Radiation protection in therapy with radiopharmaceuticals.

PURPOSE
Radionuclide therapy (RNT) involves the selective delivery of radiation, emitted from radionuclides to tumors or target organs. The techniques of RNT are increasingly being used for the treatment of various tumors. The purpose of this article is to report on the current state of RNT, to clarify the issues of radiation protection associated with RNT, and to show future prospects.


RESULTS AND CONCLUSIONS
Medical exposure of patients has unique features; application of dose limits is not undertaken, and justification and optimization do apply but in a different way from in other exposures. The expanding use of RNT has raised concern regarding potential carcinogenic and leukemogenic effects and research on second primary cancer after RNT have been developing. RNT combined with imaging and dosimetry and featuring a theranostic approach is undergoing a significant expansion, and such dosimetry-based treatment planning leads to individualization, or personalization, which is likely to improve the effectiveness and safety of patient management in RNT.


Introduction
Radionuclide therapy (RNT), also named targeted radionuclide therapy (TRT) or nuclear medicine therapy, involves the selective delivery of radiation, emitted from radionuclides, to tumors or target organs (Chatal and Hoefnagel 1999;Zukotynski et al. 2016). RNT is lately called molecular radiotherapy (MRT) by some researchers to stress its characteristics of irradiation therapy and the necessity of radiation dosimetry (Eberlein et al. 2017;Stokke et al. 2017). One of the most representative radionuclide therapies is that using iodine-131 ( 131 I) for the treatment of thyroid diseases (Bonnema and Hegedus 2012;Pryma and Mandel 2014;Luster et al. 2017). The earliest practices of radioiodine therapy in oncology were undertaken in the 1940s, when physicians started treating patients with metastases of differentiated thyroid cancer by administering therapeutic dose of radioiodine. In a report on an application of radioiodine therapy early years, radioiodine comprising iodine-130 ( 130 I) and 131 I that were produced by a cyclotron dedicated to medical purpose (Seidlin et al. 1946;Siegel 1999). In contrast with the RNT method using radioiodine which does not need a carrier for the delivery of the radionuclide, some RNTs use high-affinity molecules as carriers for the delivery of radiation, and such radiolabeled compounds for radionuclide therapy, or therapeutic radiopharmaceuticals, are usually administered orally, intravenously, intra-arterially, or even intracavitarily, and reach their target, that is, a target molecule on the surface of tumor cells or sometimes normal cells, and directly interacts with these cells. Some radiopharmaceuticals enter inside the cells and others remain on the surface of the cells. Monoclonal antibodies have thought to be efficient carrier molecules for the radionuclides to be delivered to the targets. Therapy with radiolabeled antibodies, also named radioimmunotherapy (RIT), has been a mainstream of RNT in preclinical and clinical studies for a long time. Among RIT agents that were tried to clinical application, yttrium-90 ( 90 Y)-ibritumomab tiuxetan, a radiolabeled anti-CD20 monoclonal antibody, was the first RIT agent to receive Food and Drug Administration approval in the USA in 2002 for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin lymphoma (NHL) (Wagner et al. 2002;Wiseman et al. 2003;Witzig et al. 2007). This 90 Y-ibritumomab tiuxetan was followed in 2003 by 131 I-tositumomab, which is also a radiolabeled anti-CD20 monoclonal antibody for the treatment of B-cell NHL (Kaminski 2007).
Recently, the techniques of RNT are increasingly being used for the treatment of various tumors using novel radionuclides, compounds, chelating agents, and application. Examples of recently developed methods that are in clinical practices include lutetium-177 ( 177 Lu)-labeled peptides for therapy of neuroendocrine tumors (Bodei et al. 2010), including 177 Lu-DOTATATE (Burki 2017;Strosberg and Krenning 2017), which was approved in EU in 2017 and in the USA in 2018. Radium-223 ( 223 Ra) dichloride has been recently introduced in clinical practices for the treatment of castrationresistant prostate cancer with bone metastases (Parker et al. 2013;Parker et al. 2018). Importantly, 223 Ra is the first alphaemitting radionuclide that has shown safety and efficacy for the treatment of cancer patients, and received approval in 2013 in the USA and EU.

Features of radiation protection in medicine
Radiation protection in medicine covers in principle, medical exposure, occupational exposure, and public exposure in association with various clinical circumstances. Medical exposure involves not only patients but also their comforters and carers, and volunteers in biomedical research. Medical exposure of patients has unique features that affect how the fundamental principles are applied (ICRP 2007a(ICRP , 2007b. Application of dose limits, which is one of the fundamental principles of radiation protection elsewhere, is not undertaken in medical exposure. This is because, such dose limits would often do more harm than good in the course of treating patients. Two fundamental principles of general radiation protection, justification, and optimization apply in medicine in a different way. Justification in radiation protection of patients is unique in that the very same subject enjoys the benefits and suffers the risks associated with a radiological procedure. Optimization of protection for patients is also unique in that radiation therapy gives intentional radiation for the purpose of treatment, and diagnostic procedures give the benefit and the risk to the same subjects. Therapy with radiopharmaceuticals, namely RNT, requires deliberate radiation protection standards as it uses unsealed radionuclides and gives therapeutic radiation doses in humans.

Second primary cancer in radionuclide therapy
The expanding use of RNT has raised concern regarding potential carcinogenic and leukemogenic effects (Hakala et al. 2016;Martinez et al. 2017). Research on second primary cancer after RNT has been developing especially on 131 I therapy for hyperthyroidism and differentiated thyroid cancer. To date, 131 I therapy for hyperthyroidism has not been associated with an elevated risk of cancer mortality, while evidence has been accumulated that 131 I therapy for differentiated thyroid cancer is associated with an elevated risk of solid cancers and hematological malignancies.
The conclusions reported in a study involving 35,593 hyperthyroid patients (Ron et al. 1998) are a consensus on the safety of 131 I therapy regarding potential second malignancy. The study reported that 131 I therapy did not result in a significantly increased risk of total cancer mortality, while there was an elevated risk of thyroid cancer mortality. However, the excess number of deaths was small and underlying thyroid disease appeared to play a role. And, the authors concluded 131 I therapy appeared to be a safe therapy for hyperthyroidism.
In contrast to 131 I therapy for hyperthyroidism, that for differentiated thyroid cancer appeared to be associated with a statistically elevated risk of malignancies (Rubino et al. 2003). The dose-response relationships were linear, which illustrated that a treatment of 3.7 GBq of 131 I could theoretically induce an excess of 53 solid malignant tumors and 3 leukemias, in 10,000 patients during 10 y of follow-up. However, another study reported that there was no statistical difference in risk of second primary cancer between highand low-doses of 131 I for the treatment of differentiated thyroid cancer (Ko et al. 2015). As of now, the general consensus on the risk associated with 131 I therapy seems that the evidence of serious risks associated with the therapy is weak and contradictory, and then, the potential risk of adverse effects must be weighed against the risk of dying from recurrent thyroid cancer (which is >8% in a 30-year followup period of patients not treated with 131 I therapy) (Blumhardt et al. 2014).

From radionuclide therapy to theranostics
Theranostics means generally a method of combining diagnosis and therapy and enhancing the efficacy and safety of procedures to an individual patient. In nuclear medicine, theranostics usually refers to a combination of imaging and RNT in oncological nuclear medicine (Moek et al. 2017). The use of radiopharmaceuticals for imaging and therapy, consisting of novel radionuclides, including alpha emitters, conjugated with compounds or probes, has been increasing for the management of various tumors. Such application of radiopharmaceuticals is considered as an example of theranostic approaches (Choudhury and Gupta 2017;Eberlein et al. 2017;Nitipir et al. 2017). Conventional imaging and treatment of 131 I therapy for differentiated thyroid cancer, and Zevalin therapy with indium-111 ( 111 In) antibody and 90 Y antibody to B-cell non-Hodgkin's lymphoma can be examples of theranostics. And nowadays, the combination of 68 Ga-labeled somatostatin analogs and the 90 Y-or 177 Lulabeled counterparts for neuroendocrine tumors (Bodei et al. 2010) is an effective theranostic approach and the combination of Ga-68 ( 68 Ga)-labeled PSMA (prostate-specific membrane antigen) ligands and 177 Lu-labeled or actinium-225 ( 225 Ac)-labeled counterparts for prostate cancer (Kratochwil et al. 2018).

Dosimetry-guided personalized therapy
Such theranostic procedures are currently attracting attention in nuclear medicine. The implementation of a series of somatostatin receptor imaging and PRRT (peptide receptor radionuclide therapy) for neuroendocrine tumors have proved to be promising, and a large-scale clinical trial of 177 Lu-DOTATATE against neuroendocrine tumors has been conducted (Strosberg and Krenning 2017;Hosono et al. 2018), which lead to the approval of the radiopharmaceuticals in 2017 as above. However, imaging with 68 Ga-labeled PSMA ligands and RNT with 177 Lu-labeled PSMA ligands in the management of prostate cancer are currently being conducted at an increasing number of hospitals across the globe. A study of clinical application of alpha-emitting 225 Ac-labeled PSMA ligand, reporting good tumor response in advanced prostate cancer, gave a great impact to the world (Kratochwil et al. 2018). RNT using alpha emitters (Targeted Alpha Therapy, TAT) has attracted much attention due to high linear energy transfer and relative biological effectiveness of 3-5 (Sgouros et al. 2010). From the viewpoint of radiation protection, the radiation weighting factor for alpha particles is 20 (ICRP 2007a). In these procedures, dosimetry based on imaging is critical in the research and development of procedures and also in clinical applications by guiding subsequent RNTs. Moreover, dosimetry for alpha-emitter therapy requires studies on the microscopic distribution of emitters due to a short range of a few cell diameter. Methods of micro-dosimetry should be established by considering the distribution and kinetics of the alphaemitting radiopharmaceuticals (Sgouros et al. 2011). Dosimetry-guided practices will have significant implications for the evolution of RNT (Figure 1). And such dosimetryguided approach enhances the aspects of RNT as radiotherapy, which will lead to diffusion of the concept of molecular radiotherapy (MRT). The European directive on basic safety standards (Council directive 2013/59 Euratom) mandates dosimetry-based treatment planning for radiation therapies including radiopharmaceutical therapies, and the directive came into operation in February 2018. There are arguments on the role of dosimetry in RNT. The board of European Association of Nuclear Medicine stressed that although dosimetry is an undisputed aspect of radiopharmaceutical development, its clinical use to tailor the administered activity to an individual patient should be clarified through further evidence (Giammarile et al. 2017). Whatever is the role of dosimetry, the methodologies of dosimetry by means of imaging techniques need to be established for the sake of development and clinical application of RNT (Flux et al. 2017;Stokke et al. 2017).

Conclusions
RNT combined with imaging and dosimetry and featuring a theranostic approach is undergoing a significant expansion, and such dosimetry-based treatment planning is already an established standard in some clinical circumstances. The processes of individualization, or personalization, are likely to improve the effectiveness and safety of patient management in RNT (Stokke et al. 2017).

Disclosure statement
No potential conflict of interest was reported by the authors.