Theranostics in Nuclear Medicine: Historical, Regulatory, and Evidence Context for the Practicing Nuclear Medicine Physician.

Re: “ACR/ABR Clinical Statement on Credentialing and Privileging of Radiologists for Diagnostic Nuclear Medicine, Including Multimodality Hybrid Imaging”

Theranostics refers to the pairing of diagnostic biomarkers with therapeutic agents that share a specific target in diseased cells or tissues. Nuclear medicine, particularly with regard to applications in oncology, is currently one of the greatest components of the theranostic concept in clinical and research scenarios. Theranostics in nuclear medicine, or nuclear theranostics, refers to the use of radioactive compounds to image biologic phenomena by means of expression of specific disease targets such as cell surface receptors or membrane transporters, and then to use specifically designed agents to deliver ionizing radiation to the tissues that express these targets. The nuclear theranostic approach has sparked increasing interest and gained importance in parallel to the growth in molecular imaging and personalized medicine, helping to provide customized management for various diseases; improving patient selection, prediction of response and toxicity, and determination of prognosis; and avoiding futile and costly diagnostic examinations and treatment of many diseases. The authors provide an overview of theranostic approaches in nuclear medicine, starting with a review of the main concepts and unique features of nuclear theranostics and aided by a retrospective discussion of the progress of theranostic agents since early applications, with illustrative cases emphasizing the imaging features. Advanced concepts regarding the role of fluorine 18-fluorodeoxyglucose PET in theranostics, as well as developments in and future directions of theranostics, are discussed. ©RSNA, 2020 See discussion on this article by Greenspan and Jadvar.

The field of nuclear theranostic clinical trials is continuously expanding as an increasing number of novel agents and treatment combinations are explored for treating advanced and metastatic cancers. Moving from 'bench-to-bedside' is oftentimes a complex and lengthy process. The objective of this overview is to explore the basic elements involved in designing clinical trials with a special focus on theranostics in nuclear medicine. The 'bench-to-bedside' journey involves translating basic scientific research into patient-effective treatments. Preclinical studies, a crucial initial step, are a complex process encompassing in vitro experiments, in vivo studies, and animal models to explore hypotheses in humans. Clinical trials follow, with predefined phases assessing safety, effectiveness, and comparisons to existing treatments. This process demands investments in data management, statistics, good clinical practice (GCP) accreditations, and collaborative efforts for funding and sustainable pricing. Theranostics, merging diagnostics and personalized treatment, is at the forefront. Continuous efforts to enhance existing agents involve reducing adverse effects, exploring new indications, and incorporating advanced imaging modalities. Radionuclide therapy, unique with non-uniform distribution and complex radiobiology, plays a distinct role. This article explores trends and challenges in each clinical trial phase in light of the emerging field of theranostics in nuclear medicine, emphasizing meticulous trial design, dosimetry optimization, and the necessity of collaborative stakeholder efforts for successful implementation.

Some time in the early 2000s, the word “theranostics” (or “theragnostics”) started surfacing in the medical literature. Theranostics (from the Greek therapeuein “to treat medically” and gnosis “knowledge”) is the use of individual patient-level biological information in choosing the optimal therapy for that individual [1]. In the modern era of “personalized medicine”, theranostics is increasingly pursued in many branches of medicine in order to develop ever more effective treatment regimens. There are now many studies and reviews dedicated to theranostics, and even a journal bearing the name of this principle, detailing many different concepts on how to combine imaging and therapy using, for example, complex molecules [2] or nanotechnology [3]. However, it is rarely realized by either clinicians or scientists that nuclear medicine has been employing theranostics for nearly 80 years now. In fact, the very foundations of targeted therapy in nuclear medicine are those that are only now being adopted by other medical disciplines under the designation “theranostics”. The cornerstones of theranostics can be traced back to some of the most illustrious names among the founding fathers of nuclear medicine. Soon after Chiewitz and de Hevesy [4] described the uptake of radioactive P in the bones of rats, Erf and J.H. Lawrence (brother of the physicist Ernest O. Lawrence, who built the first cyclotron) applied this same radioisotope to patients suffering from leukaemia and polycythaemia vera [5]. Although this treatment certainly was not without success, it has since been superseded by more effective nonradioactive chemotherapy. Shortly afterwards Pecher [6] discovered that Sr accumulated in secondary bone tumours in animals, and subsequently successfully used this radioisotope to treat patients with painful bone metastases (unfortunately this work was immediately classified as secret and it took more than five decades for Sr to be registered as a therapeutic drug). These two studies are perhaps the earliest examples of diagnostic studies leading to targeted therapy of cancer using radionuclides. Around the same time the most prominent example of pure nuclear theranostic medicine emerged: the diagnosis and treatment of thyroid disorders using various isotopes of iodine. Hertz et al. in 1938 described the first study of thyroidal radioiodine uptake [7], and in 1942 Hertz and Roberts reported on the treatment of the first patients with Graves’ disease with radioiodine [8]. A short time later Seidlin et al. treated the first patient with metastatic thyroid cancer with radioiodine [9] – at the time this compoundwas so rare that radioiodinewas purified from the patient’s urine and readministered. During this therapy, additional metastases were identified using a Geiger counter and the first rudimentary dosimetry was performed. It is of course only with the benefit of hindsight that we can now say that this was the first application of theranostics in targeted molecular medicine through a specific molecular target, the sodium iodine symporter, long before any of these concepts were first described as “theranostics”. Indeed, even today it is hard to think of a single combination of targeted diagnostics and therapy that is more specific than radioiodine. F. A. Verburg (*) :A. Heinzel : F. M. Mottaghy Department of Nuclear Medicine, RWTH University Hospital Aachen, Pauwelsstrase 30, 52074 Aachen, Germany e-mail: fverburg@ukaachen.de

Background: Prostate-specific membrane antigen (PSMA) is not sufficiently overexpressed in a small proportion of prostate cancer (PCa) patients, who require other strategies for imaging and/or treatment. We reviewed potential targets other than PSMA for PCa theranostics in nuclear medicine that have already been tested in humans. Methods: We performed a systematic web search in the PubMed and Cochrane databases, with no time restrictions by pooling terms (“prostate cancer”, “prostatic neoplasms”) and (“radioligand”, “radiotracer”). Included articles were clinical studies. The results were synthetized by the target type. Results: We included 38 studies on six different targets: gastrin-releasing peptide receptors (GRPRs) (n = 23), androgen receptor (n = 11), somatostatin receptors (n = 6), urokinase plasminogen activator surface receptor (n = 4), fibroblast activation protein (n = 2 studies) and integrin receptors (n = 1). GRPRs, the most studied target, has a lower expression in high-grade PCa, CRPC and bone metastases. Its use might be of higher interest in treating earlier stages of PCa or low-grade PCa. Radiolabeled fibroblast activation protein inhibitors were the most recent and promising molecules, but specific studies reporting their interest in PCa are needed. Conclusion: Theranostics in nuclear medicine will continue to develop in the future, especially for PCa patients. Targets other than PSMA exist and deserve to be promoted.

Radiologists and nuclear medicine physicians are medical imaging specialists involved in visualization of organs of the human body, nevertheless they practice disciplines that are sufficiently different and distinct for them to only rarely have a real opportunity to communicate or exchange information. In the past, there was essentially an ‘entente cordiale’ in which each discipline performed its own imaging separately: anatomical and morphological for radiologists and metabolic and functional for nuclear medicine physicians. These two disciplines worked side by side and were complementary, but never felt a real need for collaboration as their diagnostic objectives were different; although both guided by the same concern to perform optimal imaging, each discipline working independently. At the end of the 1990s, budget constraints in French hospitals led to the creation of Imaging Departments in order to group expensive equipment in the same department whenever possible. Nuclear medicine has continued to grow and develop, often fully integrated within the Imaging Department, but continuing to independently manage its own specificities. This integration process suddenly accelerated with the arrival of new hybrid positron emission tomography (PET)-computed tomography (CT) machines simultaneously combining the two modalities each of which represented a real revolution in the well-defined context of hospital medical imaging. The impact of this revolution, which is still exerting its effects today, was even more dramatic in that it was twofold. First, nuclear medicine had to adapt to a new type of tomography gamma-camera possessing detection capacities relating to particular technical specificities, and the use of a new radioisotope, fluorine-18, very different from technetium-99m which had been used for several decades. Second and more important, nuclear medicine physicians had to look at CT scans without necessarily interpreting them, while radiologists had to deal with conventional nuclear medicine imaging derived from positron emission tomography. The anatomical correlation achieved by image fusion, the strong point of PET-CT imaging, had to be acquired simultaneously and harmoniously by radiologists and nuclear medicine physicians, who each provided their own contribution. Even today, although these machines are increasingly available and their use in oncology has become more clearly defined, dual interpretation by radiologists and nuclear medicine physicians still raises organizational difficulties, especially when contrast-enhanced CT images are used for PET image fusion[1]. This results in essential upstream consequences affecting the technique of each imaging modality, both in terms of scanning parameter selection and training of radiology and nuclear medicine personnel authorised to perform these examinations. At the end of the chain, interpretation of purely CT images by a specialized radiologist and conventional nuclear medicine images by a nuclear medicine physician is essential, in view of the possibility of artefacts, false-positives and false-negatives, as imaging of glucose metabolism is based on comparison of the morphological and pathological features observed on CT. A multidisciplinary approach is almost mandatory in order to provide medically irreproachable results legally signed by skilled professionals. It is the role of scientific societies and radiology and nuclear medicine associations to propose guidelines integrating all of these criteria by organizing joint working parties, as is already the case in the United States[2]. We are therefore participating in a revolution in the field of medical imaging that can be considered to be a cultural revolution, in which each party must redefine its position and its role in patient management, in hospital rounds and in the priority of diagnostic examinations[3]. These new activities promise a fascinating future, in which the diagnostic capacities in oncology will be even further improved.

Curriculum for education and training of Medical Physicists in Nuclear Medicine: Recommendations from the EANM Physics Committee, the EANM Dosimetry Committee and EFOMP

IAEA Support to Medical Physics in Nuclear Medicine

The Asia-Pacific region, comprising more than half of the world's population, includes both developed and developing nations. Understanding the current status of nuclear medicine (NM) and theranostics in this dynamic region is essential for identifying strengths and weaknesses and for establishing a roadmap for future NM development both regionally and globally. The International Atomic Energy Agency (IAEA) conducted this survey to achieve these goals. Diverse data acquisition resources were employed to enroll eligible countries from the Asia-Pacific region. The NM staff per million population was calculated to assess the density for each NM specialty. Statistical analyses, including normality tests and the Mann‒Whitney U test, were performed via Stata version 17. Approximately 62% of the countries offer nuclear medicine services, mainly in Western Asia and Southeast Asia. Eastern Asian countries constitute more than two-thirds of all NM centers and cyclotrons in the region. Specifically, Japan also has the highest number of NMs, centers, and cyclotrons and SPECT density. Currently, only 30 countries provide radionuclide therapy and practice NM theranostics. Japan, Australia, Kuwait, and South Korea are among the countries with abundant NM staff per million people. Compared with developing countries, developed Asia-Pacific countries provide significantly more NM services (p value: 0.0001). The study reveals considerable variability among Asia-Pacific countries. Nearly half of the surveyed countries do not practice theranostics, and lack radiopharmacists. Building collaborations between model countries and those lacking NM services is crucial to enhancing theranostic practice and availability.

From Nuclear Medicine to Nuclear Medicine Theranostics.

Trends and Different Educational Pathways for Training Physicians in Nuclear Medicine

I059] Working in radiotherapy from the perspective of a nuclear medicine physicist

Somatostatin receptors expressed on tumor cells form the rationale for somatostatin analog treatment of patients with somatostatin receptor-positive neuroendocrine tumors. Nevertheless, although somatostatin analogs effectively control hormonal hypersecretion by GH-secreting pituitary adenomas, islet cell tumors, and carcinoid tumors, significant differences are observed among patients with respect to the efficacy of treatment. This may be related to a differential expression of somatostatin receptor subtypes among tumors. In addition, the property of somatostatin receptor subtypes to undergo agonist-induced internalization has important consequences for visualizing, as well as for therapy, of receptor-positive tumors using radioisotope- or chemotherapeutic-compound-coupled somatostatin analogs. This review covers the pathophysiological role of somatostatin receptor subtypes in determining the efficacy of treatment of patients with somatostatin receptor-positive tumors using somatostatin analogs, as well as the preclinical and clinical consequences of agonist-induced receptor internalization for somatostatin receptor-targeted radio- and chemotherapy. Herein, the development and potential role of novel somatostatin analogs is discussed.

PurposeTo evaluate the Dutch integrated nuclear medicine and radiology residency program from the perspective of nuclear medicine physicians and radiologists.MethodsA survey was distributed among nuclear medicine physicians and radiologists in hospitals that participate in the Dutch integrated nuclear medicine and radiology training program.ResultsA total of 139 completed questionnaires were included. Nuclear medicine physicians (n = 36) assigned a mean score of 5.7 ± 2.0, and radiologists (n = 103) assigned a mean score of 6.5 ± 2.8 (on a 1–10 scale) to the success of the integrated training program in their hospital. On multiple regression, female gender of the survey participant (B = 2.22, P = 0.034), musculoskeletal radiology as subspecialty of the survey participant (B = 3.36, P = 0.032), and the survey participant’s expectancy of resident’s ability to handle workload after completion of residency were significantly associated with perceived success of the integrated training program (B = 1.16, P = 0.023). Perceived strengths of the integrated training program included broadening of expertise, a better preparation of future imaging specialists for hybrid imaging, increased efficiency in training residents, and increased efficiency in multidisciplinary meetings. Perceived weaknesses of the integrated training program included reduced exposure to nuclear medicine, less time for research and innovation, and concerns about its international recognition.ConclusionThis study provided insights into the experiences of nuclear medicine physicians and radiologists with the Dutch integrated nuclear medicine and radiology residency program, which may be helpful to improve the program and similar residency programs in other countries.

BackgroundIt is important that referring physicians and other treating clinicians properly understand the final reports from diagnostic tests. The aim of the study was to investigate whether referring physicians interpret a final report for a myocardial perfusion scintigraphy (MPS) test in the same way that the reading nuclear medicine physician intended.MethodsAfter viewing final reports containing only typical clinical verbiage and images, physicians in nuclear medicine and referring physicians (physicians in cardiology, internal medicine, and general practitioners) independently classified 60 MPS tests for the presence versus absence of ischemia/infarction according to objective grades of 1–5 (1 = No ischemia/infarction, 2 = Probably no ischemia/infarction 3 = Equivocal, 4 = Probable ischemia/infarction, and 5 = Certain ischemia/infarction). When ischemia and/or infarction were thought to be present in the left ventricle, all physicians were also asked to mark the involved segments based on the 17-segment model.ResultsThere was good diagnostic agreement between physicians in nuclear medicine and referring physicians when assessing the general presence versus absence of both ischemia and infarction (median squared kappa coefficient of 0.92 for both). However, when using the 17-segment model, compared to the physicians in nuclear medicine, 12 of 23 referring physicians underestimated the extent of ischemic area while 6 underestimated and 1 overestimated the extent of infarcted area.ConclusionsWhereas referring physicians gain a good understanding of the general presence versus absence of ischemia and infarction from MPS test reports, they often underestimate the extent of any ischemic or infarcted areas. This may have adverse clinical consequences and thus the language in final reports from MPS tests might be further improved and standardized.