Radiation safety of current European practices of therapeutic nuclear medicine: survey results from 20 HERCA countries

The purpose of this study was to acquire up-to-date information on nuclear medicine treatments in Europe and on the implementation of the requirements of the Basic Safety Standards Directive in HERCA Heads of the European Radiological Protection Competent Authorities (HERCAs) member states. An electronic survey was distributed to competent authorities of 32 HERCA member states. The questionnaire addressed 33 explicitly considered treatments using 13 different radionuclides, and for each treatment, a similar set of questions was included. Questions covered the use of treatments, hospitalisation of patients and radioactive waste management related to therapeutic nuclear medicine involving other radionuclides than the well-known 131I. The survey also covered justification of treatments, individual treatment planning, involvement of a medical physics expert (MPE) and radiation protection instructions given to the patient at the time of release. Responses were obtained from 20 HERCA countries. All of these countries used Na[131I]I for benign thyroid diseases and thyroid ablation of adults. 223RaCl2 (Xofigo®) for bone metastases, 177Lu-somatostatin analogues for neuroendocrine tumours and 177Lu-labelled PSMA for castration resistant prostate cancer (PC) and PC-metastases were used in 90%, 65% and 55% of countries, respectively. Only a few countries had specific criteria for hospitalisation and waste management for new therapeutic nuclear medicine. Regulatory requirements for justification of new therapeutic nuclear medicine were in place in almost all countries. Individual treatment planning was required for all therapies in 55% and for some therapies in 28% of the responding countries. Implementation of the requirement for MPEs to be closely involved in nuclear medicine practices varied to a great extend among countries. Almost all responding countries answered that some radiation protection instructions existed for patients released after treatment with radionuclides other than 131I treatment, however only few countries had developed specific guidelines in the field.


Introduction
Therapeutic nuclear medicine comprises of either metabolically active radiopharmaceuticals such as radioiodine, specifically binding radiopharmaceuticals (compounds that bind to specific antigens or receptors) or locoregional therapies (e.g. microspheres administered locally for the treatment of hepatocellular carcinoma and liver metastases). A summary of the current situation in Europe on developments of therapeutic use of radionuclides is available in the EC publication Radiation Protection 194 EU Scientific Seminar November 2019 'Developments in nuclear medicine-new radioisotopes in use and associated challenges' [1].
Previously in 2015, variations in the practice of molecular radiotherapy and in the implementation of dosimetry were surveyed focusing on treatments given among 26 European countries [2]. However, new treatments have been developed and implemented since 2015 and some of the treatments that were only rarely performed then have become common practices in Europe.
The European Council Directive 2013/59/EURATOM BSSD [3] defines the legal requirements for radiation protection of individuals undergoing medical exposures in the EU. Each EU member state had to transpose the requirements of the BSSD into national legislation by the 6th of February 2018. International safety standards on radiation protection and safety concerning nuclear medicine, including treatment rooms and their shielding, are given in the IAEA Specific Safety Guide No. 46 [4].
Special attention was given to the implementation of the articles of the BSSD on justification and individual treatment planning in nuclear medicine. According to Article 19.1, the member states shall ensure that the new classes or types of practices resulting in exposure to ionizing radiation are justified before being adopted. Moreover, all individual medical exposures shall be justified in advance taking into account the specific objectives of the exposure and the characteristics of the individual involved (Article 55.2 b). According to Article 56.1, for all medical exposure of patients for radiotherapeutic purposes (including nuclear medicine for therapeutic purposes), exposures of target volumes shall be individually planned and their delivery appropriately verified taking into account that doses to non-target volumes and tissues shall be as low as reasonably achievable and consistent with the intended radiotherapeutic purpose of the exposure. The requirement for therapeutic nuclear medicine to include the individual treatment planning already existed in the former directive on medical exposure 97/43/Euratom, but publication of the BSSD increased the awareness of the need of the evaluation of the doses to the target volumes and other organ at risk amongst regulators. EANM published a report on the potential for personalised, dosimetry-based treatment planning and verification of the absorbed dose delivered in 2017 [5].
Article 56.6 of the BSSD defines the requirements on providing the patient or their representative with radiation protection instructions before leaving the hospital or clinic or a similar institution. There are five main international guidelines for radiation protection measures during and following radionuclide therapies: The EU Radiation Protection 97 'Radiation Protection following Iodine-131 therapy (exposures due to out-patients or discharged in-patients)' [6], the ICRP Publication 94 'Release of patients after therapy with unsealed radionuclides' [7], the ICRP publication 140 'Radiological protection in therapy with radiopharmaceuticals' [8], the IAEA Safety Report Series No. 63 'Release of Patients After Radionuclide Therapy' [9] that was prepared together with the ICRP Committee three members and the HERCA guideline: 131I therapy: Patient release criteria [10] and a template for a HERCA release card [11]. Four of these guidelines were published more than 10 years ago and thus do not cover radiation protection for the latest radionuclide therapies. However, all these guidelines are well established, and the radiation protection principles and methodology are still applicable in many cases especially in radionuclide therapies involving beta and gamma radiation.
Article 58 (d) (i) of the BSSD states that a MPE is required to be appropriately involved in medical radiological practices, the level of involvement being commensurate with the radiological risk posed by the practice. The levels for the involvement of the MPE in radiotherapeutic practices are 'involved' and 'closely involved' depending on whether the therapeutic nuclear medicine practice is standardised or not. The BSSD does not specify 'standardized' practices. However, EANM has recently published a position paper on implementation of the BSSD requirement [12]. The BSSD does not stipulate the meaning of 'involved' and 'cosely involved' and what level of involvement should be applied to which radionuclide therapy.
In European countries, there are separate competent authorities for regulating radiation protection, radiopharmaceuticals or pharmaceuticals and medical devices, including CE marking, respectively. This means, that in several countries there are split responsibilities in relation to licensing of use of radiopharmaceuticals, with the radiation protection authorities covering the radiation protection aspects, while pharmaceutical issues are covered by other competent authorities. HERCA is a voluntary association in which the heads of the radiation protection authorities work together in order to identify common issues and propose practical solutions for them.

Patient hospitalisation and waste management
In 65% of the 20 responding countries there is a general regulatory requirement, enforcing the patient to be hospitalized in a separate and shielded room after administration of a radionuclide, if it is suspected that a reference criterium for dose to members of the public or workers might be exceeded. The most common reference criterium derived from the regulation was in 55% of responding countries a national dose limit (for members of public 1 mSv according to the BSSD) or a dose constraint and in 15% a dose rate limitation that varied from 5 to 30 µSv per hour at 1 m distance from the patient. Only few countries had treatment specific criteria for hospitalisation (figure 2) and radioactive waste management (figure 3). Two countries had given examples of specific criteria for the waste water (table 3).

Justification of new therapeutic nuclear medicine
Regulatory requirements for justification of new therapeutic nuclear medicine were in place, not in place and in progress in 85%, 5% and 10% of the 20 responding countries, respectively. A couple radiation protection  authorities stated that other authorities are also involved in the justification of use of therapeutic nuclear medicine such as Ministry of Health.

Individual treatment planning and treatment verification
Individual treatment planning was required for all radionuclide therapies, for some therapies or not required at all in 55%, 30% and 15% of the 20 responding countries, respectively. Dosimetry was known to be used in 85% of 20 responding countries related to at least one of the following radiotherapeutic procedures: 90 Y-labelled resin microspheres (SIR-Spheres) for intra-arterial treatments in the liver, 131 I for benign thyroid diseases, 131 I-mIBG treatments, 166 Ho-labelled microspheres for hepatic treatments, 177 Lu for neuroendocrine tumours, 177 Lu-labelled PSMA and for many other radionuclides used in an experimental setting. It was not required to use a software tool provided by the manufacturer in 85% of the 17 responding countries. It was required to consider doses to non-target and target volumes and/or tissues in individual planning for some therapies in respectively 65% (n = 13) and 80% (n = 16) of the responding countries. Verification of delivery of the treatment for some radionuclide therapies was required and not required in 45% and 30%, respectively, while the situation was not known in 25% of the 20 responding countries. Measurements were required to be part of the verification and not required in 45% and 50%, respectively, while the situation was not known in 5% of the 20 responding countries. Non-target volumes were required to be verified, not required and not known in respectively 30%, 65% and 5% of the 20 responding countries.
The extent of use among the responding countries of different dosimetry guidelines is shown in figure 4. Other guidelines were from SNMMI, DIN Standards Committee Radiology (NAR), MIRD and British Nuclear Medicines Society. Moreover, available scientific publications about specific cases were mentioned.

Involvement of a MPE
The involvement of MPE is often related to non-standardized radionuclide therapies. However, most countries had not defined 'standardized' therapies. Some countries gave examples of standardized radionuclide therapies among which there were treatments with 89 Sr, 90  There were many different interpretations for the MPE to be 'closely involved' stated by the BSSD. The following expressions were used by the responding countries to clarify the involvement: 'available without delay' , 'being present during treatment' , 'involved in different steps, but not required during the dose delivery' , 'involved in the individual planning' , 'involved in patient discharge' , 'present in the hospital and reachable by phone and informed in advance that a therapy will take place' , 'to verify and validate on paper the activity to be administered to each individual patient' , 'after each administration to calculate as precise as possible, the tumor dose, organ doses and effective dose for the patient (and her unborn child)' , 'to be available for emergencies and to be involved in the lab activity' , 'part time worker at least 50%' , 'does regular site visit to perform the duties' , 'daily interaction with the radiation therapy team and to be on site for at least part of the standard working day and available for consultation during extended working days and weekends' .

Radiation protection instructions
For radiation safety different kinds of instructions are needed according to the BSSD. Instructions concerning the passing away and cremation of patients shortly after the administration of radionuclides, existed in 70%  and 65% respectively of the responding countries. All countries except one answered that radiation protection instructions exist for patients released after administration of radionuclides other than Na[ 131 I]I. However, in only very few countries specific guidelines were developed. It was also mentioned that a patient release card with information on the treatment is one option in addition to other instructions. In this case the card could include contact information of a medical practitioner or the practitioner might delegate this responsibility to an assigned collaborator, e.g. a medical physicist or a radiation protection officer.

Discussion
The use of therapeutic nuclear medicine has been increasing and new radionuclide therapies have been widely developed and implemented internationally [13]. The development in Europe during the last five years in routine or in clinical trials is in line with the international trends. The major increase is in the use of [ 177 Lu]Lu-PSMA-617 therapy for castration resistant prostate cancer and PC-metastases. The previously mentioned survey of Sjögreen et al [2] was sent to individual clinics and therefore the actual use of specific treatments at country level may be underestimated. This may cause some uncertainties into the estimated change during 2015-2020.
There are general criteria for requiring the patient to be hospitalized in a separate and shielded room after administration of a therapeutic radionuclide, however, treatment specific criteria are less prevalent. The responses to the survey showed that, for example, [ 177 Lu]Lu-PSMA-617 therapy of castration resistant prostate cancer and PC-metastases was given in 11 countries, however specific criteria for this therapy were only available in seven countries requiring hospitalisation and in four countries with radioactive waste water requirements for this therapy.
Justification was well regulated, however the process of justification and examples of assessments of justification were not surveyed in this study. Instead, HERCA has previously raised awareness of justification in multilateral discussions with professional societies and organized training for inspectors on inspection methods. Some radiation protection authorities reported that other authorities are also involved in the justification of use of therapeutic nuclear medicine, such as medicine authorities for pharmaceuticals. In Europe the responsibilities of different authorities are defined in the European Directives.
Requirements for individual treatment planning were not fully in place. Interpretation of the requirement of the BSSD for individual patient dosimetry is still not well developed. Lack of tools and knowledge can be a factor in whether it is undertaken. However, new insights on dosimetry have been published [14][15][16] that could help to improve implementation of the dosimetry requirements of the BSSD.
The involvement of MPEs for dosimetry was not explicitly defined and regulated in most countries. This may be one reason for the no or minor involvement of MPEs in 32% of clinics that was reported by Sjögreen et al [2]. If an MPE is not involved the likelihood for performing dosimetry within new therapeutic nuclear medicine is low.
The implementation of the requirements of the BSSD concerning the therapeutic nuclear medicine varies a lot from country to country. It was also reported by the competent authorities that the BSSD is not clear on the use of the words 'standardized therapy' , because there are no harmonized standards. In relation to the involvement of MPEs the graded approach is used, however, 'closely involved' has been interpreted differently by the competent authorities and interpretations were sometimes even contradicting.
HERCA has previously focused on radiation protection issues of therapies including production of guidelines on patient release criteria after administration of 131 I [10]. In this study, the emphasis was on new therapeutic nuclear medicine. This study demonstrates that general radiation protection guidelines exist, however treatment specific guidelines are rare.

Conclusions
An increase of use of therapeutic nuclear medicine within the past 5 years is concluded from this survey. The use of therapeutic nuclear medicine covers both routine use and clinical trials in this analysis.
The Even though all national regulations in HERCA countries are based on the BSSD, national regulations are country specific, and several important differences exist. General criteria for hospitalisation after an administration of a r radionuclide and for radioactive waste water management exist, but treatment specific criteria are rare.
Justification is well regulated taking into account both general and individual justification. Some authorities reported that there are also other authorities involved in justification, such as Ministry of Health.
Requirements for individual treatment planning and verification of delivery of the treatment for some radionuclide therapies were not fully in place. However, in 85% of responding 20 countries dosimetry was performed for individual treatment planning at least for one radiotherapeutic procedure. EANM dosimetry guidelines were the guidelines most commonly reported to be used.
There does not seem to be any major change in the involvement of MPEs and in the performance of dosimetry compared to the survey by Sjögreen et al [2] despite of the transposition of the latest BSSD into national legislation.
General radiation protection instructions exist for patients released after administration of other radionuclide than 131 I, however only few countries had developed specific guidelines. HERCA has previously developed a template for a patient release card that can be applied for new treatments as well.

Data availability statements
The data generated and/or analysed during the current study are not publicly available for legal/ethical reasons but are available from the corresponding author on reasonable request. The work was carried out as an ad hoc task of the HERCA work by competent authorities without specific funding. Ethics approval and consent to participate were not applicable.

HERCA WG MA, WP Nuclear Medicine, Survey
The objectives of this HERCA survey on nuclear medicine are: (a) To collect up-to-date information about nuclear medicine treatments in Europe. (b) To survey regulatory requirements for hospitalisation and release criteria of patients after treatments involving radionuclides other than I-131 to improve common understanding among HERCA countries. This includes also the requirements for waste management after a therapy. Surveys compliance with General Data Protection Regulation (GDPR): The privacy statement can be found from the STUK website at: www.stuk.fi/en/web/en/about-us/data-protection-at-stuk.

Instructions for filling in the survey
This survey is for HERCA authorities and one answer per a country is expected.
The survey is an on-line survey consisting of seven sections (A-G) with total of 152 questions (not all questions are shown by default). There are multiple choices for most of the questions. Mandatory fields are marked with * . By choosing 'Save & continue later' (optional), you will have new weblink to continue answering later. When your answers are ready/after final question choose SUBMIT. After that you can see your answers and also save the results for own use.
Here are detailed instructions for answering the questions Section A: In the participant's data (question 3) an agreement is sought to publish the results of this survey. The purpose is to present results in a way that the situation in Europe could be compared. For that aim also country names would be presented. In case this would not be preferable the second option is to publish the data anonymised without names of the countries, but this might also jeopardise the goals of this survey. The third option is not to support publishing the data.
Section B: There are five options to answer the question 4: The first options is that the treatment is used routinely, the second option is that there are clinical trials on this treatment in the country, the third option is that there is other kind of use such as compassionate use, the fourth option is that this treatment is not used and the fifth option is that it is not known if these treatments are used. There is a list of 33 different treatments.
Section C: Living rules means instructions that are given at a hospital for a radionuclide therapy patient before releasing the patient.
Section E: Dosimetry means here determination of an absorbed dose. Dosimetry does not mean a calculation of an activity to be delivered based on for example patient's weight or BMI.
Section G: Here information is gathered on existence of guidelines. Actual guides may be gathered later by HERCA.

Organisation(s)
First name Last name E-mail

If dose constrains are used what are they for members of the public and for carers and comforters
Member of the public (not carer or comforter) Pregnant women Children up to two years old Children between three and ten years old Children older than ten and adults up to 60 years old (average population) Adults older that 60 years

List other groups and their constrains (mSv/year) or (mSv/episode)?
Is hospitalisation of the patient specifically required in the following therapy?