Lutathera® Orphans: State of the Art and Future Application of Radioligand Therapy with 177Lu-DOTATATE

Lutathera® is the first EMA- and FDA-approved radiopharmaceutical for radioligand therapy (RLT). Currently, on the legacy of the NETTER1 trial, only adult patients with progressive unresectable somatostatin receptor (SSTR) positive gastroenteropancreatic (GEP) neuroendocrine neoplasms (NET) can be treated with Lutathera®. Conversely, patients with SSTR-positive disease arising from outside the gastroenteric region do not currently have access to Lutathera® treatment despite several papers in the literature reporting the effectiveness and safety of RLT in these settings. Moreover, patients with well-differentiated G3 GEP-NET are also still “Lutathera orphans”, and retreatment with RLT in patients with disease relapse is currently not approved. The aim of this critical review is to summarize current literature evidence assessing the role of Lutathera® outside the approved indications. Moreover, ongoing clinical trials evaluating new possible applications of Lutathera® will be considered and discussed to provide an updated picture of future investigations.


Introduction
Radioligand therapy (RLT) with radiolabeled somatostatin analogues (SSA) is currently a mainstay in advanced gastroenteropancreatic (GEP) neuroendocrine tumor (NET) treatment, as it represents an ideal model of a modern system of personalized medicine. However, to reach this achievement required quite a long and challenging scientific journey. The first experiences with radiolabeled SSA, dating back to the late 1990s, employed yttrium-90 labelled SSA as radiopharmaceutical for RLT [1,2]. However, renal toxicities were not negligible, hindering the widespread of this therapeutic option [3]. Afterwards, the attention shifted to lutetium-177 labelled SSA, due to their more favorable toxicity profile and to the first positive experiences obtained with [ 177 [4]. The growing interest in this radiopharmaceutical led to the NETTER-1 study, a phase III multicenter trial whose results started a new era, demonstrating the most favorable outcomes of [ 177 Lu]Lu-DOTATATE RLT plus octreotide LAR 30 mg versus octreotide LAR 60 mg alone [5]. As a consequence of NETTER-1 results, [ 177 Lu]Lu-DOTATATE was finally approved by the European Medicines Agency (EMA) in September 2017, the Food and Drug Administration (FDA) in January 2018, the Canada Health in January 2019, and the State of Israel Ministry of Health in July 2019 (Lutathera ® ) [6][7][8][9][10]. Currently, Lutathera ® is approved in 23 countries worldwide. However, this should be considered only a partial achievement as a large portion of tumors overexpressing somatostatin receptors (SSTR) still cannot be treated with Lutathera ® , giving rise to the so-called "Lutathera Orphans". Indeed, Lutathera ® is currently administered in a protected hospitalization regime and is indicated in adult patients diagnosed with well-differentiated (G1 and G2) gastroenteropancreatic neuroendocrine tumors (GEP-NET) that are progressive, non-removable or metastatic, and positive to the receptors for somatostatin. [11]. Therefore, paediatric patients cannot be treated with Lutathera ® . Similarly, patients with newly diagnosed or stable metastatic disease, even if symptomatic or affected by a large burden of disease, are not eligible for this therapy despite promising literature evidences [12]. Finally, G3 NET, neuroendocrine carcinomas (NEC), or extra-GEP-NET patients are still Lutathera ® orphans as well, even though they often show intense overexpression of SSTRs at functional imaging. Among extra-GEP-NET group, bronchial carcinoids, pheochromocytomas (PHEOs), paragangliomas (PGLs) and neuroblastomas, meningiomas, unknown primary (CUP) NETs and some other infrequent tumors can all be listed.
The aim of this review is to provide an updated picture of the literature's reporting of [ 177 Lu]Lu-DOTATATE treatment outside current indications. Moreover, ongoing clinical trials aiming to evaluate new possible applications of Lutathera ® will be considered and discussed in order to provide a starting point for allowing access to RLT for a greater percentage of NET patients in the future.

Materials and Methods
A critical literature review was conducted on PUBMED and Scopus databases up to the 31 January 2023 with the aim of analyzing papers describing the applications of Lutathera ® or [ 177 Lu]Lu-DOTATATE outside currently approved indications. In particular, evidence discussing RLT in G3 GEP-NETs, bronchial carcinoids, pheochromocytomas and paragangliomas, meningiomas, CUP-NETs, and other rare tumors overexpressing SSRT2 and RLT retreatment (named salvage RLT) were all collected and discussed. Only articles in the English language were selected. Papers reporting the use of RLT associated with other oncological therapies were not considered.

G3 GEP-NET and NEC
Currently, Lutathera ® is approved only for G1 and G2 GEP-NETs. Only a few examples, mostly retrospective studies, have been published regarding the possible role of RLT in G3 GEP-NET or NEC [14][15][16][17]. Overall, results have demonstrated a survival benefit, expressed as improved progression-free survival (PFS) (between 9 and 23 months) and overall survival (OS) (between 19 and 53 months) as well as a significant disease control rate (DCR) ranging between 30% and 80%. In particular, patients with a Ki-67 index < 55% seem to better respond to RLT in comparison to those with a higher proliferation index. Furthermore, the rates of toxicity in G3 patients were only mild and comparable to those involving G1-G2 patients [18]. Therefore, following these preliminary encouraging results, ESMO guidelines suggest RLT as a therapeutic option for G3 NET patients, although with a level of evidence of IV and grade of recommendation of C [19].
Based on valid results of the above mentioned retrospective studies, two phase III clinical trials are currently ongoing: the NETTER-2 (NCT03972488) and the COMPOSE (NCT04919226) [20,21]. The first is a multicenter, randomized, and open-label study aiming to assess the impact of Lutathera ® combined with long active octeotride on PFS. In particular, the study is enrolling GEP-NET patients with G2 (Ki-67 ≥ 10%) and G3 (Ki-67 ≤ 55%) diseases. Conversely, the COMPOSE trial aims to evaluate the outcomes and safety of RLT with another radiopharmaceutical agent, [

Bronchial Carcinoids
Bronchial carcinoids (BCs) are uncommon neuroepithelial neoplasms representing a separate biological-molecular entity from neuroendocrine lung carcinomas [27]. BCs are classified as typical carcinoids (TCs)-characterized by slow growth and better outcomesand atypical carcinoids (ACs)-very infrequent (about 0.2%), aggressive tumors with great potential of metastatic spread. Differently from GEP-NET, Ki-67 expression does not differentiate between TCs and ACs, and according to WHO guidelines, BC grading relies on mitotic index and tumor necrosis [28].
Treatment of bronchial carcinoids is not simple and requires a multidisciplinary approach. Surgery remains the mainstay of treatment for local disease, while in advanced disease, management includes chemotherapy, "cold" somatostatin analogues, immunotherapy, everolimus, and others target therapies [28,29]. RLT is an option for selected patients with advanced or metastatic BCs overexpressing SSTR in progression to "cold" SSAs therapy. Although the experience of [ 177 Lu]Lu-DOTATATE is more limited in BCs than GEP-NET, off-label use can be considered with promising results [30,31]. A prospective phase II trial in 34 patients with stage IV BCs treated with cumulative activity of 18.5-27.8 GBq in four or five cycles of [ 177 Lu]Lu-DOTATATE documented a DCR of 80% (6% complete response, 27% partial response, and 47% stable disease) and a median PFS of 20 months [32]. In this study, negative prognostic factors were AC histology, tumor thyroid transcription factor-1 (TTF-1) expression, and a positive [ 18 F]FDG PET imaging. Comparable results (median PFS of 17 months) were reported in a group of patients with diffuse extrahepatic metastases treated with RLT after several lines of therapies [33].
Higher activities were administered in a study by van Essen et al. [34], who treated nine patients with metastatic BCs, delivering a cumulative dose of 22.2-29.6 GBq of [ 177 Lu]Lu-DOTATATE, demonstrating an overall response rate comparable to that of other GEP-NET (50% vs. 47%, respectively for BCs and GEP-NET). Moreover, tumor regression was reported in 66.6% of patients, without any outcome discrepancies between TCs and ACs. Comparable median OS and response rate between BCs and others GEP-NETs were reported also in another recent retrospective study [35]. Likewise, the efficacy of RLT in BCs was demonstrated by Brabander et al. [36]  Functioning BCs could secrete various hormones, causing ectopic Cushing syndrome, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and carcinoid syndrome. A recent study [37] analyzed the effect of [ 177 Lu]Lu-DOTATATE treatment in patients with NETs and carcinoid syndrome insufficiently controlled by "cold" SSa, demonstrating that RLT can be effective in reducing diarrhea and flushing, and it can be considered as an alternative treatment in symptomatic patients. RLT has also been demonstrated to improve the quality of life in BCs and in GEP-NETs [38].
Long term results were analyzed by Mariniello et al. [39]

Pheochromocytomas and Paragangliomas
PHEOs and paragangliomas PGLs (collectively named PPGLs) are infrequent neuroendocrine neoplasms originating from chromaffin cells. PHEOs arise from the adrenal medulla, whilst PGLs are extra-adrenal tumors, potentially arising from any part of the sympathetic or parasympathetic nervous system [40,41]. The majority of these neoplasms are considered benign even though the local growth can cause mass effects, particularly for PGLs localized in the head and neck region [42]. Nevertheless, a variable number of these tumors, ranging between 2-26%, can develop metastasis. Currently, histopathology is unable to distinguish between benign and malignant PHEOs or PGLs. Therefore, most updated guidelines suggest considering that any lesion can have metastatic potential [43,44]. A strong genetic component is described in these neoplasms, and the most frequent mutations involve succinate dehydrogenase (comprehending A/B/C/D/AF2, collectively called SDHx mutations) and von Hippel-Lindau (VHL) genes. In particular, patients with SDHB mutation-which is often inherited as an autosomal dominant germline-have a high risk of metastatic disease occurrence [45]. Overall, PGLs originating from the sympathetic chain and PHEOs can be functioning, as they may secrete catecholamines. The deriving sympathetic overactivity can cause secondary hypertension, palpitations, headache, sweating, and a state of anxiety. Therefore, the therapeutic management of these patients is often complicated as a balanced alpha-and beta-adrenergic blockade is needed [41].
Metastatic PPGLs represent a challenging disease entity with limited therapeutic options available [46]. A nuclear medicine theranostic approach utilizing [ 123 I]metaiodobenzyl guanidine ([ 123 I]MIBG) as diagnostic and [ 131 I]MIBG as therapeutic agent has been tested and approved by FDA (Azedra ® ) [47]. However, this theranostic model presents several drawbacks, including dosimetric issues and consequent high risk of therapy-related myelosuppression [46]. In recent years, growing evidence of the overexpression of SSTR type 2 and 3 in PPGLs determined an increased use of [ 68 Ga]Ga-DOTA-SSA PET/CT [48][49][50]. Overall, a lesion-based sensitivity of 92% was reported across a wide range of mutations, outperforming any other functional imaging investigation, in particular for SDHx mutated metastatic PPGLs and in non-metastatic head and neck PGL [49].
As a consequence, we saw a rising interest in a potential radiolabeled-SST agonist theranostic approach for PPGLs, with several spontaneous studies reporting of the treatment of metastatic or inoperable tumors with Lutathera ® and other similar radiocompounds, with promising preliminary results [51,52]. The first RLT experience in PPGLs was reported by van Essen et al. [53], who treated a heterogeneous cohort of patients, including 12 PGLs. Despite the authors reporting lower response rates than those obtained in GEP-NET patients, ORR and DCR were 18% and 73%, respectively. These results are consistent with  14 due to uncontrolled secondary hypertension and 6 to radiological PD. A DCR equal to 86% was reached, including five patients with ORR (36%). Of note, 62% of symptomatic patients required a dose reduction of antihypertensive medications, and 57% reported a subjective therapeutic benefit in terms of tumor-related symptoms. Comprehensive PFS was 39 months, including two patients with early recurrence (2 and 5 months post-RLT, respectively) and one patient with remarkable tumor downsizing that allowed a second-step curative liver surgery. Of note, the patient was still disease-free at the time of the study. The results of the largest cohort of PPGLs treated with RLT were reported by Severi et al. [58], who treated 46 patients reaching a comprehensive DCR of 80%. Interestingly, 34 patients treated with [ 177 Lu]Lu-DOTATATE obtained a longer median OS in comparison to those treated with [ 90 Y]Y-DOTATOC (143 vs. 92 months, respectively). According to the authors, this result may be related both to DOTATATE's higher affinity for SSTR2 (which is the type most overexpressed in PPGLs) and to the longer half-life of 177 Lu and, consequently, prolonged residence time within the tumor lesions. Moreover, this study reports that sympathetic functioning PPGLs were associated to a shorter median PFS compared to non-functioning PPGLs. Prado-Wohlwend et al. [40]  [ 117 Lu]Lu-DOTATATE treatment was safe and well-tolerated in the vast majority of patients treated, with only mild and transient side effects reported [40,41,53,[55][56][57][58]. Of note, a patient presented a reactive painful swelling of tumor metastases that required escalation of analgesia [55]. In a very few cases, treatment was prematurely terminated due to hematologic toxicity (thrombocytopenia and anemia) [53]. Catecholamine crisis is an early infrequent complication in symptomatic PPGLs treated with [ 177 Lu]Lu-DOTATATE. A combined α/β-adrenergic blockade should be considered when treating these patients, with a protocol similar to that used before adrenal surgery [59].
A special mention should be made for neuroblastoma, which is an aggressive tumor mainly affecting pediatric patients, that can overexpress SSTR [60,61]. However, there are still few studies conducted, and they are on a small number of patients. In particular, Fathpour et al. [62] treated five pediatric patients who were affected by relapsed or refractory metastatic neuroblastoma with [ 177 Lu]Lu-DOTATATE. As a result, the authors report two complete responses, one partial response, and two progressive diseases, with an OS of 14.5 months. Hopefully, a pair of ongoing clinical trials (discussed below) aiming to evaluate intensified RLT in these aggressive tumors will provide more favorable results.

Meningiomas, CUP-NETs, and Other Rare Tumors Overexpressing SSTR
Meningiomas are the most common primary intracranial tumors, originating from arachnoid cap cells [63]. In most cases, meningiomas are single and benign, but occasionally, they can occur in multiple forms both in the brain and in the spinal cord. Despite being generally slow-growing, meningiomas can become very large, and the consequent mass effect can determine disability and become life-threatening. The WHO classifies meningiomas in three different grades of dedifferentiation that are associated with very different outcomes: from grade I (benign) to grade II (atypical) and III (anaplastic or malignant) [63]. In high-risk or symptomatic meningiomas, first choice treatment is usually surgery plus/or radiation therapy. The use of systemic treatments is not standardized, and the most promising results have been obtained with antiangiogenic treatments and mTOR inhibitors [64].
Meningiomas usually overexpress SSTRs. In particular, SSTR2 are usually overexpressed among skull base meningiomas. Conversely, spinal meningiomas usually express other SSTRs, while WHO grade III meningiomas are often SSTR-negative due to dedifferentiation and consequent loss of SSTR expression [65]. Overexpression of SSTR2 potentially allows RLT with [ 177 Lu]Lu-DOTATATE, although this treatment is not currently approved for meningiomas due to the lack of large-scale randomized trials [66]. Nevertheless, in the future, RLT could hopefully carve out a role in recurrent or in unresectable meningiomas after other standard therapies have failed.
Several studies confirmed the poor outcome for high grade meningiomas treated with RLT [68,71]. Conversely, Minczeles et al. [72] documented both a decline in tumor growth rate and a relatively good disease control in 15 patients who received [ 177 Lu]Lu-DOTATATE, with low systemic toxicity. Probably, baseline SSTR2 expression may play a key role in the correct selection of patients with aggressive meningiomas to address to RLT.
An increase in treatment efficacy may be achieved via intra-arterial RLT injection, providing a significant tracer accumulation and promising improvement for the salvage treatment of meningioma patients [73,74]. Moreover, aggressive meningiomas may benefit of the combination of RLT with external beam radiotherapy [75,76], although further studies are necessary to determine its efficacy and survival improvements.
A special mention should be made for CUP-NETs, definable as metastatic NETs diagnosed from the histopathological assessment of a metastasis. CUP-NETs are not that infrequent, representing 20-25% of all diagnosed NETs. These tumors might originate from very small lesions, probably mainly arising from the GEP-NET district, and the absence of a known primary site is a negative prognostic factor, as it limits available therapeutic options [77]. Indeed, [ 68 Ga]Ga-DOTA-SSA PET/CT is estimated to detect the unknown primary tumor only in about 60% of CUP-NET patients and this is an important limit to overcome, as CUP-NETs-despite usually intensively overexpressing SSTRs-are still "Lutathera ® orphans" [78,79].
Unfortunately, the literature lacks specific trials assessing RLT efficacy and safety on CUP-NETs, and the only available literature evidence is provided by mixed trials also including a few patients with SSTR-positive CUP-NETs [36,56,80,81]. In a large cohort of patients treated with [ 177 Lu]Lu-DOTATATE, Brabander et al. [36] reported of 82 CUP-NET patients. Overall, DCR was reached in 78% of patients and median PFS and OS were 29 and 53 months, respectively. These results show that RLT may be effective in CUP-NETs patients, with a response rate intermediate between that obtained in GEP-NETs-who showed longer median OS (60 vs. 53 months, respectively)-and BCs-who showed shorter median PFS (20 vs. 29 months, respectively). These results are consistent with those reported by Demirci et al. [56] [83], mantle cell lymphoma [84], radioiodine refractory thyroid cancer [85], sarcoma [86], and breast cancer [87].
Medullary thyroid carcinoma (MTC) represents 1-5% of all thyroid malignancies, and it usually overexpress SSTR [88]. A few authors reported MTC patients treated with RLT, and a recent review reports biochemical and objective responses in 37.2% and 10.6% patients, respectively [89,90]. Maclean  The most relevant papers regarding RLT in "Lutathera ® Orphan" neoplasms are reported in Table 1. ORR = overall response rate; DCR = disease control rate (complete, partial, and stable disease); mo.= months; nr = not reached; RA = retrospective analysis; PA = prospective analysis.

RLT Retreatment
NETTER-1 clinical study has represented the milestone for approving RLT with Lutathera ® in patients with progressive and unresectable midgut, well-differentiated (G1, G2) NET with positive SSRT imaging. Indeed, patients group treated with Lutathera ® had a longer survival, expressed as PFS and OS, compared to those treated with only high-dose octreotide [5]. Nevertheless, despite these encouraging results, most patients relapse after RLT within a variable interval of time, leaving few options for future therapy. Therefore, retreatment with RLT, the so called "salvage RLT", might represent a new valuable strategy for patients who present disease progression, although it is not currently approved. Until now, few clinical studies have been published [94][95][96][97][98][99][100][101][102] or are under investigation (NCT04954820, expected completion in 2029). All the studies, although conducted on small cohort of patients, have demonstrated an acceptable safety profile with a limited number of grade 3-4 toxicities, comparable to first-course RLT. Moreover, patients who underwent salvage RLT showed prolonged survival in terms of both PFS and OS. Recently, one of the largest clinical trials (involving 168 GEP-NET and 181 BCs) with the longest follow-up (80.8 months) showed a PFS of 14.6 months after re-treatment with two additional cycles of [ 177 Lu]Lu-DOTATATE. In addition, OS was significantly longer in patients with BCs, GEP-NET, and midgut NET treated with salvage RLT compared to those in the nonrandomized control group. It is of note that adverse events were comparable between the initial four cycles of RLT and the salvage RLT group [94]. Similarly, van der Zwan et al. [100] demonstrated the efficacy and safety of retreatment in BCs patients, obtaining a significant longer OS in patients treated with salvage PRRT than in the control group (80.8 vs. 51.4 months). No grade III/IV renal toxicity occurred after retreatment, with mild and transient short-term side effects reported. Infrequent severe long-term toxicities comprehended acute leukemia or myelodisplasy but occurred only in 2% of patients. Furthermore, Sitani et al. [101] reported similar encouraging results in terms of the efficacy, survival, and toxicity of salvage RLT using the indigenous "direct route" [ 177 Lu]Lu-DOTATATE, which is a cost-effective procedure for producing 177 Lu adopted in most RLT centers in India.
Nevertheless, from the above mentioned studies emerge some questions that should be clarified in order to establish new recommendations for patients with progressive NET and potential candidates for salvage RLT [103,104]. Indeed, there is a wide variability in terms of cumulative administered activities, ranging between 14. 8 84.6% DCR for salvage RLT, and PFS was similar to that of primary RLT (22 vs. 28 months, respectively). Moreover, low incidence of severe toxicities after salvage RLT was reported, with hemoglobin levels restored within 3 months after treatment and only one patient with persistent renal damage.
Another aspect that should be standardized regards the number of additional cycles, which is between 1 and 13. Recently, a prospective, randomized, phase II clinical trial was proposed, aiming to compare four versus two Lutathera ® retreatment cycles in patients with new progressions of a well-differentiated intestinal NET [102].
The answer to these open questions could be provided by personalized dosimetry [105]. Notably, Garske-Romàn et al. [106] performed salvage RLT with variable cycles (3-9) until reaching 23 Gy of absorbed dose (AD) to the kidneys unless the treatment had to be stopped due to other reasons. Remarkably, patients reaching the AD threshold to the kidneys (61.5%) showed longer median PFS (33 vs. 15 months) and OS (54 vs. 25 months) than those who did not. Despite reaching 23 Gy of AD to the kidneys, only 4% of patients demonstrated G2 kidney toxicity, while only one patient (0.5%) had G4 kidney toxicity. These results are consistent with those of Sundlöv et al. [107], who also reported that individualized RLT, tailored on renal dosimetry, seems feasible and safe without grade 3-4 toxicity being observed. These results hint that salvage RLT is safe and effective, particularly if offered with a tailored dosimetric approach. Moreover, this approach leads to an increased number of cycles in the majority of patients, thus providing a potential advantage in terms of outcomes.
The identification of other prognostic biomarkers is another open challenge for patients with NET undergoing salvage RLT. Galler et al. [81] analyzed whether two clinical variables associated with PFS during primary RLT were also prognostic parameters for salvage RLT. At multivariate analysis, only the higher size of the largest lesion was able to predict PFS, whereas aspartate aminotransferase/alanine aminotransferase ratio (named "De Ritis ratio") was not.

Ongoing Clinical Trials
Overall, 74 trials were retrieved from the research on https://clinicaltrials.gov/ (accessed on 13 February 2023). Thirty-nine trials met the inclusion criteria defined for this review, and their details were included in Table 2.  To establish the MTD of cabozantinib in combination with Lutathera ® at a standard dose followed by continuation cabozantinib.  Among those, 2 trials were withdrawn and 2 are already concluded, with the remaining 35 currently ongoing. Interestingly, most trials include meningiomas or other infrequent tumors overexpressing SSTR (n = 16) and non-GEP NET (n = 7). Moreover, the evaluation of RLT outcomes in PPGLs is the main aim of six trials. Notably, seven trials are recruiting also pediatric patients, who are currently excluded from Lutathera ® indications. Among those, two trials are designed to investigate an intensified dosing schedule in pediatric patients affected by neuroblastoma. Indeed, trials investigating [ 177 Lu]Lu-DOTATATE in neuroblastoma patients failed so far, and this can be due both to the insufficient activities administered and to the too long intervals between the cycles of therapy [109]. Therefore, following the example of [ 131 I]MIBG, current trials are evaluating intensified cycles for this poor prognosis rapidly proliferating tumor. One trial is assessing RLT as neoadjuvant treatment in pancreatic NET, which is another promising future indication of [ 177 Lu]Lu-DOTATATE [12]. Finally, eight trials involve NET G3, five BCs, and one trial aims to assess efficacy and safety of salvage RLT.

Discussion
Lutathera ® approval represented a milestone in the history of NET management. Indeed, these infrequent and very heterogeneous neoplasms have always represented a challenge for clinicians, as patients may present at diagnosis with very high burden of disease, poorly responsive to conventional therapies [114]. Therefore, allowing access to RLT to the largest possible population may offer an additional weapon to improve NET patients' outcomes. Nevertheless, only a limited portion of NET patients are currently eligible for RLT outside clinical trials.
G3 GEP-NET tumors with Ki-67 index < 55% currently have very few therapeutic options but may be among the first "orphans" to gain access to Lutathera ® thanks to the NETTER-2 trial [18]. Probably, these neoplasms, which present a moderate differentiation and a high Ki-67 index, may benefit from combined RLT and chemotherapy (i.e., capecitabine and/or temozolomide), with the latter working both as radiosensitizer agent and offering a therapeutic effect on [ 18 F]FDG-positive lesions [115]. These approaches could be useful also in treating aggressive meningiomas, mainly grade II. Even though the literature is limited in describing therapy for these tumors, available data suggest that RLT, alone or combined with systemic drugs, might be taken into account based on meningiomas' SSTR expression at baseline imaging. Similarly, the literature results indicate that RLT proved to be promising in prolonging survival and delaying disease progression in BCs, which are already treated with off-label RLT in some countries. However, the optimal timing of RLT in the therapeutic management of BCs is still debated and prospective trials are needed to strengthen current preliminary evidence.
PPGLs represent another group of "Lutathera ® orphans". Despite quite promising literature evidence in terms of safety and efficacy of RLT, further prospective trials are still needed to reach treatment approval [116]. A high baseline uptake at [ 68 Ga]Ga-DOTA-SSA PET/CT is reported as a strong predictor of RLT efficacy in these neoplasms, that currently present very poor therapeutic options available [57]. Interestingly, RLT seems to be particularly useful to improve the quality of life in patients with catecholamine secretion, allowing to reduce anti-hypertensive drugs [41]. Overall, a DCR between 70-80% is reported for these neoplasms treated with RLT, which is higher than that reached by [ 131 I]MIBG and with a safer toxicity profile [40,41]. Notably, the treatment of patients with catecholamine secretion must be handled gingerly due to the infrequent but possible therapy-induced catecholamine crisis. Therefore, this treatment could have a future limited to a small number of selected RLT referral centers capable of managing this kind of emergency.
Finally, literature evidence reports that retreatment with RLT is safe and effective and will hopefully obtain approval in the upcoming years [94,100]. NET patients usually have long life expectancy, and they often relapse after treatment [117]. Therefore, the possibility of offering a second-course RLT would be of great clinical usefulness. Future trials should focus on obtaining a joint standardized therapeutic program for salvage RLT both in terms of number of cycles and activity to inject per cycle. Dosimetry is expected to play a key role for this "orphan indication", helping to improve personalization and maximizing the possible treatment benefits, albeit helping to maintain safe AD to the organs at risk.