European Nuclear Medicine Guide
Test
Theranostics in a broad sense means to detect or measure a key modification or landmark of a disease prior to treat or inhibit the specific modification. The key modification can be a genetic mutation leading to a signal pathway activation, receptor overexpression or any other hallmark of disease.
The fundamentals for theranostic thinking in a broader sense were published in a white paper of the FDA 2004 “Challenge and Opportunity on the Critical Path to New Medical Technologies” [1]. It was written since the “medical product development process is no longer able to keep pace with basic scientific innovation” and aimed to bring innovation faster and with more biological understanding to the individual patient disease. Since then many companion diagnostics to modern oncology treatments have been developed for example as PD – L1 Immunohistochemistry for Pembrolizumab (Merck/MSD, New Jersey, USA) in lung cancer or the BRAF V600 real-time PCR for Vemurafenib/Cobimetinib (Roche Pharma, Basel, Switzerland) in malignant melanoma. These diagnostic tests and many more were accepted by the FDA [2]. and linked to the respective treatment and as a consequence are theranostic procedures.
Theranostics in Nuclear Medicine means more specifically to visualize a target with diagnostic radiopharmaceuticals prior to treat using a therapeutic radiopharmaceutical targeting the same structure [3]. The first and still one of the most effective theranostic approaches in Nuclear Medicine is the treatment of thyroid diseases. Specific iodine uptake over the sodium-iodine symporter (NIS) is the exclusive metabolic hallmark of thyroid cells [4]. Therefore, iodine-123 and iodine-131 can be used as diagnostic and therapeutic pair isotopes. Iodine-123 emits gamma rays and visualizes thyroid tissue and iodine-131 depletes the same tissue by 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 applies also for hyperthyroidism in case of functional adenomas or refractory Graves’ disease [6].
The modern development of theranostics in Nuclear Medicine mainly focuses on three distinctive paths 1) to find an optimal pair of a diagnostic/therapeutic nuclides, 2) to find optimal theranostic carriers e.g. peptides, small molecules or antibodies and 3) to perform well-defined controlled trials to understand the real value of nuclear medicine theranostics.
Many years Iodine-123/Iodine-131 was the only clinically used theranostic pair. Recently, much effort was given to establish new pairs for example diagnostic PET imaging nuclides to have more precise and quantitative imaging or therapeutic alpha-particle emitting nuclides with more linear energy transfer (LET). Even though this is a very important area of research, the most commonly clinically used theranostic nuclide combination (but not a direct isotopic pair) outside of iodine still is Gallium –68/Lutetium–177 and more rarely Gallium–68/Actinium–225. The lack of new and innovative pairs in theranostics for clinical use as for example Scandium-44/Scandium-47, Copper-64/Copper-67 or Terbium-152/Terbium-161 has many reasons, most importantly the relatively costly infrastructure to develop and maintain new radio-nuclides, the complex good manufacture production (GMP) process for such radioisotopes, the complex supply routes for such radiopharmaceuticals and the lack of clinically valid superiority studies for these new theranostic pairs versus established combinations such as Gallium-68/Lutetium-177.
Besides optimal physical properties of new radioisotopes, the development of new targeting molecules, peptides or proteins as carriers for such theranostic pairs has been in the centre of latest research. A nuclear medicine theranostic target should be A) to the best of all means be disease specific B) accessible via an injected radiotracer (e.g. cell surface receptor) and C) must be stably expressed over time and in most (or all) of the metastases.
Despite the rising knowledge, ongoing randomized trials Van Overmeire, E., et al., Hypoxia and tumor-associated macrophages: A deadly alliance in support of tumor progression. 2014. 3(1): p. e27561.
[7,8]. and public interest, many open questions remain. One challenging point is the need of individual dosimetry for personalized therapy [9]. Indeed, in interventional procedures as liver radioembolisation, the need for each patient’s dosimetry is proven to lead to significant improvements in cure rate and overall survival [10,11]. In other procedures like PRRT in neuroendocrine neoplasms and prostate cancer the scientific background for individual dosimetry is less clear and mainly derived from retrospective analysis [12,13]. After initial dosimetry, which can be seen as analogy to phase I trials, phase II and III studies are mainly performed using standard activities. This is in one hand very useful, since the treatment can be made available for a maximum number of patients without the need for time consuming dosimetry procedures, however the real value and a chance for theranostics to have a maximum impact on oncology may be lost. The ultimate goal of theranostics should be to skip the phase III paradigm. We probably do not need hundreds of patients to treat with theranostic treatments since we aim to predict outcome. It is a missed opportunity to skip the prediction individual outcome as with treatment planning in external beam radiation. We run into the risk of need of costly and time-consuming large phase III trials, which might be over-powered, and only large pharma companies have the financing possibility to perform such trials. Of course, we need randomized trials, but the extensive and costly phase III paradigm needs to be challenged in the light of theranostic thinking.
Another challenge is to embrace the theranostics potential in the light of modern oncology developments. The main improvement of future oncology will come by cure of carefully selected patients receiving immune oncology (IO) treatments [14]. To cope with this rapidly evolving development our strict nuclear medicine theranostic “search the target and kill the target” thinking might be thought too short and excludes nuclear medicine from this exciting IO development. Theranostics must be seen as in the initial thinking by the FDA, to guide a following treatment. The need for a strict diagnostic and therapeutic concept of nuclear medicine restricts us from having the highest impact in modern medicine.
Theranostics needs to be seen as most precise 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 defined by 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 as macrophage polarization and therefore are 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].
In line with this thinking to expand theranostics to IO treatment, we face new challenges. First, and most importantly, resistance of the TME is not driven only by one parameter but is a multitude of inhibitory receptors and cell types [19]. Second, trials showing the benefit of such imaging measurements are highly complicated and demand, also ethically, a very complex trial design. Third, socioeconomic studies need to be performed validating successfully if we can augment the clinical effectiveness or drastically reduce overall cost of IO treatments by excluding the right patients by biomarker imaging results.
Besides these latter three challenges the question remains if guiding immunotherapy by visualizing the target finally remains a true form of theranostics. If we look at the initial foundation of theranostics in the meaning of the FDA to accelerate drug production by better prediction of outcomes in the individual patient, certainly yes, but does it also apply for nuclear medicine theranostics? To expand the paradigm of theranostics in the context of immunotherapy in cancer the term “Immunotheranostics” has been recently introduced. It means to modulate the TME by nuclear medicine theranostic treatment to overcome its local anti-inflammatory barrier and to make it more accessible to IO therapy with the ultimate goal to rise the percentage of cure by this exciting therapy option.
Overall theranostics is a concept to measure a target prior to treating the target. It applies for many different treatments also outside nuclear medicine. Nuclear medicine theranostics means to visualize a target using diagnostic radiopharmaceuticals prior to treat the same target using therapeutic radiopharmaceuticals. It leveraged nuclear medicine to one of the most important partners to clinical oncology. Still, challenges and opportunities remain. Most importantly, besides large trials, nuclear medicine needs to be prepared to enter this large and competitive clinical arena. We have to work especially on how to train our young physicians to have a full spectrum clinical background to mandate this highly important treatment platform for all patients, which might profit from this treatment. The opportunity is to bring a safe, effective and highly fascinating nuclear medicine therapy to our patients.