European Nuclear Medicine Guide
Broadly speaking, theranostics means detecting or measuring a key modification or landmark of a disease prior to treating or inhibiting this specific modification. The key modification can be a genetic mutation leading to activation of a signal pathway, receptor overexpression or any other hallmark of disease.
The fundamentals of the theranostic approach in a broader sense were published in a 2004 white paper by the FDA (U.S. Food and Drug Administration), “Challenge and Opportunity on the Critical Path to New Medical Technologies” [1]. It was written due to the conviction that the “medical product development process is no longer able to keep pace with basic scientific innovation”, and aimed to accelerate innovation along with greater biological understanding of the individual patient’s disease. Since then, many companion diagnostics for modern oncology treatments have been developed, for example PD – L1 Immunohistochemistry for Pembrolizumab (Merck/MSD, New Jersey, USA) for lung cancer or the BRAF V600 real-time PCR for Vemurafenib/Cobimetinib (Roche Pharma, Basel, Switzerland) for malignant melanoma. These diagnostic tests and many more were accepted by the FDA [2] in association with the respective treatment, and as a consequence have now become theranostic procedures.
In nuclear medicine, theranostics in most cases more specifically means visualizing a target with diagnostic radiopharmaceuticals prior to treatment using a therapeutic radiopharmaceutical targeting the same structure [3]. The first and still one of the most effective theranostic approaches in nuclear medicine is used in the treatment of thyroid diseases. Specific iodine uptake via the sodium-iodine symporter (NIS) is the exclusive metabolic hallmark of thyroid cells [4], therefore iodine-123 or a low activity of therapeutic I-131 can be used for diagnostic purposes to guide iodine-131 as treatment. Iodine-123 emits gamma rays and visualizes thyroid tissue, and iodine-131 depletes the same tissue through high-dose local electron radiation. Examples are high-risk thyroid carcinomas, where iodine-123 is used to visualize a thyroid remnant and iodine-131 depletes the latter tissue [5]. The same principle also applies for hyperthyroidism in functional adenomas or refractory Graves’ disease [6].
The modern development of theranostics in nuclear medicine mainly focuses on three distinctive paths: 1) finding an optimal pair of a diagnostic/therapeutic radionuclides, 2) finding optimal theranostic carriers e.g. peptides, small molecules or antibodies, and 3) performing well-defined controlled trials to understand the real value of nuclear medicine theranostics.
For many years, iodine-123/iodine-131 or 99mTc-MAA/90Y microspheres for radioembolization, 111In-Octreoscan/90Y-DOTA-TOC and TATE were the most clinically used theranostic pair. Recently, much effort has been devoted to establishing new pairs, e.g. diagnostic PET imaging nuclides for more precise and quantitative imaging, or therapeutic alpha-particle-emitting nuclides with greater linear energy transfer (LET). Even though this is a very important area of research, the most common theranostic nuclide combination (but not a direct isotopic pair) in clinical use, besides iodine, is still gallium–68/lutetium–177. Recently, however, new pairs have come under investigation, including gallium–68/actinium–225, lead-203/lead-212, or therbium-152/155 for imaging and therbium-149/161 for radionuclide therapy. Further innovative pairs in theranostics and interesting candidates for clinical use are scandium-44/scandium-47 or copper-64/copper-67. Despite these new options and interesting perspectives, phase three trials have to show superiority to more classical theranostic pairs or prove their efficacy after lutetium base treatment.
Besides the optimal physical properties of new radionuclides, the development of new targeting molecules, peptides or proteins as carriers for such theranostic pairs has been at the centre of the latest research. A nuclear medicine theranostic target should be A) as far as possible disease specific or tumour microenvironment specific B) accessible via an injected radiotracer (e.g. cell surface receptor) and C) stably expressed over time and in most (or all) of the metastases.
Despite the huge interest shown by the pharmaceutical industry, the intriguing clinical results and the generally low toxicity profile, some hurdles remain. One ongoing debate centres on the need for individual dosimetry for personalized therapy [9]. Indeed, in interventional procedures such as liver radioembolization, the need for individualized dosimetry for each patient is proven to lead to significant improvements in cure rate and overall survival [10,11]. In other procedures like peptide receptor radionuclide therapy in neuroendocrine neoplasms and peptide receptor ligand therapy in prostate cancer, the scientific background for individual dosimetry is currently not proven in prospective trials and is mainly derived from retrospective analysis [12,13]. Although such findings are interesting in a conceptual way, at the same time we have to understand what dosimetry in nuclear medicine means on a biological basis. In the absence of such an understanding and of phase III trials in radioligand therapy guided by dosimetry, we have to be cautious about mandating such unproven concepts. Another challenge is to embrace theranostics’ potential in the light of modern oncology developments. The main improvement in future oncology will come from carefully selected patients receiving immune oncology (IO) treatments [14]. In the light of this rapidly evolving field, nuclear medicine theranostics’ strict “search for and kill the target” mindset might be perceived as being too narrow, and excludes nuclear medicine from these exciting IO developments. Theranostics must be seen, as in the initial thinking by the FDA, to guide the subsequent treatment. The need for a strict diagnostic and therapeutic concept of nuclear medicine restricts us from having the greatest impact in modern medicine.
There is a need to consider theranostics as an accurate tool for personalized medicine. Molecular imaging in nuclear medicine overcomes the restrictions of local biopsy, since we generally perform whole-body (or partial-body) diagnostic imaging and it can also be easily repeated over time. The success of IO treatment is highly dependent on the host’s local tumour microenvironment (TME), which varies in each metastasis and is also highly variable inside a given tumoral lesion [15]. Factors like local hypoxia, for example, drive resistance mechanisms such as macrophage polarization and are therefore site-specific and time-dependent [16]. Only molecular imaging can embrace these spatial changes over time. We therefore need to rethink the theranostic paradigm and extend it to oncology in the context of personalized medicine in a broader sense. For example, first trials to assess PD-L1 or PD1 expression have been performed and show better prediction of outcome than standard immunohistochemistry [17,18].
This approach of expanding theranostics to IO treatment throws up new challenges. First, and most importantly, resistance of the TME is not driven solely by one parameter, but by a multitude of inhibitory receptors and cell types [19]. Second, trials showing the benefit of such imaging measurements are highly complicated and call for a very complex trial design, not least with regard to the ethical considerations. Third, socioeconomic studies need to be performed to validate whether we can augment the clinical effectiveness or drastically reduce the overall cost of IO treatments by excluding the right patients on the basis of biomarker imaging results.
Besides these latter challenges, the question remains whether guiding immunotherapy by visualizing the target ultimately remains a true form of theranostics. If we look at the initial foundation of theranostics as defined by the FDA, i.e. to accelerate drug production by better prediction of outcomes in the individual patient, certainly yes, but does that also apply for nuclear medicine theranostics? To expand the paradigm of theranostics in the context of immunotherapy in cancer, the term “immunotheranostics” has recently been introduced. It means using nuclear medicine theranostic treatment to modulate the TME, overcome its local anti-inflammatory barrier and make it more accessible to IO therapy, the ultimate goal being to increase the cure rate by means of this exciting therapy option.
Generally speaking, theranostics is the concept of measuring a target prior to treating that target. It applies to many different treatments, including those outside nuclear medicine. Nuclear medicine theranostics means visualizing a target using diagnostic radiopharmaceuticals prior to treating the same target using therapeutic radiopharmaceuticals. It has made nuclear medicine one of the most important partners of clinical oncology. Still, challenges and opportunities remain. Most importantly, besides conducting large trials, nuclear medicine needs to be prepared to enter this large and competitive clinical arena. We have to focus especially on how to train our young physicians to have a full-spectrum clinical background, in order to mandate this highly important treatment platform for all patients who might benefit from it. We need to leverage this opportunity to bring a safe, effective and highly fascinating nuclear medicine therapy to our patients.