Clinical and Translational Imaging https://doi.org/10.1007/s40336-018-0267-x

EXPERT REVIEW

Peptide receptor radionuclide therapy for neuroendocrine tumours Siraj Yusuf1   · Shahad Alsadik1 · Adil AL‑Nahhas1 Received: 28 December 2017 / Accepted: 12 February 2018 © Italian Association of Nuclear Medicine and Molecular Imaging 2018

Abstract Background  Neuroendocrine tumours (NETs) are a heterogeneous group of tumours that arise in different tissues and organs and have an endocrine and neurological interface that differentiates them into a stand-alone entity. One of their interesting and unique criteria is the overexpression of somatostatin receptors (SSRs) on their cell membrane, which has allowed for specific diagnostic imaging techniques and targeted therapy like peptide receptor radionuclide therapy (PRRT). Objective  The aim of this study is to provide a literature review summarizing the latest available studies concerning the use of PRRT in treatment of neuroendocrine tumours including patient selection, the choice of PRPP, efficacy, side effects, and complications. Methods  A comprehensive search strategy was used based on SCOPUS and PubMed databases. We considered all studies published in English evaluating the use of PRRT (177Lu-Dotatate and 90Y-Dotatate) in treatment of NETs and its effectiveness and side effects and complications. Results  PRRT was found to be effective as monotherapy or in combination with other therapies. 90Yttrium may be more appropriate for larger tumour lesions, while 177Lutetium is more appropriately used for smaller ones. A combination therapy with 90Yttrium and 177Lutetium has been suggested for variable sized lesions. Mild acute side effects were reported more in 177Lutetium, while sub-acute and long-term side effects are more with 90Yttrium. Heamatotoxicity is usually mild and reversible and only < 15% may progress into severe toxicity. Renal toxicity was greatly reduced to < 3% by kidney protective measures. Conclusions  PRRT is well-tolerated and effective treatment modality for non-operable and/or metastatic neuroendocrine tumours. Side effects are usually mild and reversible. More work needs to be done regarding standardization of dosing, timing, and patient selection criteria and ways of follow-up to obtain the maximum potential benefit. Keywords  PRRT​ · Neuroendocrine tumours · 177Lu-Dotatate · 90Y-Dotatate · SSTR 1–5 · 68Ga-Dotatate PET/CT

Introduction Peptide receptor radionuclide therapy (PRRT) is a targeted internal radiation therapy using a radiolabelled peptide. The aim is to use a molecular binding ligand with a high affinity to specific receptors on the target cell thereby delivering the maximum therapeutic radiation dose to its target tissue, with minimal radiation burden to normal tissue elsewhere. Neuroendocrine tumours (NET) have been a particular focus of

* Adil AL‑Nahhas Adil.al‑[email protected] 1



Department of Nuclear Medicine, Hammersmith Hospital, Imperial College NHS Trust, Du Cane Road, London W12 0HS, UK

PRRT, due to the overexpression of somatostatin receptors found on their cell surface.

Neuroendocrine tumours Neuroendocrine tumours are a heterogeneous group of epithelial tumours with predominant neuroendocrine differentiation and can arise in many different organs. They were originally described as multiple distinct entities based on their site origin, hormonal symptoms, and metastatic behavior [1]. Although rare, neuroendocrine tumours have demonstrated an increased incidence over the past 30 years, possibly due to improved diagnosis. Recent analysis by Public

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Health England suggests an incidence of neuroendocrine tumours in the UK of 8 per 100,000 [2]. NET may be functional or non-functional based on their hormone secretion profile, in particular those arising in the pancreas. Functional tumours, such as VIPomas, gastrinomas, and insulinomas, may present early with clinical symptoms. Non-functional or subclinical tumours invariably present later, with an indolent course and increased risk that they will have become locally advanced or metastatic at time of presentation. They may also present as part of one of several complex hereditary disorders with a predisposition to tumours in endocrine glands, such as multiple neuroendocrine neoplasia type 1 (MEN-1) or von Hippel–Lindau syndrome (VHL). Classification systems for NET are almost as varied as the tumours themselves, in part due to their diverse clinical and biological characteristics. Early attempts at classification were based on embryological origin (foregut, midgut and hindgut), as well as histopathological and receptor features; these have varied based on site-specific features. Subsequent, more comprehensive, classification of neuroendocrine tumours moved away from a site-based classification to a system based on morphological, functional as well as biological features. These classifications include mitotic count, Ki-67 proliferation index (which reflect the dynamics of tumour growth) and the histopathological appearance as part of the grading system, dividing the disease into low, intermediate, and high grades (grades 1–3), respectively. This has resulted in the most recent classifications including the WHO classification in 2010 for NET in the digestive tract and WHO classification in 2015 for NET in the lung [3–9] (Tables 1, 2). In 2017, a new WHO classification emerged for pancreatic neuroendocrine neoplasm that divided G3 into: well-differentiated neuroendocrine tumours and poorly differentiated neuroendocrine carcinoma (Table 3) [10, 11]. However, that new change in classification did not affect the use of PRRT as it is still indicated for G1 and G2 only. Staging of the tumour usually remains based on the TNM system. One of the more specific features of neuroendocrine tumours is the overexpression of somatostatin receptors on their cell membrane. There are several somatostatin receptor subtypes that are presented on the surface on neuroendocrine Table 1  WHO 2010/ENETS classification of gastroenteropancreatic NET Neuroendocrine tumour G1 (Ki-67 < 2%) Neuroendocrine tumour G2 (Ki-67 3–20%) Neuroendocrine carcinoma G3 (Ki-67 > 2%)  Large cell  Small cell

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Clinical and Translational Imaging Table 2  WHO 2015 classification of lung NET Typical carcinoid (TC)/low-grade malignant tumours Atypical carcinoid (AC)/intermediate-grade malignant tumours  Large cell neuroendocrine carcinoma (LCNEC)  Small cell lung carcinoma (SCLC)  High-grade malignant

cells in humans, SSTR1, SSTR2, SSTR 3, SSTR4, and SSTR5, that have so far been characterised [12]. Symptoms relating to NET can present themselves in various ways depending on the predominant hormonal and functional criteria as well as the local involvement and pressure on adjacent tissues. Despite being slow in their development and delayed in their presentation, they can eventually progress and metastasize leading to significant morbidity and mortality. NETs can metastasise to several organs potentially depending on the site of primary tumour. Metastases commonly involve lymph nodes, liver, bone, and less commonly lungs and pituitary gland [13]. Early diagnosis and treatment are key factors in the management of these tumours. Diagnosis of NETs is a multi-modality approach in which cross-sectional imaging plays a part side by side with functional imaging that utilize the presence of the various SSTR on the cell membrane of these tumours.

Literature search Our aim was to search the literature to assess the outcome of PRRT in the treatment of NETs compared with other treatment modalities, answering the following questions: • How to select patients and how to choose the optimum

PRRT?

• What is the efficacy of PRRT?

Table 3  WHO 2017 classification of pancreatic NETs Ki-67 index (%) Well-differentiated NENs Neuroendocrine tumour (NET) G1 < 3 Neuroendocrine tumour (NET) G2 3–20 Neuroendocrine tumour (NET) G3 > 20 Poorly differentiated NENs  Neuroendocrine tumour (NEC) G3 > 20   Small cell type   Large cell type Mixed adenoneuroendocrine carcinoma (MANEC)

Mitotic index < 2/10 HPF 2–20/10 HPF > 20/10 HPF > 20/10 HPF

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• What is the side effect and complications of PRRT?

Study rationale Neuroendocrine neoplasms are under massive focus during the last 20 years, since its incidence increased remarkably. Significant advances and breakthroughs were achieved so far. However, this rapid development is challenging and requires more thorough work in assessing the newly evolved therapeutic modalities.

Search strategy A comprehensive search strategy for articles was adopted in the SCOPUS, and PubMed databases. The terms used for the search included ‘PRRT’, ‘Neuroendocrine tumours, ‘177Lu-Dotatate, ‘90Y-Dotatate’, ‘SSTR 1–5, and’ 68Ga-Dotatate PET/CT’. The initial search reveals 300 relevant papers published in the last 10 years. We considered all studies published in English evaluating the use of PRRT (177Lu-Dotatate and 90Y-Dotatate) in treatment of NETs and its effectiveness and side effects and complications. The included studies’ abstracts were checked for their relevance to the research question, and the eligible articles were extensively assessed for inclusion in this work. Additional papers were obtained for the bibliographies of the included studies. A thorough evaluation was conducted on the studies that have been chosen regarding their relation to the topic, results and outcome.

Inclusion criteria 1. Studies in the English language 2. Studies of human only 3. Original Research paper about the use of PRRT in neuroendocrine tumours.

Treatment options Although surgery is the only truly curative option for both functional and non-functional NETs, not all cases are operable [14]. Unfortunately, most patients with NETs have metastatic disease at time of diagnosis [15]. Metastatic disease may be amenable to a range of treatment options including chemotherapy, octreotide analogues, and PRRT. Chemotherapy may have a greater role in high-grade metastatic NETs. Novel targeted chemotherapy agents, such as Everolimus, have shown some promise in early trials in increasing progression free survival [16–18]. PRRT is usually the second or third treatment option in metastatic grade 1 and 2 NETs. It could be used as mono-therapeutic or in combination with other treatment modalities. An example is a case of pituitary metastasis of

NET, which was treated using combined ‘cold’ and “hot” (radiolabelled) octreotide and showed very encouraging results [13]. Combined PRRT with radio-sensitising chemotherapy was found to enhance the effect of PRRT. However, the potential increase in side effects is a major limiting factor [19, 20]. Patients with limited oligo-metastatic disease may benefit from targeted treatment options: these include localized ablative therapy in the liver, such as selective internal radiation therapy (SIRT) or trans-arterial chemoembolization (TACE), both ensuring higher dose of tumour exposure with less non-targeted tissue damage elsewhere. PRRT can also be used as neoadjuvant mainly for inoperable pancreatic NET to decrease tumour size and render it operable. [21, 22].

Choice of PRRT​ 111

In-DTPA Octreotide (111In-pentetreotide) has been a wellestablished tracer for scintigraphic imaging for tumours that express somatostatin receptors, in particular neuroendocrine tumours. Octreotide is an analogue of somatostatin, with a high affinity to the SSTR2 and SSTR5 subtypes. Use of high dose 111In-pentetreotide using the emitted Auger electrons to deliver cytotoxic doses of radiation to the target cells, demonstrated early promise with symptomatic relief in metastatic disease, and possibly prolonged survival, but little objective tumour response [23–25]. Nonetheless, 111In-pentetreotide showed significant drawbacks and has been superseded by the more efficient β− emitting somatostatin targeting agents, 90Yttrium (90Y) and 177Lutetium (177Lu) being the most common radioisotopes in current use. 90 Y is a pure β-emitter, with a maximum penetration of 12 mm in soft tissue, and a half-life of 64 h. 177Lu is a βand γ-emitter, with a half-life of 162 h; the β− particles have a lower maximum energy than for 90Y, with a maximum penetration of 1.7 mm in soft tissue. However, this is compensated for by a longer half-life of 177Lu compared to 90Y. In addition, relatively abundant γ emission from 177Lu at an appropriate energy also allows scintigraphic imaging of the distribution of the therapy dose. 90 Y and 177Lu can be chelated with the modified somatostatin analogues, commonly [­DOTA0,Tyr3]Octreotide (DOTATOC), ­[DOTA0,Tyr3]Octreotate (DOTATATE) and [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]1-Nal3-octreotide (DOTANOC), respectively. The DOTAchelated somatostatin agonists show high affinity for the SSTR2, with DOTATATE having a higher affinity than the DOTATAOC [7, 13].

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Although a randomised trial comparing 90Yttrium (90Y) and 177Lutetium (177Lu) -based PRRT is lacking, outcomes of both PRRT were comparable [26]. Pre- clinical studies report 90Yttrium as being more appropriate for larger lesions due to longer path length of the high energy of b-emission while 177Lutetium is more appropriately used for smaller ones due to short path length of the medium energy b-emission. A combination therapy with 90Yttrium and 177Lutetium has been suggested to for clinical situations involving variable sized lesions [13, 20]. Villard et al. treated a large group of 486 patients either with 90Y-DOTATOC monotherapy or with the combination of 90Y-DOTATOC and 177Lu-DOTATOC. Patients who were able to complete three or more treatment cycles of the combination therapy had a significantly longer survival than patients receiving 90Y-DOTATOC alone [27].

Efficacy of PRRT​ The efficacy of PRRT is usually measured through imaging response, using anatomical and functional imaging with 68-Gallium (68GA) DOTA PET/CT, biochemical response like chromogranin A (CgA), 5-hydroxy-indoleacetic acid (5-HIAA) or any other peptide hormone (e.g., proinsulin, gastrin, etc.) or clinical response including symptoms, quality of life, and survival analysis. A large phase II open label trial of over 1100 patients at a single centre looked at treatment effects in patients receiving repeated cycles of 90Y-DOTATOC (up to 10) for neuroendocrine tumours. They reported longer median survival and clinical response [28]. There have also been several studies undertaken with smaller groups of patients receiving 90 Y-DOTATOC in metastatic GEP-NETs, although these showed variation in administered dose cycles and cumulative dose, in addition to patient and tumour characteristics. Given this, the studies reported progression free survival ranging from 16 to 29 months and overall survival from 22 to 37 months [29–32]. An early study looking at the efficacy of 177Lu-DOTATATE in 310 patients with GEP-NETs suggested that there was a complete response rate of 2%, and partial or minor response rate of 28 and 16%, respectively [33]. The recent publication of the preliminary results of the only large multinational randomized Phase-3 Trial of PRRT using 177Lu-DOTATATE for midgut neuroendocrine tumours (NETTER-1) has been eagerly awaited by those with an interest in PRRT. It randomized patients into two groups, one to receive 4 cycles of 177Lu-DOTATATE in combination with best supportive care, including octreotide long acting repeatable (LAR), and the other to receive higher dose octreotide LAR only (control group). The study found

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those randomized to receive 177Lu-DOTATATE had longer progression free survival (65.2% at 20 months compared to 10.8% in the control group), as well as a higher response rate using Response Evaluation Criteria in Solid Tumours— RECIST (18% demonstrated partial or complete response compared to 3% in the control group) [34–36]. Indeed, several clinical factors can predict potential therapy efficacy including: primary tumour localization, tumour grade and stage at initial diagnosis, resection status after curative surgery, and previous or concomitant treatment.

Side effects and complications Acute side effect PRRT remains well tolerated, even with extensively metastasised disease. The main reported acute side effects include fatigue or mild hair loss. This was noticed only with 177Lutetium and not with 90Yttrium [37]. Other rare acute side effect is exacerbation of a clinical syndrome or carcinoid crisis which may be due to excessive release of active amines or peptides into the blood. This side effect was reported in around 1% (6 of 479 patients) of patients included in De Keizer et al. [38].

Sub‑acute and long‑term side effects The bone marrow and kidney are the dose limiting organs for PRRT that determine the maximum cumulative administrable activity. Although usually mild and reversible, haematotoxicity is the most common sub-acute complication from PRRT. This side effect frequently occurs at 4–6 weeks after starting PRRT. It is usually transient and blood count is almost always restored within 2 months. Radiation-induced bone marrow suppression may only progress into severe toxicity in < 15% [39–41]. Myelodysplastic syndrome and acute leukaemia in around 1–2%. A risk factors include the previous chemotherapy and poor renal function [42]. Heamatotoxicity was reported more with 90Yttrium compared with 177Lutetium (12 vs 4%) and that can be explained by the longer tissue penetration [39, 43]. The other major potential complication of PRRT is renal toxicity. This occurs due to proximal tubular reabsorption of radio-peptide causing renal irradiation and associated renal toxicity [43]. Reduction in nephrotoxicity can be achieved by ensuring adequate baseline creatinine clearance prior to and between treatment cycles, as well as adequate pre-hydration. The co-infusion of positively charged amino acids inhibits reabsorption in the proximal tubules. Its mandated use as part of an administration protocol has reduced the risk of grade 3–4 renal toxicity to less than 3% of patients [44, 45].

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European guidelines propose an amino acid solution of 2.5% lysine and 2.5% arginine in 1 L infused over 4 h, starting 30 min prior to administration of the radiopharmaceutical [46]. Despite these kidney protective measures, there is mild loss of creatinine clearance of up to 3.8% per year for 177Lu DOTATATE and loss of up to 7.3% per year for 90Y-DOTATOC, inevitably likely to be worse in patients who already have increased risk factors for nephropathy including diabetes and hypertension [47, 48]. The amino acids can also cause nausea and vomiting, and an appropriate antiemetic should be administered prior to commencing the infusion. Risk factors for renal toxicity include; pre-existing poor renal function, hypertension, diabetes, age (> 60 years), morphological renal abnormalities, trans-arterial chemoembolization, and previous chemotherapy with nephrotoxic agents [49]. With these factors in mind, it is critical that appropriate patients are selected who will get the most benefit from PRRT.

Patient selection It is important to confidently identify those patients who would benefit from PRRT, a process that should be undertaken by a multidisciplinary team with expertise in the imaging and management strategies that are available to the patient. Extensive guidelines have been produced to guide the team in the management of neuroendocrine tumours [50–52]. These highlight the indications, as well as absolute and relative contraindications. The main category of patients who would be suitable for PRRT has NET that express SSTR2, usually of gut or lung origin, in particular those who are grade 1 or 2 by WHO classification. Following the publication of the NETTER-1 trial outcomes, the most recent European Neuroendocrine Tumours Society (ENETS) consensus guidelines update suggests that PRRT is used in appropriate patients following failed first-line medical therapy: this may be as second line therapy after failure of somatostatin analogues treatment, or as a third line therapy after failure of Everolimus treatment. Imaging provides the mainstay of staging of NET, involving conventional diagnostic CT, MRI and ultrasound, as well as functional and hybrid imaging. Somatostatin receptor imaging (SRI) with 111In-octreotide may help assess the burden and distribution of somatostatin receptor expression on tumour cells, but many centres now use the increased sensitivity provided by PET imaging with 68Ga-Dota –peptides (sensitivity of 97% in PET vs 52% using planar scintigraphic imaging) [53]. Functional imaging may also identify sites of disease occult on conventional imaging, including within the bowel or skeleton.

Histopathological assessment of tumour samples is used to grade the disease. However, clinical assessment, including neuroendocrine functional state and overall performance status may be pivotal in determining further management. Although tissue biopsy will confirm the diagnosis of NET, the sample can only give the grade of the particular site targeted for biopsy. There can be marked intra-tumoural and inter-tumoural variability in grade of disease [54, 55]. Functional imaging may also be useful in grading disease. Well to moderately differentiated sites of disease (grade 1 or 2) are more likely to express somatostatin receptors, and likely in greater abundance than poorly differentiated sites of disease (grade 3). As the disease de-differentiates, they become more malignant, lose the somatostatin receptor expression, and become more metabolically active (due to increased metastatic). Identifying these cases is important, and PET-CT imaging using 18F-fluorodeoxyglucose (FDG) may be helpful in identifying these sites in the process of planning therapy [56, 57]. PRRT should be considered for patients with positive expression of SSTR2, metastatic and or inoperable NETs. Well- to moderately differentiated (WHO classification grade 1 or 2) metastatic neuroendocrine tumours are most suitable candidates for PRRT, either as a palliative therapy or as an adjunct to surgery. Care must also be made to minimise radiation to other radiosensitive organs as much as possible, in particular the liver, which is a common site for metastatic disease. Modern protocols divide doses to allow sufficient targeted activity and minimise dose to non-target organs. Various published guidelines are available in the literature to help guide the total administered activity along with the number of cycles and interval between therapies. At our centre, all cases that may be potentially eligible are discussed at a multidisciplinary neuroendocrine MDT, involving nuclear medicine physicians, oncologists, radiologists, pathologists, surgeons and endocrinologists. Although the decision to treat is made on a case by case basis, broadly the inclusion criteria include patients with metastatic neuroendocrine disease, with positive somatostatin receptor imaging (SRI) using 111In- or 68Ga-peptides, life expectancy of over 12 weeks, creatinine less than 150 and good GFR (and if necessary a 99mTc-MAG3 renogram), Hb greater than 8.9, WCC greater than 2, Platelets greater than 100, and a Karnofsky performance status greater than 60%. The disease should also be ideally of grade 1 or 2 by WHO classification. 177 Lu-DOTATATE is given in a cycle of 4 administrations at a dose of 7.4 GBq each and repeated every 3 months.

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Follow‑up During and immediately following completion of administering of activity, suitable radiation protection requirements are required and will need to be continued for an appropriate time following discharge from the administering centre. In addition to this, the patient needs to complete their amino acid infusion and to ensure adequate hydration to minimise the risk of nephrotoxicity. An assessment can be made of the uptake of activity following administration using post-therapy scintigraphic imaging, either using planar or SPECT imaging (Fig. 1). This is easier with the 177Lu-based radiopharmaceuticals, with its direct γ emission. Imaging is possible using Bremsstrahlung emission produced with 90Y based radiopharmaceuticals, but this may be more difficult to quantify and undertake dosimetry. Following discharge, it is also important to arrange follow-up for the patient. In addition to clinical review, it is imperative to assess for radiation effects on the kidneys and bone marrow. Serum creatinine can be used as a surrogate for renal function, and if there is further concern formal assessment can be made using a GFR quantification

Fig. 1  Maximum intensity projection images of SPECT across the upper abdomen after the first (a), second (b), third (c), and fourth (d) cycle of 177LuDOTATATE PRRT in a patient with metastatic neuroendocrine tumour of pancreatic origin. There is temporal reduction in uptake of the radiopharmaceutical on each cycle, corresponding to reduction in somatostatin receptor expression. The endof-treatment 68Ga-DOTATATE PET-CT confirmed a good (partial) response to treatment (see Fig. 2)

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technique. Marrow toxicity can be assessed on a blood screen, while being aware that mild, reversible haematotoxicity may occur. Interval or end-of-treatment assessment of the degree of tumour burden requires correlation with conventional imaging, such as CT or MRI. Assessment of receptor burden can also be made using SRI with 68Ga DOTATATE PET-CT (Figs. 2, 3, 4). This may be particularly useful for sites of occult disease on conventional imaging. However, using somatostatin receptor burden to determine response should be used in conjunction with the conventional imaging, and the clinical response of the patient. A reduction in somatostatin expression (represented by reduced tracer uptake on the SRI) may well represent an element of tumour response, in particular if there is a reduction in size of tumour bulk on the conventional imaging. However, tumours may also show reduced tracer uptake as a result of reduction in somatostatin expression due to de-differentiation of tumour to a more malignant grade—this may be associated with features such as increase in tumour bulk or necrosis on the conventional imaging. If there is concern regarding de-differentiation, functional assessment for metabolic activity using FDG PET-CT may be appropriate.

Clinical and Translational Imaging Fig. 2  Maximum intensity projection images of 68GaDOTATATE PET from vertex to mid-thigh in a patient with metastatic neuroendocrine tumour of pancreatic origin. There is marked somatostatin receptor expression in the extensive liver metastasis on the baseline pre-PRRT PET (a). The post-treatment PET (b) shows small residual somatostatin expression in the primary disease in the tail of the pancreas (arrow), and in two small liver metastases (arrows)

The future Following the publication of the results from the NETTER-1 trial, The European Medical Agency has since adopted a positive opinion of 177Lu-DOTATATE, and has granted it marketing authorisation. In the UK, 177Lu DOTATATE has been used off licence in the treatment of metastatic neuroendocrine tumour under guidance of specialists. Approval by the British National Institute of Heath and Care Excellence is still awaited, as is formal approval from the FDA in the United States. There may be an argument for further personalised tailoring of therapy to the patient, with individualised or combination dosing which is adjusted for patient habitus, renal function as well as tumour and receptor burden.

Newer targeting agents are also in the pipeline, currently in the pre-clinical stage of testing. Antagonists of the somatostatin receptor (compared to the agonists currently in clinical use) are less likely to cause any stimulatory activity from binding and may in fact block agonist-induced activity. Somatostatin antagonists are being investigated for their use as targeting agents of radiopharmaceuticals for imaging and therapy. Although early studies with these agents show low internalisation rates of the radiotracer compared to the agonist-based tracers, they appear to have greater binding affinity, with more binding sites than agonists and, therefore, demonstrate greater tumour uptake [58–61]. One of the most promising has been the analogue JR11 (Cpa-c[d-Cys-Aph(Hor)d-Aph(Cbm)-Lys-Thr-Cys]-d-Tyr-NH 2 ), a rather specific antagonist for the SSTR2. A small pilot study of

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Fig. 3  Maximum intensity projection images of 68Ga-DOTATATE PET from vertex to mid-thigh (left posterior oblique view) in a patient with metastatic neuroendocrine tumour of lung origin. There is marked somatostatin receptor expression in the extensive pulmonary, pleural and mediastinal deposits on the baseline pre-PRRT PET (a). The post-treatment PET (b) shows marginal reduction in somatostatin expression in the anterior and inferior pleural disease (arrows)

Fig. 4  68Ga-DOTATATE PET-CT in another patient with metastatic neuroendocrine tumour of pancreatic tail origin. Axial PET, CT and fused images through the tail of pancreas and liver There is somato-

statin receptor expression in the pancreatic tail and liver on the baseline pre-PRRT PET (a, c). The post-treatment PET (b, d) shows no residual somatostatin expression in the metastatic deposits in the liver

4 patients with metastatic neuroendocrine tumours indicated an average of 3.5 times greater tumour doses than with conventional 177Lu-DOTATATE [59, 61–63].

Other novel peptide agents for targeting other receptors both for neuroendocrine tumours (such as for insulinomas) and for other malignancies (such as prostate specific

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membrane antigen PSMA in prostate cancer) are also showing potential in pre-human studies. Use of other α and β− emitting metal radioisotopes are also being investigated for somatostatin radiolabelling. Copper has several radioisotopes including the positron emitting 60Cu and 62Cu, as well as the positron and β− emitting 66Cu isotope. The α emitting Bismuth-213 (213Bi) has the potential to give a higher dose to the target cells above background and may have a role in targeting therapy in patients who are refractory to β-radiation [64–66].

Conclusion The recent developments in functional imaging and targeted therapy have paved the way for a specific and more effective management of neuroendocrine tumours. Despite their low incidence and slow growth, these tumours will have significant morbidity and mortality unless early diagnosis and therapy are employed. Surgery remains the main option for accessible tumours, but this approach is limited due to late presentation with metastatic disease. Oligometastasis will benefit from ablation therapy but more extensive disease requires a systemic approach that is targeted to the tumour sites and associated with minimal side effects. In the current environment, PRRT appears to fulfil these criteria more efficiently compared to other modalities. Author contributions  SY: content planning, literature search and review, manuscript writing, and editing. SA: literature search and review, manuscript writing, and editing. AA-N: content planning, literature search and review, manuscript writing, and editing. Funding  The authors declare that there have been no financial contributions to this article.

Compliance with ethical standards  Conflict of interest  The authors, Siraj Yusuf, Shahad Alsadik, and Adil AL-Nahhas, have no conflict of interest to declare. Ethical standards  This article does not contain any studies with human or animal subjects performed by the any of the authors.

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