Abstract
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.
Introduction
Theranostics in nuclear medicine is the unique combination of radionuclide-based agents used for both diagnostic and therapeutic purposes. The first described example of a theranostic is the radio-iodine treatment in both benign and malignant thyroid disease. Since the introduction of radio-iodine-based theranostics, new theranostic agents have been explored. Some have proven their success, such as metaiodobencylguanide-based treatment for adrenal disease, peptide-receptor radionuclide therapy (PRRT) in neuroendocrine tumors, and more recently, prostate-specific membrane antigen (PSMA)-peptide-based treatment in prostate cancer. Conversely, many other potential theranostics proved unsuccessful, oftentimes in early preclinical phases, yet some failed in advanced clinical trials.
There is a growing interest in exploring novel theranostic agents for various advanced and metastatic cancers, including combination therapies and innovative targets (Bodei et al. 2022). Advances in hybrid imaging, such as the combination of single photon emission computed tomography (SPECT) with CT and positron emission tomography (PET) with CT or MRI, are propelling the growth of theranostics. These developments enhance cancer detection and monitoring, with the potential to optimize cancer diagnosis, personalized treatment, and ultimately, patient outcomes (Howlader et al. 2020, Markham et al. 2020).
Clinical trials are fundamental for assessing new treatments and follow structured phases (preclinical phase, phase 0, phase I, phase II, and phase III). These phases evaluate safety and toxicity, effectiveness, and short-term adverse events and risks associated with the treatment. Regulatory approval marks the beginning of phase IV trials, which are conducted to determine long-term safety and effectiveness and to identify adverse events that may not have been apparent in prior trials. Organizations such as the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) maintain strict standards for biomedical research throughout the drug development process, including clinical trials (Umscheid et al. 2011, Bighelli & Barbui 2012).
In this overview, we explore theranostic considerations within each phase, highlighting aspects such as patient selection, imaging modalities, therapy strategies, and outcome measures, aiming to provide tools for future theranostic trial designs.
Preclinical phase and phase 0: exploratory and ‘first-in-human’
Preclinical studies play a crucial role in the development of therapeutic agents, aiming to predict their effect in humans. In the context of radionuclide therapy, these studies focus on comprehending three key aspects: biodistribution (how the drug is distributed in the body), tissue retention, and pharmacokinetics (how the drug is metabolized and excreted). These factors are critical in determining both the potential effectiveness and potential toxicity of the treatment in humans. Of note, toxicity is generally related to the absorbed dose in non-target tissue. The potential pharmacologic toxicity of the carrying agent is usually considered low as the amount of agent administered is generally in the order of just micrograms. Dosimetry studies are of utmost importance to address the absorbed dose in both target and non-target tissue and hence to evaluate the potential radiobiological effects of consequent radionuclide therapy.
In the preclinical phase, experiments start in vitro with cell cultures and tissues, enabling researchers to observe processes at the cellular level using imaging. Following this, in vivo model systems come into play, typically in small animal rodents, which can include cell-line-based models, patient-derived xenograft models, and genetically engineered mouse models, for example (Langdon 2012, Tentler et al. 2012). Small animals can be evaluated with imaging techniques that are comparable to those routinely applied in clinical settings, such as animal PET, SPECT, CT, and/or MRI (Timpson et al. 2011).
In nuclear medicine, small-animal imaging is required to assess the biodistribution and pharmacokinetics of therapeutic agents in preclinical studies. However, it is essential to note that nuclear medicine imaging cannot distinguish between intact carrier-associated radioactive agents and dissociated free radioactive agents. Therefore, complementary in vitro and in vivo competitive inhibition and control studies are needed (Sgouros et al. 2014).
As phase 0 progresses to the initiation of phase I clinical trials, the activities to be administered are calculated based on the absorbed dose to the dose-limiting organ and the tolerance absorbed dose values. Currently, these dosimetry approaches are based on experiences and models for external beam radiotherapy in humans for that particular organ. As experiences with targeted radionuclide therapy increase, important differences with respect to external beam therapy-based dosimetry are being discovered, however. Preclinical studies serve as the critical foundation that ensures a safe and effective transition from the laboratory to the clinical application of radionuclide therapy (Emami et al. 1991, Bentzen et al. 2010).
Methodological requirement for radionuclide therapy
Quality control of radiopharmaceuticals
In Europe, both diagnostic and therapeutic radiopharmaceuticals, including investigational medicinal products used in clinical trials, are required to adhere to good manufacturing practices (GMP) during the production process (Decristoforo et al. 2021). These GMP guidelines are essential to ensure the safety, efficacy, and consistency of radiopharmaceuticals. To produce radiopharmaceuticals in line with GMP, several critical requirements must be met (Elsinga et al. 2010).
Moreover, the final radiopharmaceutical must undergo a thorough analysis to ensure it meets pharmacopoeial standards. This analysis involves verifying the identity of materials and checking the certificate of analysis for sterility, radioactivity, purity, stability, and other factors such as batch size, appearance, and shelf-life (Verbruggen et al. 2008).
Stability assays play a vital role in this process, as they help determine a radiopharmaceutical's stability under typical storage conditions for a specified shelf life. It is crucial for a radiopharmaceutical formulation to retain its properties, including purity and its affinity for the intended target. Over time, radiopharmaceuticals may aggregate, deteriorate, undergo radiolysis, experience changes in their properties during storage, or (when used in vivo) undergo enzymatic degradation. A lack of stability can significantly impact both scientific results, clinical effectiveness, and safety (e.g. adverse events) of these products (International Atomic Energy Agency 2023).
Dosimetry
The International Atomic Energy Agency has formulated basic safety standards requiring the optimization of protection and safety for each medical exposure, including the administration of radiopharmaceuticals for therapeutic purposes. The type and activity of the radiopharmaceutical administered to each patient have to be appropriate. The dosimetry calculations performed should account for patient-to-patient variation in pharmacokinetics and anatomy. In radionuclide therapy, dosimetry can be divided into two main aspects: pretherapy and posttherapy, as well as target (e.g. tumor) and non-target (e.g. healthy tissue/organs and bone marrow). Pretherapy dosimetry is crucial for treatment planning and predicting biodistribution, while post-treatment dosimetry can quantify the actual effective half-life and absorbed target- and non-target doses. In fractionated therapies, dosimetry guides (personalized) subsequent cycles, adjusting doses or stopping the treatment. Lesional dosimetry aims to deliver a predetermined radiation dose to a tumor while maintaining a safe absorbed dose in non-target tissue. The rationale behind lesional dosimetry is that the absorbed dose by the tumor may have a direct relationship with the response. Currently, the most commonly utilized lesional dosimetry is performed in locoregional radionuclide therapies, such as selective intra-arterial liver-directed radionuclide therapy. On the other hand, systemically administered radionuclide therapies may not consistently achieve the desired absorbed dose in every tumor without causing toxicity to non-target organs. The maximum targeted activity dosimetry aims to administer the highest safe activity while avoiding toxic dose concentrations, especially in organs at risk (Lawhn-Heath et al. 2022).
The absorbed radiation dose, as measured in the SI unit Gray (Gy, J/kg), relies on factors such as the rate of radioactive decay, the energy emitted, tissue retention time, tissue volume, and the energy deposited in the tumor or organ. To calculate the absorbed dose, multiple measurements in time are generally necessary for evaluating pharmaceutical uptake, retention, and washout. These measurements result in time–activity curves for which the area-under-the-curve is used for estimating the cumulated activity per selected volume of tissue. As these curves generally follow an exponential course, ideally, a minimum of three data points is required. In practice, this means that measurements must be performed, for example, on the day of administration (between the first and fourth hours after administration) and in the following days up to day 7 (depending on the radiopharmaceutical used) (Sjögreen Gleisner et al. 2022).
In clinical trials and the evaluation of novel therapeutics, dosimetry is vital, especially in phase I ‘dose-escalation’ assessments and pre-therapeutic planning. Dosimetry helps establish organ-specific doses, determine the maximum tolerated activity, and recommend phase II doses. In the case of a dose escalation study, dosimetry assessments must occur at each level and should be correlated with safety laboratory data.
The upcoming use of alpha-emitting radionuclides imposes a new challenge in dosimetry. While traditionally used beta-emitting radionuclides are reliably measured using SPECT or PET cameras. Alpha emitters, such as Ac-225, have typically very few (gamma) emissions in their decay scheme, making dosimetry quite difficult. The dosimetry of other alpha-emitting isotopes, such as Ra-223 or Th-227, is more feasible (Staudacher et al. 2014).
Phase I: safety and dosage
Phase I studies have two primary objectives: ensuring the safety of the drug and finding the most effective dose for later phases of research. In these trials, researchers might work with healthy volunteers, but with radionuclides, it is preferred to include individuals with the specific disease under investigation, such as cancer patients. The main goal of phase I trials is to evaluate how the drug interacts with the human body and identify the maximum tolerated dose (MTD) without causing severe side effects.
To establish the MTD in radionuclide therapies, various approaches are employed. The choice of a dose-escalation methodology, whether predetermined or adjusted based on toxicity, depends on specific trial considerations and requirements, such as dose–toxicity and dose–efficacy curves of the drugs, rate of dose escalation, or interpatient variability (Le Tourneau et al. 2009). A traditionally used dose-escalation study is the ‘3 + 3 design’. In this design, three patients are initially enrolled in a specific dose cohort (Le Tourneau et al. 2009, Ivy et al. 2010). If none of the patients experience dose-limiting toxicities (DLTs) according to the Common Toxicity Criteria from the National Cancer Institute (CTCAE), the trial progresses to the next higher dose cohort. In cases where one patient in a specific dose level experiences a DLT, three additional individuals are enrolled in that cohort to collect more data. If two or more out of the total six patients exhibit DLTs, further dose escalation is halted, indicating that the MTD has been exceeded.
Another commonly used method involves a fixed percentage increase per dose group, typically around 20–25%. Predetermined approaches often utilize a modified Fibonacci series to determine dose increments, while toxicity-adjusted escalation plans take into account the highest toxicity grade observed in the prior dose level. For instance, no toxicities may trigger a 100% escalation, Grade I toxicities may lead to a 50% increase, Grade II to a 25% increase, and Grade III or higher toxicities result in halting the escalation and expanding the cohort. If less than one-third of patients experience Grade III or higher toxicities, a further 25% escalation may be implemented. The choice of dose-escalation methodology is ultimately guided by trial considerations and specific requirements (Kurzrock et al. 2021).
Throughout the phase I study, participants are closely monitored, and data on the drug's pharmacological behavior and immediate and short-term side effects are collected. While phase I studies may assess therapeutic effectiveness, their primary focus is on establishing safety, determining the appropriate dosage, and comprehending the drug's pharmacokinetics. The results obtained from phase I studies provide essential insights that guide subsequent phases of clinical development (Meredith 2002).
Phase II: efficacy and side effects
Phase II studies are the next step in the process of evaluating new radiopharmaceuticals. The primary goal of phase II trials is to assess the effectiveness of the treatment while ensuring patient tolerability and safety. To achieve this, a common approach is to use a dose set at about 80% of the highest dose that patients can tolerate without severe side effects, also known as the MTD, as established in phase I studies. The secondary goal of Phase II trials is to consider factors like the duration of the response, progression-free survival, and overall survival rates after treatment (overall survival).
To make the trial process efficient, a two-stage design is often used. This design allows for an early stop to the trial if no responses are observed within an initial group of 14 patients, indicating a low likelihood of achieving a response rate of 20% or more. Conversely, if promising responses are observed, researchers can adjust the required number of patients needed to confirm a response rate of at least 20%, based on the fraction of patients who respond positively.
It is important to note that in phase II trials, personalized dosing strategies are considered. These strategies take into account factors like a patient's body weight, race, and other biological characteristics. These considerations are carefully factored into the trial's design and implementation.
Patient selection
Patients are typically recruited for theranostic trials when they have reached the advanced or end-stage of their disease. These are often individuals with conditions that cannot be treated with surgery, and they may have experienced suboptimal outcomes or side effects from previous treatments. Nevertheless, ongoing trials aim to evaluate the effectiveness and safety of theranostic approaches, like PSMA radioligand therapy, in earlier stages of diseases such as prostate cancer, including hormone-naive prostate cancer and hormone-sensitive metastatic prostate cancer (Zhang et al. 2021).
The use of diagnostic tools is essential for patient selection in theranostics. PET/CT is generally inherent in theranostics for assessing whether radionuclide treatment is appropriate. For example, if the pathology to be treated does not show sufficient targeted uptake on the PET images, the patient is generally not an appropriate candidate for targeted radionuclide treatment. In addition, diagnostic CT and/or MRI may be used for response assessment in terms of radiologic imaging-based Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Patient characteristics also play a significant role in the selection process. Factors like a patient's overall health, World Health Organization (WHO) performance status, medical history, and comorbidities are essential when determining their eligibility for theranostic trials. Generally, patients with a good performance status, indicating their ability to cope with potential side effects and treatment demands, are preferred. Patients with a fast rate of progression and relatively short life expectancy (e.g. <3–6 months) are generally not suited for targeted radionuclide therapy because the treatment is generally given in multiple cycles with an interval of multiple weeks (e.g. PRRT and PSMA 6–8 weeks interval) and need time for the treatment to take effect.
Side effects
Radionuclide therapy, while effective, has potential inherent adverse effects, particularly affecting non-targeted normal tissues. To assess and manage these adverse effects during clinical trials, standardized scoring systems are utilized. Two common systems are the CTCAE (Dueck et al. 2015) and the grading system associated with the WHO (Franklin et al. 1994). These systems use a grading scale ranging from 0 (no significant toxicity) to 4 (potentially life-threatening toxicity) to categorize the severity of side effects. Other indicators that may be monitored include the time it takes for moderate to severe side effects to develop, how long severe side effects last, and the impact of side effects on factors like a patient's performance.
In radionuclide therapy, the bone marrow often plays a crucial role as a dose-limiting organ for many systemic treatments. Patients undergoing radionuclide therapy may experience transient subacute bone marrow compromise, leading to temporary anemia, leukopenia, and/or thrombocytopenia. Chronic adverse events are of particular concern as they are often permanent. The occurrence of chronic adverse events may vary depending on the specific organs involved. Some events, such as renal failure or salivary gland impairment, exhibit a dose-dependent relationship, meaning the risk increases with higher radiation doses. Conversely, certain events, like therapy-related myeloproliferative syndrome, can occur randomly without a clear dose-dependent relationship, although the probability of such events tends to increase with higher radiation doses and pretreatment with chemotherapy.
Phase III: efficacy and monitoring of adverse reaction
Phase III studies are designed to determine the true benefits of a new treatment for a specific group of patients. These trials offer essential insights into both the effectiveness and safety of a new treatment, particularly in uncovering less common side effects that might have been missed in earlier phases. Phase III trials differ from phase II by their larger scale (i.e. more patients) and longer follow-up duration, to capture longer-term and possibly less frequent side effects. In this context, a phase III trial typically undergoes evaluation by means of a head-to-head comparison with the current standard of care or the established treatment. The aim is to discern whether the new radionuclide treatment surpasses the standard in terms of effectiveness or offers other advantages, such as diminished side effects, all while delivering equivalent therapeutic benefits.
Response evaluation
Evaluating treatment response in theranostics presents unique challenges, primarily because established criteria for assessing response with modern hybrid imaging techniques are lacking. Although the reduction in tumor size is a widely recognized indicator of treatment response, clinical experience has shown that stable disease can also be indicative of a positive response. This stability may result from tumoral volume being replaced by fibrotic tissue, often going unnoticed by conventional imaging methods like the RECIST (van Vliet et al. 2013).
Moreover, specific non-measurable lesions complicate the assessment process. These include small tumors with diameters less than 10 mm, bone metastases lacking distinct soft-tissue components, pleural tumor seeding, lymphangitic tumor spread, and peritoneal or leptomeningeal tumor diseases (Ruchalski et al. 2022).
To overcome these issues, molecular imaging techniques and biologic markers, such as PET, come into play. Criteria like Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.1 provide valuable tools for evaluating these non-measurable lesions. PERCIST involves assessing changes in the tumor's standardized uptake value (SUV). For example, a significant decrease in metabolic intensity in terms of standardized SUV measurements or relative uptake with respect to other organs such as the liver, spleen, or blood pool may signify a more favorable treatment outcome. However, an ongoing debate exists in the field regarding the applicability of PERCIST to various PET tracers (Wahl et al. 2009). This debate arises from fundamental differences in the uptake mechanisms between tracers like [18F]FDG and other tracers, such as PSMA or DOTATATE PET, which assess glucose metabolism versus PSMA or SSTR expression. As a result, many experts in molecular imaging exercise caution when applying PERCIST and often restrict its use to predefined thresholds for progressive disease and partial response (Grubmüller et al. 2019, Huizing et al. 2020, Rosar et al. 2022).
Tracer-specific response criteria are in development, however. One example is early response evaluation in men with mCRPC treated with 177Lu-PSMA, which has shown higher prognostic value and inter-reader reliability as compared to conventional CT assessment or other imaging modalities: response evaluation criteria in PSMA PET/CT (RECIP) 1.0 (Gafita et al. 2022). Additionally, artificial intelligence is making strides in assisting radiologists by automating the segmentation of PET images to obtain prognostic parameters (Kendrick et al. 2023). Recent advancements in radiomics and quantitative PET techniques hold the promise of providing more refined parameters for assessing tumor heterogeneity, phenotypes, and overall tumor burden. These developments aim to establish PET as a significant prognostic biomarker across various cancers, thereby improving treatment response assessment in theranostics (Schöder & Moskowitz 2016, Winther-Larsen et al. 2016).
Quality of life
Improving the quality of life (QOL) for oncology patients stands as a paramount objective with profound implications for treatment decisions. QOL, in this context, encompasses the holistic impact of a disease on a patient's physical, psychological, and social well-being, as perceived by the patient themselves. Measuring QOL, however, presents several notable challenges. These include selecting appropriate tools, determining the frequency and timing of measurements, simplifying data interpretation and comparison, and identifying the minimum clinically important difference. While generic measures offer a broad perspective on QOL issues, they might lack the sensitivity to capture the specific changes in how cancer affects individual patients. Nonetheless, many studies now recognize the importance of incorporating QOL indicators into clinical trials, spanning from generic to cancer-specific and site-specific measures (Soni & Cella 2002, Khan et al. 2011, Strosberg et al. 2018).
Phase IV: post-marketing surveillance
Phase IV trials play a crucial role in the post-market safety monitoring of approved drugs or devices, following their clearance by regulatory authorities such as the FDA or EMA. These trials are aimed at identifying and assessing any potential side effects or adverse events that may not have been observed in earlier phases of clinical testing.
Moreover, phase IV trials offer a unique opportunity to scrutinize the long-term effectiveness and sustainability of a new treatment approach. During this phase, researchers and healthcare professionals examine the real-world impact of the treatment beyond the controlled environment of clinical trials. This extended view allows for the detection of any unexpected or rare side effects that may emerge in a larger patient population, providing crucial insights into the safety profile of theranostic agents.
Phase IV trials generally generate large sets of data that require professional data management and vast financial investments in personnel, analyses, and storage, which might sometimes be better outsourced to professional organizations.
Beyond safety considerations, phase IV trials also provide essential data from a financial perspective in terms of cost-effectiveness and economic implications. This aids healthcare providers and decision makers in making informed assessments of the treatment value and impact on healthcare and healthcare costs, which is vital for financially sustainable healthcare.
Overall, phase IV trials serve as a bridge between clinical research and real-world implementation, contributing to the ongoing improvement of patient care. By continuously monitoring the safety and effectiveness of approved treatments, we can enhance patient outcomes, refine healthcare practices, and make informed decisions about the allocation of healthcare resources.
Special considerations
Combination therapies
The integration of theranostic agents with established systemic therapies represents a compelling and emerging approach that holds great potential in improving patient outcomes. This strategy involves exploring various combinations, such as chemotherapy, radiosensitizers, external beam radiation therapy, and immunotherapies, to harness synergistic effects and develop more effective and comprehensive treatment strategies. This field of research has garnered significant interest and has been the subject of studies. (Nonnekens et al. 2016, Cullinane et al. 2020, Huang & Zhou 2020, Czernin et al. 2021, Satapathy et al. 2021).
Nuclear theranostic agents primarily induce DNA damage as part of their mode of action. To amplify their effectiveness, they can be combined with chemotherapy or radiosensitizers. These combinations obstruct crucial processes, like DNA damage repair and immune checkpoints. For instance, PARP-1, involved in repairing both single-stranded and double-stranded DNA breaks, is a potential target for radiosensitization. Immune checkpoint blockers that target programmed death receptor 1 (PD-1) ligand 1 (PD-L1) have significantly improved survival across various cancer types. Employing targeted radionuclide therapy to deliver systemic radiation to tumors can potentially transform the tumor microenvironment across all metastatic sites and enhance the effectiveness of immune modulators. However, it is important to note that combining these therapies can lead to increased adverse events, possibly due to overlapping toxicities (Chan et al. 2020). Nonetheless, the results of studies combining radionuclide therapy with other therapies are promising for improving patient outcomes and broadening our understanding of synergistic treatment modalities.
Discussion
Clinical trials are the gold standard for establishing the safety and efficacy of new treatments, including new radionuclide therapies. These trials require highly controlled variables and a well-defined patient population, in order to determine the ‘true’ effect of the medical intervention on patients. However, one should acknowledge that these controlled conditions may not fully mirror real-world scenarios.
Clinical trials and the real world
The advancement of radionuclide therapies has leaned significantly on ‘compassionate use programs at academic centers and single-center trials. Regulatory agencies such as the EMA provide recommendations with respect to compassionate use, but these do not create a legal framework, and different countries set their own rules and procedures. Nonetheless, compassionate use pathways have played a crucial role in development in theranostics. However, when it comes to official approval of new drugs, including radiopharmaceuticals, formal clinical trials are mandated.
As thorough as clinical trials may be, a shortcoming is that the results from these trials may not always perfectly match what happens in the real world, where patients have varying disease burdens, other health issues, different ages, and ethnic backgrounds. To address this gap, surveys of large patient groups that collect real-world evidence or ‘real-world data’ are becoming of increasing importance.
Access to theranostics
Ensuring global access to theranostics financial aspects must be taken into account. Affordability and reimbursement of these agents are pivotal in ensuring equitable access. It is imperative for stakeholders, including governments, insurers, and healthcare providers, to come together and develop sustainable pricing models and reimbursement strategies. This collaborative approach can help alleviate the financial burden on patients and healthcare systems, ultimately making theranostics accessible to a broader population.
Building and fortifying nuclear medicine facilities in various countries is essential for the effective implementation of theranostics. This encompasses training healthcare professionals, establishing the necessary infrastructure, and ensuring the availability of required equipment and radiopharmaceuticals. International collaborations, knowledge sharing, and technology transfer can provide crucial support for developing these facilities in regions where they are currently limited.
How to handle the results of trials
Effectively handling the results of trials, even when they are negative, plays an important role in drug discovery, especially in the realm of novel theranostic approaches. Sharing these outcomes through established platforms can minimize waste, promote transparency, and stimulate innovation, leading to sustainable and beneficial solutions.
Conclusion
In conclusion, theranostics combines diagnostics and treatment for personalized cancer care. Clinical trials are an essential part of moving promising targeted radionuclide treatment from ‘bench-to-bedside’ (Fig. 1). This article explores trends and challenges in each clinical trial phase in light of the emerging field of theranostics in nuclear medicine.
Key elements of theranostics development across preclinical and clinical trials.
Citation: Endocrine Oncology 4, 1; 10.1530/EO-23-0045
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
The authors declare that there is no funding for this study.
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