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The theranostic promise for Neuroendocrine Tumors in the late 2010s - Where do we stand, where do we go?

More than 25 years after the first peptide receptor radionuclide therapy (PRRT), the concept of somatostatin receptor (SSTR)-directed imaging and therapy for neuroendocrine tumors (NET) is seeing rapidly increasing use. To maximize the full potential of its theranostic promise, efforts in recent years have expanded recommendations in current guidelines and included the evaluation of novel theranostic radiotracers for imaging and treatment of NET. Moreover, the introduction of standardized reporting framework systems may harmonize PET reading, address pitfalls in interpreting SSTR-PET/CT scans and guide the treating physician in selecting PRRT candidates. Notably, the concept of PRRT has also been applied beyond oncology, e.g. for treatment of inflammatory conditions like sarcoidosis. Future perspectives may include the efficacy evaluation of PRRT compared to other common treatment options for NET, novel strategies for closer monitoring of potential side effects, the introduction of novel radiotracers with beneficial pharmacodynamic and kinetic properties or the use of supervised machine learning approaches for outcome prediction. This article reviews how the SSTR-directed theranostic concept is currently applied and also reflects on recent developments that hold promise for the future of theranostics in this context.


Introduction
More than 25 years after the first peptide receptor radionuclide therapy (PRRT) with [ 111 In]-pentetreotide at the Department of Nuclear Medicine at the Erasmus Medical Center, Rotterdam, the concept of somatostatin receptor (SSTR)-targeted imaging and therapy for neuroendocrine tumors (NET) is seeing rapidly expanding use, in particular as cumulative experience with NET is now readily transferred to other diseases [1]. The most notable examples of this are prostate-specific membrane antigen (PSMA) radioligand therapy for the treatment of prostate cancer [2] or CXCR4-directed Ivyspring International Publisher endoradiotherapy for chemokine receptor-expressing malignancies [3].
In recent years, the theranostic concept in NET has continuously evolved to meet the challenging needs of NET patients and to exploit its full theranostic potential that is maximum treatment effect with minimal risk of potential harm [6]. Such efforts include, but are not limited to, harmonization of SSTR-targeted PET/CT interpretation, expansion of the theranostics concept to applications beyond oncology, and the introduction of novel radionuclides for the treatment of NET [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In the present manuscript, the theranostic principle will be briefly introduced, the potential paradigm shift in the use of current "state-of-the-art" theranostic radionuclides will be summarized, and novel applications for PRRT will be reviewed. In addition, recently introduced standardized framework systems for the interpretation of SSTR-targeted PET/CT and their impact on subsequent decision-making will be discussed. Moreover, emerging novel radiotracers for theranostics in NET which may become a therapeutic option after treatment failure with conventional PRRT will be presented. Finally, future perspectives in the field of molecular imaging and treatment for NET will be outlined.

The Theranostics Principle in NET
Theranostic Concept. As an underlying biological rationale for the theranostic principle in NET, membrane-bound receptors on the NET cell surface offer the possibility to be targeted by molecular diagnostic and therapeutic probes. Those receptors include SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5, and the available radionuclides differ in their binding affinities towards such receptors with most agents having the highest affinity for SSTR2 and SSTR5 [4,21,22]. In brief, following confirmation of high SSTR expression with diagnostic SSTR-targeted radiotracers, therapeutic radiolabeled compounds ("hot" somatostatin analogs) can be administered and bind to the SSTR on the tumor cell surface. After internalization into the NET cell, ß-irradiation from the compound provokes DNA strand breaks, which ultimately lead to cell death. Of note, current "state-of-the-art" therapeutic radiopharmaceuticals (e.g. [ 177 Lu]-DOTATATE/-TOC) use an agonistinduced mechanism to enter the cell. Thereafter, endosome-mediated recycling leads to the replacement of SSTR on the tumor cell surface within 24 hours. Thus, the theranostic concept in NET resembles a Trojan horse mechanism, as the SSTR density on the tumor cell surface opens the door for high affinity binding of the radiolabeled compound with subsequent internalization into the NET cell [4,23].
The NETTER-1 Trial. As the first randomized, controlled trial demonstrating the efficacy and safety of [ 177 Lu]-DOTATATE PRRT, the NETTER-1 trial marked an important milestone for the treatment of NET: In patients with well-differentiated, metastatic midgut NET that failed 1 st -line therapy with unlabeled somatostatin analogs, a PRRT group ([ 177 Lu]-DOTATATE plus "cold" octreotide long acting release (LAR) 30mg) was compared with a control group receiving only high-dose octreotide LAR (60mg). PFS had not yet been reached in the PRRT group at the time of publication of NETTER-1, but was 8.4 months in the control group. The estimated rate of PFS at month 20 was 65.2% in the [ 177 Lu] group and 10.8% in the cold octreotide LAR group. A recently published update on PFS further corroborated those initial findings [24]. Moreover, at date of censoring, 14 deaths had occurred in the [ 177 Lu]-DOTATATE arm (vs. 26 in the control group), i.e. the estimated risk of death was 60% lower for patients undergoing PRRT. Common Terminonology Criteria for Adverse Events (CTCAE) grade 3 or 4 toxicities were observed for hematotoxicity (myelosuppression in 9%), while no severe nephrotoxicity (grade 3 or 4) was recorded [25]. In addition, time to health-related Quality of Life (QoL) deterioration showed that the time span until worsening of global health status, disease-related mental stress, or symptoms (e.g. diarrhea) was significantly longer in the PRRT arm as compared to the control group [26]. Furthermore, PFS of the [ 177 Lu] group was not impacted by an initially impaired renal function [27]. Taken together, the NETTER-1 trial provided evidence that PRRT, in combination with low-dose octreotide LAR, not only markedly improved PFS, response rates, and survival probability, but also inferred a significant QoL benefit to patients [25,26].

Expanding Current Recommendations for "State-of-the-Art" Theranostic Agents
In 2013, spearheaded by Bodei et al., the "Joint International Atomic Energy Agency, European Association of Nuclear Medicine and Society of Nuclear Medicine and Molecular Imaging Practical Guidance" provided advice on how to implement PRRT for NET in clinical practice [5]. This document included indications, contraindications, and patient preparation advice. In this regard, several paradigms towards an ideal application of PRRT were established [5], which later were also adapted by other national and international guidelines [28,29]. However, given the high number of patients treated at multiple sites with long and continuously increasing follow-up, recent studies have added to the complexity of PRRT in NET and expanded upon those previously established principles.
For instance, current international guidelines recommend to restrict PRRT to WHO Grade 1/2 (Ki67 ≤ 20%) NET patients and thus, the majority of the performed studies to date (including the NETTER-1 trial) are limited to well-differentiated G1-2 diseases [5,25,28]. However, PRRT might be an option in a subgroup of G3 neuroendocrine neoplasms: The "NORDIC Neuroendocarcinoma (NEC)" study included 305 patients from 12 Nordic hospitals with gastrointestinal G3 disease [30]. The vast majority of the patients had received platinum-based chemotherapy (252/305, 82.6%), while the remainder had been treated with best supportive care (53/305, 17.4%). A Ki67 < 55% demonstrated less responsiveness to chemotherapy (based on radiological response assessment) [30]. Those findings have been compared to a pilot study cohort of G3 NEN with a Ki67 > 55% vs. < 55% treated with PRRT (in combination with radiosensitizing chemotherapy). It could be demonstrated that the median OS for those subjects with a Ki67 below that threshold was considerably longer in the PRRT cohort (46 months vs. 14 months in the NORDIC trial), while the opposite was documented in patients with a Ki67 > 55% (PRRT, 7 months vs. NORDIC, 10 months) [30,31]. Based on this preliminary data, PRRT might be a promising treatment option in progressive G3 NET. However, temozolomide alone or in combination with capecitabine and/or bevacizumab as 2 nd -line treatment in patients with Ki67 < 60% have also demonstrated high response rates of up to > 70% in patients with progressive disease after 1 st -line treatment [32,33] and no head-to-head comparison has been performed so far.
Nicolini and coworkers identified a Ki67 ≤ 35% as the optimal threshold to predict disease control under PRRT [34]. Altogether, given high SSTR-expression as treatment rationale/pre-requisite, PRRT (combined with a radiosensitizer) may be an alternative option in G3 NEN patients with Ki67 < 55% (or more preferably in subjects with Ki67 ≤ 35%). Nonetheless, future prospective, randomized, controlled studies are warranted to corroborate these preliminary findings.
Current guidelines suggest 3-5 cycles of [ 177 Lu]-based PRRT [5,28]. However, Yordanova et al. expanded upon that recommendation as they retrospectively evaluated a total of 15 patients who had received a median of 9 cycles (range, 8-13 cycles) with a median cumulative administered activity of 63.8 GBq (range, 52-95.6 GBq). First and foremost, no life-threatening adverse events (CTCAE 4) occurred. No CTCAE 3/4 nephrotoxicity and only one reversible case of CTCAE 3 hematotoxicity were documented, further emphasizing the favorable safety profile of such repeated treatment cycles. Of note, compared to historical controls receiving a maximum of 4 cycles, a considerably higher survival benefit of 85.6 months (vs. 69.7 months in the group with less cycles) was demonstrated [35]. In a similar vein, McEwan and coworkers from Edmonton, Canada are currently performing a maintenance protocol, which includes up to 8 PRRT cycles with 3.7 GBq (every 6 -10 months) after an induction protocol of 4 cycles up to 5.55 GBq/cycle (every 2.5 -3.5 months). Notably, in their enrolled cohort of 138 patients, the median PFS has not been reached at 59.3 months [36].

Novel Targets for PRRT: Beyond Current Applications
Beyond current applications in gastroenteropancreatic (GEP)-NETs, other potential targets in oncology include meningioma, lung NET (including small cell lung cancer), and malignant pheochromocytoma/paraganglioma [5,[37][38][39]. For the latter tumor entity, favorable results have been recently demonstrated: In a proof-of-concept study including four patients suffering from hereditary paraganglioma in whom surgical resection was not feasible, up to 5 cycles of [ 177 Lu]-DOTATATE led to partial response or stable disease in all subjects [40,41].
In addition to the tumor cell surface, SSTR are also expressed by other cell types in non-oncologic conditions. For instance, Tarkin et al. and others were recently able to demonstrate SSTR2 gene overexpression exclusively in pro-inflammatory M1 macrophages and subsequent specific binding of [ 68 Ga]-DOTATATE in macrophage-rich inflammatory atherosclerotic carotid plaques [42,43]. In a pilot study, Schatka et al. have already investigated a cohort of oncology patients who had been scheduled for PRRT and reported on the feasibility of characterizing SSTR2 expression in atherosclerotic plaques using [ 68 Ga]-DOTATATE. In addition, a potential reduction effect in plaque activity using the therapeutic equivalent [ 177 Lu]-DOTATATE was documented, thus suggesting avenues for anti-atherosclerotic interventions based on SSTR2-directed (endoradio-)therapies [11]. Beyond atherosclerosis, marking macrophage activity with radiolabeled SSTR2 ligands has been demonstrated in other inflammatory conditions, including myocardial infarction, myocarditis and sarcoidosis [44][45][46].
In a proof-of-concept study, two patients suffering from multi-organ involvement of sarcoidosis received a standard activity of 7.7 GBq in four treatment cycles, and, notably, both patients demonstrated a considerable benefit from PRRT (partial response, accompanied with a pronounced pain reduction in one patient and stable disease in the second patient, Figure 1). No adverse effects were recorded [10].

Potential Novel Radiotracers after Failure of Conventional PRRT
Notably, several new theranostic radiotracers for GEP-NET have been recently introduced and applied in a therapeutic setting. Thus, those agents may eventually be available to serve as an option after failure of conventional, agonist-based PRRT.
[ 177 Lu]-DOTA-EB-TATE. Based on the common radionuclide [ 177 Lu]-DOTATATE, first reports in multiple xenograft models reported on efficacy maximization by using an Evans blue modification of octreotate [13]. Given the markedly increased binding to circulating serum albumin, a slower clearance through the urinary tract and thus, an extended half-life in blood was observed. Consequently, an increase in tumor retention was demonstrated by using [ 86 Y]/[ 90 Y]-DOTA-EB-TATE in a variety of different cell lines and dedicated animal models with long term efficacy relative to DOTATATE in mice bearing SSTR2 xenografts [13]. The same research group subsequently investigated this radiotracer in a pilot cohort of NEN patients.  [14].
[ 213 Bi]-DOTATOC. Following animal studies using the alpha-emitters [ 213 Bi]-DOTATOC (in a rat pancreatic tumor model) and 225 Ac-DOTATOC (in nude mice), Kratochwil and coworkers performed targeted alpha therapy (TAT) with an intra-arterial infusion of [ 213 Bi]-DOTATOC in 7 patients with advanced NET. All patients had undergone previous PRRT cycles with beta emitters ( 90 Y or 177 Lu) and presented with relapsed/refractory disease [52][53][54]. Notably, TAT showed considerable anti-tumor effects, and even overcame resistance against beta radiation. Moderate acute hematological side effects were observed, and chronic kidney impairment was in an acceptable range [54]. Recent improvement of labeling chemistry showed that labeling of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(meth ylenephosphonic acid) (DOTP) with [ 213 Bi] instead of the currently used DOTA led to higher efficiency and in vitro stability [55]. Nonetheless, further studies enrolling larger patient cohorts are warranted to determine the role of TAT, in particular as an additional treatment line after resistance to common beta-emitters.  [12]. However, this "proof-of-concept" study definitively needs further research enrolling a larger patient cohort, in particular as other therapies may alter CXCR4 expression on the cell surface [57].

Harmonization of SSTR-Targeted PET/CT Interpretation for Standardized Treatment
MI-RADS [7]. While reading SSTR-targeted PET/CT scans, certain pitfalls have to be considered and false-positive or false-negative findings may also have an impact on patient selection for subsequent PRRT [58]. Thus, similar to the existing reporting and data systems for multiple other organs (BI-RADS for breast, or TI-RADS for thyroid), a standardized framework system for molecular imaging, titled "Molecular Imaging RADS" (MI-RADS), has recently been introduced [7, 59, 60]. MI-RADS may serve as an attractive option for the interpretation of PET/CTs using radiotracers with potential theranostic implications and includes PSMA-RADS for PSMA-targeted PET/CT (for patients with prostate cancer) as well as SSTR-RADS for SSTR-targeted PET/CT [8,[61][62][63]. MI-RADS takes the site of disease and the uptake intensity into account, assists the reader in navigating through pitfalls and indeterminate lesions, facilitates communication with referring clinicians, and provides recommendations for appropriate workup of equivocal findings. Notably, MI-RADS systems (PSMA-and SSTR-RADS) can be applied reciprocally, i.e. if the interpreter is familiar with the structure of SSTR-RADS for NET, PSMA-RADS for prostate cancer can be readily applied as well [7].
SSTR-RADS [8]. Numerous pitfalls on SSTRtargeted PET may complicate the reliable interpretation of an SSTR-targeted PET/CT scan [7,58]. Apart from physiological biodistribution in pituitary glands, major salivary glands, thyroid gland, adrenal glands, liver, and spleen, as well as excretion via the urinary tract, variable uptake can also be appreciated in the uncinate process of the pancreas [22,58]. Other common pitfalls on SSTR-targeted PET include inflammatory disease (e.g., sarcoidosis or tuberculosis) and non-GEP NET tumors, e.g. breast cancer or papillary thyroid carcinoma [58]. Thus, SSTR-RADS may increase the reader's level of confidence in interpreting SSTR-PET/CT scans as specific categories and recommendations regarding those pitfalls are incorporated into the system. In brief, SSTR-RADS assigns lesions to a 5-point scale (from 1 = definitively benign to 5 = NET certainly present) by considering the site of disease and the level of uptake defined as a three-point qualitative assessment scoring using the relative lesion uptake compared to blood pool (Level (L) 1: ≤ blood pool) and physiological liver uptake (L 2: uptake > blood pool but ≤ liver and L 3: uptake > liver). Each SSTR-RADS classification provides instructions for the next step in the diagnostic and treatment algorithm (a workflow chart for the different SSTR-RADS classifications is provided in Figure 3).   SSTR-RADS-1A refers to benign lesions, without any abnormal uptake (L 1) and SSTR-RADS-1B (L 2-3) to benign lesions, but with focal uptake (e.g. benign prostatic hyperplasia). SSTR-RADS-2 (L 1) includes uptake in soft-tissue sites or bone lesions atypical of metastatic NET rendering such lesions likely benign, e.g. uptake in a bone lesions suggestive to be degenerative (e.g. a Schmorl node). SSTR-RADS-3 is segregated into 4 sub-classifications and is focused on the concept of equivocal findings on SSTR-targeted PET, which may need further work-up. SSTR-RADS-3A and SSTR-RADS-3B lesions (L 1-2, respectively) are suggestive of, but not definitive for NET. While SSTR-RADS-3A describes lesions that demonstrate equivocal uptake in soft-tissue sites typical for NET (e.g. a regional lymph node), SSTR-RADS-3B includes such lesions in the skeleton (e.g. low-level uptake in the rib). On the other hand, SSTR-RADS-3C lesions are suggestive of an SSTR-expressing, non-NET benign tumor or malignant process, i.e. uptake (up to L 3) at a site highly atypical for NET, such as the breast. SSTR-RADS-3D sites are not SSTR-avid and have a high likelihood for a dedifferentiated NET lesion or another type of non-SSTR-expressing malignancy, i.e. further work-up to rule out potential tumor escape or secondary malignancy is mandatory. SSTR-RADS-4 and -5 have both a high level of uptake (L3) at typical disease sites. SSTR-RADS-4 does not show corresponding findings on conventional imaging, while SSTR-RADS-5 does demonstrate such findings. Notably, in terms of multiple lesions, an overall scan impression can be indicated by establishing an overall SSTR-RADS score (highest target lesion score takes priority over the other lesion, Figure 4).
The NETPET Grade [9]. While SSTR-RADS may serve as a reliable tool that addresses the need for baseline criteria in the field of SSTR-PET, Chan and coworkers developed a grading score that unifies a dual-tracer assessment with SSTR-targeted agents and have FDG > SSTR uptake). Notably, the P2 to P4 categories can be further divided into "a" and "b", which primarily refers to the number of investigated lesions.
While further validation studies for SSTR-RADS (e.g. interobserver studies or comparison of SSTR-RADS scoring with histopathological evidence) are still lacking, the NETPET Grading Score has been retrospectively evaluated and a considerable distinction in the survival probability between the P1 vs. P2-4 vs. P5 groups was recorded (P5, worst outcome, P1, best outcome, with P2-4, intermediate outcome). Notably, none of the other investigated variables (age, extrahepatic disease, histological grade) served as an independent outcome predictor, while the NETPET grade remained significant in a multivariate analysis. Thus, this proposed grading scheme may serve as a prognostic biomarker in identifying high-risk patients and guide appropriate therapy [9]. It may also trigger further workup (e.g. for P2a with biopsy of a single FDG(+) lesion) or to refrain from PRRT (e.g. for P5 with the vast majority of the findings being exclusively FDG(+)). Nonetheless, a dual-tracer approach is not routinely applied [64,65]. The NETPET Grading Score may be most valuable to determine the most effective next steps in patients with an intermediate Ki67 and the risk for de-differentiated NET lesions.    [67]. However, the kidneys are known as the dose-limiting organ, and impairment in renal function may lead to suspension or even early termination of treatment [67]. Thus, closer monitoring of renal function may be regarded as one of the cornerstones for continuing PRRT with radiolabeled agonists over several cycles or for administration of novel radiotracers with potentially increased kidney doses [5,13]. However, at the time being, established clinical risk factors provide only a limited estimate of nephrotoxicity and so far unidentified individual susceptibilities to radiation may be present [67].
For monitoring renal function, both the tubular extraction (TER) as well as glomerular filtration rate can be assessed. Since the primary target of radiation after PRRT is the proximal tubule, some articles have recommended using TER in patient follow-up [5,68]. In contrast, TER measured by [ 99m Tc]mercaptoacetyltriglycine turned out not to be a reliable prognostic marker for renal impairment in another study [68]. On the other hand, glomerular injury is usually the first step in radiation-induced kidney injury and more sensitive means of GFR assessment may be appropriate. As a novel strategy, PET-based approaches to monitor kidney function have recently been reported. Hofman [73]. Striving for a personalized treatment assessment, a currently recruiting prospective trial aims to expand the concept of SPECT-based dosimetry to NET lesions as well: PRRT will be tailored to specific needs of the patients, i.e. the absorbed radiation dose to sites of disease will be maximized, but limited according to the respective organs at risk (NCT02754297) [74].
However, the short half-life of [ 68 Ga]-DOTATATE/-TOC (68 min) does not allow for pre-therapeutic dosimetry based on SSTR-targeted PET. Given the time-consuming nature of current SPECT dosimetry approaches, which result in a high burden for patient and personnel [72,75] [76]. These encouraging results led to a proof-of-concept PET study using [ 152 Tb]-DOTATOC in a patient suffering from NEN of the terminal ileum (Ki67 < 5%) [18]. Notably, scans were conducted over a time span of 24h, allowing for the demarcation of very small metastases at late time points. Moreover, due to the long half-life of [ 152 Tb], existing delivery networks could readily be used and distribution by commercial vendors could be viable. As a drawback, the availability of this radiotracer is currently limited [18].
Machine Learning for Theranostics. Artificial intelligence (AI) is currently on the forefront of research in numerous radiological applications and recent efforts in the field of theranostics aimed to investigate the capability of outcome prediction using software tools for intratumoral heterogeneity (radiomics) based on SSTR-targeted SPECT or PET [77,78]. However, machine learning and AI for theranostics are not limited to therapy response prediction, but could also potentially be applied in clinical decision making by the creation of multidisciplinary large datasets (clinical information obtained from gastroenterology, endocrinology, surgery, radiology, nuclear medicine, and pathology). Other potential areas of interest are automated detection and separation of benign vs. malignant findings on SSTR-targeted PET, post-processing of obtained imaging data, automated dose estimations based on post-therapeutic SPECT, or integrity analytics of molecular images [79]. Nonetheless, current supervised machine learning approaches need continuous input and labeling of data from highly experienced radiologists (or in the field of theranostics, nuclear medicine physicians) and thus, novel approaches to address this issue are needed [80]. One potential approach is the introduction of Deep Convolutional Generative Adversarial Networks (DCGANs), which are primarily used to augment existing datasets without time-consuming, human labeling procedures (synthetic data augmentation). In brief, DCGANs use adversarial networks, in which one network is creating artificial images, while the other network is continuously learning to separate artificial from true images [80][81][82]. For instance, DCGANs could be expanded to the field of theranostics, e.g. by augmenting an existing dataset of (already conventionally labeled) SSTR-targeted PET/CT using SSTR-RADS. Hence, further time-consuming labeling procedures by human experts could be omitted and finally, (SSTR-)RADS reporting could be automated by effective data augmentation. This applies especially to "rare" lesions, such as SSTR-RADS-3A or SSTR-RADS-3B lesions (indeterminate findings with low-level uptake), which may not be encountered to the extent that machine learning could be effectively trained from real images [8]. As part of MI-RADS, DCGANs could also expanded to radioligand therapy and PSMA-targeted PET/-RADS [7].

Conclusions
25 years after its initial introduction for the diagnosis and treatment of NET, the theranostic principle is as relevant as ever. The NETTER-1 trial demonstrated that PRRT (in combination with low-dose octreotide LAR) lengthens the time-to-progression, the time to health-related QoL deterioration, and increases survival probability [25,26]. Moreover, efforts in recent years have expanded upon common recommendations from current guidelines, such as the dogma to perform a maximum of 4 treatment cycles with [ 177 Lu]-SSTR agonists. Notably, the concept of PRRT has been also applied beyond oncology, e.g. for the treatment of granulomatous or other inflammatory disorders [10,11,19]. New framework systems, such as SSTR-RADS or NETPET Grading may facilitate communication with referring clinicians, but also provide workflows of appropriate workup for indeterminate findings [8,9]. In addition to established radiotracers for theranostics in NET (e.g. [ 68 Ga]-/[ 177 Lu]-DOTATATE/-TOC), recent developments of novel theranostic ligands may outperform those "state-of-the-art" SSTR-targeting agents. Future perspectives in the field may focus on supervised machine learning for outcome prediction by creating large multidisciplinary datasets from different disciplines involved in NET management [79,80]. In this light, the theranostics concept has a promising future in NET and will continue to play a pivotal role in patient care.