Somatostatin Receptors and Analogs in Pheochromocytoma and Paraganglioma: Old Players in a New Precision Medicine World

Neuroendocrine tumors overexpress somatostatin receptors, which serve as important and unique therapeutic targets for well-differentiated advanced disease. This overexpression is a well-established finding in gastroenteropancreatic neuroendocrine tumors which has guided new medical therapies in the administration of somatostatin analogs, both “cold”, particularly octreotide and lanreotide, and “hot” analogs, chelated to radiolabeled isotopes. The binding of these analogs to somatostatin receptors effectively suppresses excess hormone secretion and tumor cell proliferation, leading to stabilization, and in some cases, tumor shrinkage. Radioisotope-labeled somatostatin analogs are utilized for both tumor localization and peptide radionuclide therapy, with 68Ga-DOTATATE and 177Lu-DOTATATE respectively. Benign and malignant pheochromocytomas and paragangliomas also overexpress somatostatin receptors, irrespective of embryological origin. The pattern of somatostatin receptor overexpression is more prominent in succinate dehydrogenase subunit B gene mutation, which is more aggressive than other subgroups of this disease. While the Food and Drug Administration has approved the use of 68Ga-DOTATATE as a radiopharmaceutical for somatostatin receptor imaging, the use of its radiotherapeutic counterpart still needs approval beyond gastroenteropancreatic neuroendocrine tumors. Thus, patients with pheochromocytoma and paraganglioma, especially those with inoperable or metastatic diseases, depend on the clinical trials of somatostatin analogs. The review summarizes the advances in the utilization of somatostatin receptor for diagnostic and therapeutic approaches in the neuroendocrine tumor subset of pheochromocytoma and paraganglioma; we hope to provide a positive perspective in using these receptors as targets for treatment in this rare condition.


INTRODUCTION
The theranostic revolution began over three decades ago, following the medical conception of somatostatin receptors (SSTRs) and their analogs (SSA). The identification of specific tumor targets for diagnosis and therapy of advanced diseases has been a continuing trend in oncology since its innovation. Neuroendocrine tumors (NETs) with the overexpression of SSTRs are ideal cancer models for discovering the dual ability of diagnosis and treatment using SSAs.
Two decades after the identification of somatostatin (SST) as the central regulator of neuroendocrine cell physiology in the early seventies, five SSTR subtypes were discovered (1)(2)(3)(4). The discovery of SSTRs led to the successful introduction of somatostatin analogs (SSAs), initially as antisecretory agents, and recently as antiproliferative agents based on the results of two large phase III trials (5)(6)(7).
Moreover, clinical imaging using radiolabeled SSAs to target SSTRs, known as somatostatin receptor imaging (SRI), became a prominent method in the diagnosis and management of NETs. The earliest success of SRI was pivotal in gastroenteropancreatic (GEP)-NETs and glomus paraganglioma (PGL) localization using 111 In-pentetreotide (Octreoscan ® ) (28,29). The progression of SRI in NETs increased with the introduction of radiolabeled isotope 68 Ga-SSAs for positron emission tomography (PET) imaging. Then, Lutetium-177 ( 177 Lu)-SSA was developed for peptide receptor radionuclide therapy (PRRT). A particular SST-based PRRT, 177 Lu-DOTA0-Tyr 3 -Octreotate ( 177 Lu-DOTATATE), was shown to be superior to other modalities in terms of progression-free survival (PFS) in a subset of GEPNETs (30). In 2018, based on the results of the NETTER-1 trial, 177 Lu-DOTATATE (Lutathera ® ) was approved by the FDA for foregut, midgut, and hindgut GEPNET treatment. Current management algorithms for GEPNET patients use radiolabeled, and "cold" or unlabeled SSAs for their antiproliferative and cytotoxic abilities.
The discovery of SSTR overexpression in pheochromocytomas and paragangliomas (PPGLs) occurred in the 1990s (31), predicting a limitless therapeutic potential of SSA; however, its role in PPGL management was not developed in parallel with GEPNETs. Initial efficacy testing of SSAs, both cold and radiolabeled, was futile, mostly due to small clinical trials without any clear accrual of therapeutic benefits (32)(33)(34) in PPGLs. Despite the therapeutic responses of SSAs in GEPNETs showing significant success (35)(36)(37)(38)(39), the application of cold and radiolabeled SSA in PPGL was prematurely abandoned. In the last decade, there was a rise in the use of octreotide and radiolabeled SSA for recommended therapies approved by the FDA for both functioning and nonfunctioning GEPNETs, without enough studies confirming the clinical benefits of these compounds in PPGLs for federal approval. Figure 1 is a timeline comparing important findings and trials in SSTRs and 121 SSAs between NETs and PPGLs.
The primary therapy of choice for PPGL is surgical resection, but not in the case of unresectable advanced and metastatic tumors. A significant proportion of patients with PPGL is due to an inheritable genetic component, where the incidence of metastatic PPGL (mPPGL) occurs due to succinate dehydrogenase subunit B (SDHB) germline mutation patterns (49). Interestingly, SDHBrelated PPGLs overexpress SSTRs, mainly SSTR 2 (48). To advance and expand the clinical utilization of SSAs in this PPGL, it is imperative to view the SDHB subgroup as a prime example of clinical benefits that these analogs could provide.
This review summarizes the studies on the role of SSTRs focusing on PPGLs. We detail the discovery of PPGL receptors and the creation of diagnostic and therapeutic radionuclidebound moieties to target these receptors. We also explore future perspectives for SSTRs and SSAs in driving precision-based care of PPGL patients.

PHEOCHROMOCYTOMA AND PARAGANGLIOMA
PPGLs are rare NETs arising from neural crest cells, specifically chromaffin cells. Differentiated based on anatomic locations, tumors from the adrenal medulla are defined as pheochromocytoma (PCC), whereas tumors from the sympathetic and parasympathetic ganglia are known as paraganglioma (PGL). While both these tumors present with similar molecular findings on pathology, they vary in manifested symptoms based on their biochemical profile (50).
More than 20 susceptibility genes (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, EPAS1, CSDE1, MAML3, RET, NF1, MAX, HRAS, TMEM127, HIF2A, PHD1/2) indicate predisposition to PPGLs (50). SDHB-related PPGLs are considered aggressive, causing more than 40% of all the metastatic cases (47). The risk of metastatic progression necessitates early diagnosis and intervention for obtaining good outcome in patients. It is important to identify symptoms and perform laboratory tests using plasma or urine metanephrines to confirm the diagnosis, followed by tumor localization through imaging. Imaging allows personalized therapy by assisting clinicians in deciding whether surgical interventions can render the patient disease-free. PPGLs occur in a wide range of anatomical locations, from the base of the skull to the bladder, making computed tomography (CT) with intravenous contrast the initial choice of imaging modality. However, magnetic resonance imaging (MRI) with or without gadolinium is recommended if there are contraindications to CT imaging, for example contrast allergy, pregnancy, young age, and surgical clip artifacts (51).
Several predictors increase the risk of metastases: PPGL tumor > 5 cm, noradrenergic phenotype, dopaminergic phenotype, familial PPGLs (especially SDHB and SDHA), young age at initial diagnosis, multiple tumors, and recurrent disease (52,53). PPGLs are more likely to metastasize to the lungs, liver, bones, and lymph nodes (54). While MRI has high sensitivity and specificity for PPGLs, functional imaging has shown to surpass it (55,56). The advent of functional imaging utilizing SSTRs dramatically improved PPGL localization and identification, enabling clinicians to guide precision medicine.

ADVENT OF SSTR-BASED IMAGING IN PHEOCHROMOCYTOMA AND PARAGANGLIOMA
Success in nuclear imaging of PPGLs was achieved in 1990, when Lamberts et al. conducted a study on three NETs, including one PGL, by labeling Tyr 3 -octreotide with radioisotope 123 Iodine ( 123 I-Tyr 3 -octreotide) to target SSTRs and capturing them using gamma cameras to produce single photon emission computed tomography (SPECT) and planar images. Results showed that 29 of the 31 possible PGLs were identified, and the two missed lesions were less than 5 mm in size (40). Although it was a relatively small study in terms of patient number, these findings on SRI-related PGLs could not be ignored. Subsequent studies improved the radiolabeled nucleotide by substituting 123 Iodide with 111 Indium in octreotide ( 111 In-pentetreotide), chelated by a diethylene triamine penta-acetic acid (DTPA) group, thus solving the problems of short half-life half-life: 13 hours for 123 Iodide versus 24-48 hours for 111 Indium and obscured pathology identification due to biliary excretion with subsequent accumulation in the intestines (57). A study detected 94% of PGLs in 25 patients, and an additional 36% of tumors that were not recognized with conventional imaging [CT, ultrasound, 123 I-metaiodobenzylguanidine ( 123 I-MIBG), MRI, and bone scanning] were detected using 111 In-pentetreotide. The study showed that using 111 In-pentetreotide could identify the PGLs identified by conventional imaging and others that were not initially visualized (58). In PCCs, 123 I-MIBG significantly outperformed 111 In-pentetreotide in detection (57). 111 Inpentetreotide had higher sensitivity than 123 I-MIBG in detecting head and neck PGLs (HNPGLs) (59-61) and mPPGL (62,63). The ability of 111 In-pentetreotide to bind with SSTRs, especially SSTR 2 , provided an additional diagnostic tool for clinicians to identify PPGL; however, their sole gammaemitting capability allows the application of only SPECT to visualize them. SPECT images do not provide spatial resolution to pinpoint the precise anatomical location of PPGL. 68

GA-BASED-SSA: A PREFERRED IMAGING RADIOISOTOPE IN PPGL
PET, which captures emitted positrons from radiotracers and combines them with low dose CT (PET-CT) for targeted receptor localization, was developed in the late nineties (64). Not only does PET have better spatial resolution than SPECT, it can also quantify radiotracer uptake in the form of a standardized uptake value (SUV) (65). To utilize PET-CT hybridized imaging, radiotracers -emitting positrons and targeting SSTRs were created. The first discovered radiotracer was a somatostatin analog 1-Nal3-octreotide (NOC) combined with 68 Gallium ( 68 Ga)-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), better known as 68 Ga-DOTANOC. 68 Ga-DOTANOC targets SSTR 2,3, and 5 (66,67) subtypes, while another moiety, 68 Ga-labeled DOTA-Tyr 3octreotide ( 68 Ga-DOTATOC), showed affinity for SSTR 5 , which is not specific to PPGLs. The last moiety of the three 68 Ga-labeled DOTA peptides is 68 Ga-DOTA-Tyr 3 -octreotate ( 68 Ga-DOTATATE), which showed a strong tendency to bind with SSTR 2 and is ideally suited for PPGLs because of the preferential expression of these SSTR subtypes (68). These three radiolabeled somatostatin analogs were compared with previous somatostatin-targeting 111 In-pentetreotide. The overall sensitivities for NET detection, including metastatic lesions, were much higher with 68 Ga-labeled DOTA-peptides by PET imaging than 111 In-pentetreotide by SPECT imaging (69)(70)(71)(72)(73)(74)(75). While these studies were not specific to PPGL tumors, one study found 16 and 12 additional PGLs on 68 Ga-DOTATATE compared to only two on 111 In-pentetreotide (71). The other study included two patients with PGLs, comparing 68 Ga-DOTATOC to 99m Technetium-labeled hydrazinonicotinyl-Tyr 3 -octreotide ( 99m Tc-HYNIC-TOC). While the study proved that 68 Ga-labeled DOTA-peptide was superior, individual details of these PGL patients cannot be inferred from the analysis because it was performed on a regional basis, and on other NETs (75). There were no studies comparing the efficiency of 68 Ga-DOTATATE to that of its predecessor, 111 In-pentetreotide, but it was widely shown to be effective in tumors that express SSTRs. In an individual case of metastatic PGL with SDHD germline mutation, 68 Ga-DOTATATE PET/CT produced higher resolution of tumors than Octreoscan ® , as seen in Figure 2.
Among the three radiolabeled somatostatin analogs, 68 Ga-DOTATATE provided a brighter outlook for PPGL evaluation. SSTR expression by PPGLs, mainly extra-adrenal PGLs and mPPGLs, was found to be the subtype 2 variety (76). This subtype was the preferred target of 68 Ga-DOTATATE (68). 68 Ga-DOTATATE was shown to be superior to alternative PET radiotracers in imaging for genotypes, phenotypes, metastases, and PGL-predominant diseases. The two alternative PET radiotracers used to diagnose PPGLs, 1 8 Flourine-fl uorodeoxyglucose ( 1 8 F-FDG) and 1 8 Ffluorodihydroxyphenylalanine ( 18 F-FDOPA), were inferior to 68 Ga-DOTATATE in the following cohorts of patients with: i. sporadic metastatic PPGL (77) ii. PGLs (78) iii. HNPGLs (78,79) At a molecular level, the utility of 68 Ga-based SRI in these patient cohorts can be explained by the current knowledge that SDHx-based lesions and extra-adrenal PGLs have higher proportions of SSTR 2 than other PPGL types. Even though 68 Ga-DOTATATE has lower sensitivity in other types of PPGLs than 18 F-FDOPA, it remains the secondary radiopharmaceutical of choice in the evaluation of PPGL genotypic and phenotypic subtypes that do not fit in the cohorts mentioned above.
In two recent meta-analyses, 68 Ga-DOTA-SSA had outperformed several radiotracers, including 18 F-FDOPA and 18 F-FDG. The pooled detection rate of unknown genetic mutational status in 68 Ga-DOTA-SSA was 93% ([95% CI, 91%-95%], P < 0.005), higher than 80% in 18 F-FDOPA ([95% CI, 69%-88%], P < 0.005) or 74% in 18 F-FDG PET ([95% CI, 46%-91%], P < 0.005). The analyses showed that while genetic mutations can help select the type of radiotracers to be used in staging and diagnosing PPGL, it was not always required prior to the selection of 68 Ga-DOTATATE, 68 Ga-DOTATOC, and 68 Ga-DOTANOC PET exams (83). A second meta-analysis pooled results of mPPGLs with germline mutational status, and the outcomes showed that 68 (84). 68 Ga-DOTATATE PET/CT proved to be more than a complementary imaging modality to traditional CT and MRI imaging modalities. 68 Ga-DOTATATE PET/CT has taken the place of 111 In-pentetreotide (Octreoscan ® ) in becoming the SRI modality of choice in PPGLs, subject to the availability of a PET/ CT scanner and radiotracer. It also outperformed 18 F-FDOPA and 18 F-FDG for detection of PGLs, mPGLs, HNPGLs, and SDHx PPGLs in adults and children. Figure 3 illustrates the superiority of 68 Ga-DOTATATE PET/CT compared to 18 F-FDOPA and 18 F-FDG of metastatic lesions in a PPGL patient with a SDHB mutation. While 68 Ga-DOTATATE PET/CT effectively localizes PPGL tumors, the benefit was ultimately attributed in conversion of the 68 Ga radiometal to a stronger beta-emitting one for therapeutic purposes.

EXPERIENCES WITH PEPTIDE RECEPTOR RADIONUCLIDE THERAPY USING SOMATOSTATIN ANALOGS IN PPGLS
An interchange of radiolabeling on a chelated SSA (e.g., DOTA-SSA) caused a functional switch of the molecular compound from diagnostic to therapeutic capabilities. 68 Ga-DOTA-SSA precisely located SSTRs on the surface of PPGL lesions through the capture of 68 Ga-beta emissions by PET/CT scanners. A change in radiometal to 177 Lutetium ( 177 Lu) or 90 Yttrium ( 90 Y) gave radiolabeled DOTA-SSA the ability to emit not only imageable radiations but also deliver beta radiations to the target lesions. Lutathera ® was approved by the FDA for GEPNET treatment; hopefully, it is only a matter of larger-model experiences and extensive reporting until its approval in surgically unamenable or metastatic PPGLs. More trials and research are needed to determine its actual applicability in PPGLs and to support the studies mentioned in this section.  (85) and should be considered in metastatic HNPGL with associated SDHB mutations (86). The same team recently published a retrospective study highlighting disease control of progressive mPGL in 6 out of 9 patients treated with 177 Lu-DOTATATE with negative 131 I-MIBG scans. These patients tolerated treatment without any significant adverse events (87).
A retrospective study in 2019 by Vyakaranam et al. involved 22 PPGL patients (nine with progressive disease and 13 with stable disease at the start of PRRT) and their responses to 177 Lu-DOTATATE. The response rates of the therapy, such as biochemical response, scintigraphy, response evaluation criteria in solid tumors (RECIST), overall survival (OS), and progression-free survival (PFS) showed favorable outcomes. 177 Lu-DOTATATE showed that only one of the 19 patients reviewed with SPECT/CT had progressive disease, while with CT, according to RECIST 1.1, all patients either had stable disease (n=20) or partial response (n=2). The median OS calculated was 49.6 months and median PFS was 21.6 (88); these were not established in other recent studies (87,89,90).
Another retrospective study focused on 30 patients with either parasympathetic PGL, sympathetic PGL, or PCC; after four cycles of 177 Lu-DOTATATE, results showed either stable disease or partial response in 90% of these patients. Among these patients, 20 had progressive disease prior to the start of 177 Lu-DOTATATE, of which 85% showed the disease controlled posttreatment (91). 90

Y-Based-SSA PRRT
The alternative beta-emitting radiometal, 90 Y, was utilized and studied in SSA-based PRRT. 90 Y had shorter half-life, longer path length, and greater emitted energy compared to 177 Lu (92,93). 90 Y also cannot be imaged using gamma cameras post-therapy because of its inherent property of being a sole beta emitter (93). With longer half-life, shorter path length, lower beta emission, and partial gamma emission, 177 Lu had a significant advantage over 90 Y; however, studies showed the therapeutic benefit of 90 Ylabeled SSA as PRRT.
In a prospective study from 2019 by Kolasinska-Cwikla et al., 13 patients with metastatic SDHB and SDHD (n=5 and 8, respectively) were treated with 90 Y-DOTATATE, with an 82% response of stable disease after 1 year. The median OS and PFS were 68 months and 35 months, respectively, with no difference in the endpoints in patients who were either secretory or nonsecretory (94). A retrospective study assessing 90 Y-DOTATATE and 131 I-MIBG concluded that mPGLs were best suited for treatment by SSA-based PRRT. The study reviewed the treatment responses of 22 patients with mPCC or mPGL after three different targeted radionuclide therapies. While only two patients received 177 Lu-DOTATATE, 90 Y-DOTATATE performed better in terms of median PFS and RECIST 1.1 base response to treatment compared to 131 I-MIBG (these were the two statistically significant findings) in mPGL with no significant difference observed when considering all the mPPGL patients (95).
These studies showed some positive responses to either 177 Luor 90 Y-based SSA therapy ( Table 1, summarizing experiences using SSA-based PRRT therapies in PPGL). There are still insufficient data for FDA approval of these therapies for PPGLs.

CLINICAL SIDE EFFECTS OF SOMATOSTATIN ANALOG BASED PEPTIDE RECEPTOR NUCLEOTIDE THERAPY
The clinical side effects of SSA-based PRRT include nausea, vomiting, fatigue, and abdominal pain (106). Nausea and  vomiting have been attributed to commercial amino acid infusion for renal protection prior to infusion of the selected PRRT. The occurrence of nausea and vomiting can be reduced by substituting the commercial amino acid infusion with an alternative containing L -lysine and L -arginine. More serious side effects include neutropenia, lymphopenia, thrombocytopenia, and nephrotoxicity. In a review of 45 PPGL patients treated with PRRT, 3% had grade 3/4 neutropenia, 9% had thrombocytopenia, 11% had lymphopenia, and 4% had nephrotoxicity. A long-term complication of myelodysplastic syndrome was also observed in an unreported number of PPGL patients receiving the therapy (105). In a case report by Wolf et al., a dangerous side effect of Lutathera ® in two mPGL patients was hyperprogression of mPGL disease after three cycles of 90 Y/ 177 Lu-DOTATOC (cycle one was 90 Y, and cycle two and three were 177 Lu) in patient A and two cycles of 177 Lu-DOTATATE in patient B (107). Future reporting of adverse effects of SSA-based PRRT is important in assessing the safety of this therapy in PPGL patients to determine whether the therapy can be effectuated in patients, without life-threatening side effects.

FUTURE AVENUES OF SOMATOSTATIN-BASED THERAPY IN PPGLS
The following section will focus on ongoing studies that focus on the targeting of SSTRs by SSA based therapeutic compounds.

Ongoing PRRT Clinical Trials
An ongoing phase II study at the National Institutes of Health (NIH), NCT03206060, could make a strong case for federal approval. The study is using Lutathera ® for treating progressive and inoperable PPGL patients with either germline SDHx mutation or sporadic disease. This prospective clinical trial will identify important clinical benefits of this treatment, focusing on the primary endpoint of PFS and several secondary endpoints, such as safety profile, OS, and quality of life. There are two other trials on Lutathera ® currently recruiting children (NCT03923257 in Iowa, USA) and adults (NCT04029428 in Warsaw, Poland) with nonresectable or treatment-refractory SSTR-positive PPGLs. Similar prospective clinical studies should be conducted to uncover the therapeutic potential of SSTR-targeting radiotherapy.

Ongoing Lanreotide Clinical Trial
The long history of adoption and trial of SSA with good outcomes perpetuated an environment of ongoing clinical research and investigation. This culminated in large studies, such as the PROMID and CLARINET trials, which showed the clinical benefit of SSAs in GEPNETs (6,7). However, the subset of NETs focused on in this review did not have extensive trials for testing the efficacy of cold SSA. There are reports of clinical stabilization of surgically unamenable PPGLs, two of which were patient experiences observed by our clinical team (80,108), but there were no prospective or retrospective studies to either strengthen or refute these claims (80,(108)(109)(110)(111). A prospective clinical trial (NCT03946527 in New York, USA) will evaluate the effectiveness of lanreotide in mPPGLs (LAMPARA) by observing tumor growth rate, overall survival, overall response rate, progression-free survival, and biochemical response.

Next Generation Cold SSAs
Overexpression of SSTRs on the cell surfaces of PPGLs has led to ongoing investigations that target and manipulate these receptors. The antiproliferative and apoptotic effects of somatostatin and its analogs upon binding with SSTRs were identified through extensive and detailed studies (112,113). Targeting SSTR 2 due to their preferential expression is the current and future direction of therapeutic management in these tumors (93,114,115). Cold SSAs, such as octreotide and lanreotide, have a proclivity to target SSTR 2 , which have been studied and utilized in various endocrine-related diseases, including GEPNETs and acromegaly (116). Pasireotide, a second-generation SSA, targets five SSTR subtypes, unlike octreotide and lanreotide. Although it was not superior to octreotide in terms of therapy or safety profile, it could be beneficial in tumors with broader expression of SSTR subtypes, including SSTR 1 , SSTR 2 , SSTR 3 , and SSTR 5 (117,118). Somatoprim, another second-generation SSA, is a multi-receptor targeting analog with a preference for SSTR 2 , SSTR 4 , and SSTR 5 , which was trialed in vitro on growth hormone (GH)-secreting pituitary adenomas. The results showed that it had anti-secretory effects on GH adenomas that were not controlled by octreotide (119). It would be worthwhile to investigate whether somatoprim has the same antisecretory effect in PPGLs. Dopastatin, a novel chimeric analog with dual binding ability to SSTR2 and dopamine receptors (D2), also exhibited an antisecretory effect on GH in acromegaly patients (120), and antitumor effects in midgut carcinoid cells in vitro (121). D2 receptors were expressed in larger amounts in 52 PPGL patients than 35 GEPNET patients (122), providing another targetable receptor for dopastatin analogs through radiopeptide imaging and therapy.

SSTR Antagonists
Development and research on SSA, which were recognized to antagonistically bind to SSTRs, are ongoing. According to an in vitro study by Ginj et al. (123), SSTR antagonists (SSTR-ANs) bound to NET SSTRs (especially SSTR 2 and SSTR 3 ) better than agonists but did not undergo subsequent internalization. These antagonists, sst3-ODN-8 and sst2-ANT were chelated to In by DOTA to create a receptor-targeting radioligand. These findings captured by gamma cameras were impressive in displaying antagonist-based radioligands, which bound more receptors for longer durations than their counterparts (123). The study caused a shift from the traditional theory that better binding and more benefits are derived from agonist-based analogs, mainly due to their ability to internalize the compound. A subsequent clinical comparison showed an antagonist-based SST ligand, 111 In-DOTA-BASS, which allowed better visualization and had higher uptake in NETs than 111 In-pentreotide (124). Based on the impressive results from first-generation SSTR-ANs, secondgeneration ones, such as LM3, JR10, and JR11, were developed. These second-generation SSTR-ANs were further improved in their SSTR binding capacity by using the chelator NODAGA  (125). A comparative study showed that 68 Ga-NODAGA-JR11 had higher tumoral uptake despite its lower affinity to SSTR 2 than 68 Ga-DOTATATE (126). The benefits were just as clear when 177 Lu-DOTA-JR11 was used for treating four patients with 18 advanced NETs, with a ten-fold higher dose than 177 Lu-DOTATATE and with reversible adverse events (127). A phase I/ II study (NCT 02592707) focusing on the endpoints of safety, tolerability, efficacy, biodistribution, and dosimetry of 177 Lu-OPS201 (also known as 177 Lu-DOTA-JR11) in unresectable GEPNETs, lung carcinoids, and PPGLs is currently underway. This study could provide an additional research perspective to identify therapeutic options for PPGLs.

Alpha Emitting 255 Ac-DOTATATE PRRT
Alpha-emitting radiometals are also being explored in the treatment of GEPNETs and PPGLs. A study explored the utility of 225 Actinium ( 225 Ac)-DOTATATE, a targeted alpha therapy (TAT), in 32 patients with metastatic GEPNETs refractory or stable after 177 Lu-DOTATATE therapy. Four patients with paraganglioma received TAT but were excluded from the analysis. Of the 32 GEPNET patients, 24 were assessed by RECIST 1.1 and found to have either stable or partial response. A positive biochemical response in chromogranin A (CgA) was observed as well, showing stable or decreased levels in 32 patients. There were also minimal grade III/IV toxicities reported in patients, which included gastritis in 7, weight loss in 5, flushing in 3, and headaches in 2 (128). Another study used 225 Ac-DOTATATE as compassionate care in two patients with progressive PCC after 3 cycles of 177 Lu-DOTATATE; however, results on the effectiveness and toxicity were not published (89).

Cytotoxic Compounds Conjugated to SSA
Another frontier of therapeutic innovation in SSTR targeting was that of compounds linking SSA and cytotoxic agents. The SSA, Tyr 3 -octreotate, was conjugated with a microtubule-targeting agent, DM1, creating PEN-221. SSTR 2 targeting of this agent was accomplished by the Tyr 3 -octreotate analog of the compound; after endocytosis, the DM1 portion induced a toxic payload within the targeted cells (129). A current phase I/II study (NCT 02936323) is ongoing for investigating the utility of PEN-221 in advanced NETs, including PPGLs.

CONCLUSION
The "Old Players" in the title of this review shows that SSAs have a historic role in treating and managing NETs. The review hopes to restore clinical awareness of these analogs through successes achieved in PPGLs. The theranostic utility of SSAs in PPGLs can be realized once federal approval is achieved. However, research and innovation should not be halted once an approval of Lutathera ® for unresectable PPGLs is garnered. Research should be continued for targeting SSTRs with secondgeneration SSAs, SSTR-ANs, chimeric dual receptor-targeting peptides, chemotactic delivery through SSTRs, and other novel methods.

AUTHOR CONTRIBUTIONS
MP and IT share first co-authorship; they contributed to the conception of the idea, creation of the outline, writing, reviewing, and editing. AJ contributed to creating an outline, conceptualization, reviewing, and editing. DT contributed to reviewing. KP contributed to creating an outline, conceptualization, review, and edit of the manuscript. All authors contributed to the article and approved the submitted version.