnostic reference levels for nuclear medicine within Europe should be undertaken. The large differences between European countries can only partially be explained by differences in equipment. Repetitions of national surveys for new national diagnostic reference levels are unlikely to change this situation. An update of the nuclear medicine section of the EU 1999 document RP109 'Guidance on diagnostic reference level for medical exposures' is urgently needed.
- For easier access of the general public to dosimetry and biokinetic data in nuclear medicine the establishment of a publicly available web-based database would overcome the difficulties in finding and accessing the data on radiopharmaceutical dosimetry.
- Urgent efforts should be undertaken to resolve the current situation of the use of ICPR 60 versus ICRP 103 as the data on the phantoms for nuclear medicine to be used in conjunction with the risk factors of ICRP 103 are not publicly available yet.
- There is a need to consider alternative means of assessing stochastic risk such as the use of organ doses and BEIR VII risk models.
- For hybrid imaging (PET/CT, SPECT/CT), the following action items are recommended:
- standardisation of CT-protocols for the different applications such as attenuation correction, localization and diagnostic CT;
- establishment of European CT diagnostic reference levels;
- mandatory use of dose reduction techniques such as iterative reconstruction;
- more studies on image quality for dose reduction techniques.
- More in-depth discussion on new instrumentation within the nuclear medicine community should be started with respect to finding a balance between:
- patient-dose reduction
- image quality improvement
- acquisition time reduction.
- As some of the radiopharmaceuticals applied in nuclear medicine show a very inhomogeneous distribution on a microscopic scale further research on the influence of absorbed dose distributions in this case should be encouraged.
- A standardised teaching and training program should be established for physicians and scientists in nuclear medicine with respect to the:
- need for improved understanding of stochastic risks from ionizing radiation;
- need for better understanding and consideration of CT doses in hybrid imaging;
- need for improved instrumentation and software based dose reduction strategies;
- need for better understanding the limitations of the effective dose concept in medical dosimetry of the patient.
An extension of the concept of this project to radionuclide therapy with their deterministic radiation effects is strongly recommended.
References
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4. Eberlein U., Bröer J. H., Vandevoorde C., Santos P., Bardiès M., Bacher K., et al. Biokinetics and dosimetry of commonly used radiopharmaceuticals in diagnostic nuclear medicine - a review. Eur J Nucl Med Mol Imaging. 2011;38(12):22692281.
5. ICRP. Publication 103: The 2007 recommendations of the International Commission of Radiological Protection. Ann ICRP. 2007;37 (2-4).
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24. National Council on Radiation Protection and Measurements. NCRP Report No. 160, Ionizing Radiation Exposure of the Population of the United States. Bethesda, Md: National Council on Radiation Protection and Measurements. 2009.
25. Boellaard R., Oyen W. J. G., Hoekstra C. J., Hoekstra O. S., Visser E. P., Willemsen A. T., et al. The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials. Eur J Nucl Med Mol Imaging. 2008;35(12):23202333.
26. Boellaard R., O'Doherty M. J., Weber W. A., Mottaghy F. M., Lonsdale M. N., Stroobants S. G., et al. FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. Eur J Nucl Med Mol Imaging. 2010;37(1):181200.
27. Boellaard R. Standards for PET image acquisition and quantitative data analysis. J Nucl Med. 2009;50 Suppl 1:11S20S.
28. Sgouros G., Frey E. C., Bolch W. E., Wayson M. B., Abadia A. F., Treves S. T. An Approach for Balancing Diagnostic Image Quality with Cancer Risk: Application to Pediatric Diagnostic Imaging of 99mTc-Dimercaptosuccinic Acid. J Nucl Med. 2011;52(12):19231929.
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Potential impact:
As this Support Action is based mainly on a review of the available literature and its intention was not to perform research the potential impact of this project is restricted to recommendations to the EC based on the critical evaluation of the available data by applying scientific criteria.
Due to the fact that the MIRD-scheme is state of the art concerning dosimetry and ICRP publications are the de facto international standard there will probably no impact on those who rely on ICRP. The responsible task group of ICRP is aware of the results of this project and is planning to calculate revised absorbed doses for Rb-82 and other radiopharmaceuticals. The absorbed doses for radiopharmaceuticals besides Rb-82 relying on old measurements may be recalculated but without new measurements the data basis for biokinetic models will remain unchanged.
The German Federal Office for Radiation Protection - and possibly also other national bodies - is planning to determine new diagnostic reference levels and will consider the results of this project.
Main dissemination activities
In order to promote PEDDOSE.NET its objectives and research results, general and scientific information were disseminated to diverse recipients - within the relevant scientific groups (e.g. nuclear medicine) as well as in the general and scientific public.
Three public events are noteworthy regarding the dissemination of PEDDOSE.NET project results: project partners organised a final public workshop in the framework of the Annual EANM-Congress in Birmingham, UK in October 2011 under the title 'Do we apply too much radiation in diagnostic nuclear medicine?' and organised and chaired one thematic session under the title 'Practical aspects of CT during the International Conference on Clinical PET and Molecular Nuclear Medicine (IPET-II-2011) - Trends in Clinical PET and Radiopharmaceutical Development' organised by the IAEA in Vienna, AT in November 2011.
Further, a PEDDOSE.NET session on 'Multimodality Imaging: Do we apply too much radiation?' was held during the European Congress of Radiology (ECR) on 4 March 2011 in Vienna, Austria.
Other important dissemination activities undertaken during the project lifetime of PEDDOSE.NET were the distribution of print material at conferences, to devise articles and press releases on the project, to announce project outcomes and events in the quarterly EIBIR eNewsletter, the ESR eNewsletter and two EIBIR annual reports.
During the EANM Annual Congress 2011, which was held from 15 - 19 October 2011, the project PEDDOSE.NET was presented at the EIBIR booth.
Results of the PEDDOSE.NET project were published in scientific and peer reviewed publications:
2011: Biokinetics and dosimetry of commonly used radiopharmaceuticals in diagnostic nuclear medicine - a review, Uta Eberlein et al. in the European Journal of Nuclear Medicine and Molecular Imaging, online publication in August 2011.
Journal publication: December 2011, 38(12).
http://www.springerlink.com/content/j50177h5p8183p4v/
A particular highlight is the development of 'PedDose' in 2011, an iApp derived from the EANM Pediatric Dosage Card. 'PedDose' is considered as very easy to use in clinical practice, provides for an estimate of the effective dose delivered (according to ICRP references), and proposes a printout of the summary of the procedure (radiopharmaceutical, patient's weight, recommended injected activity and effective dose delivered for a reference patient) that can be appended to the patients file. This application is currently being evaluated for administrative approval by the Apple Store.
Further, an educational Power Point presentation on 'CT radiation exposure in multimodality imaging was developed in 2011, which can be downloaded free of charge from http://www.peddose.net.
Exploitation of results / foregrounds
As the results of the project are mainly reports based on literature surveys there is no potential for future economic exploitation. The results, however, can be exploited for defining future areas of research, for deriving EU-wide recommendations and for education and training.
Project website: http://www.peddose.net
