Role of radiopharmaceuticals in the diagnosis and treatment of neuroendocrine tumours

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Introduction

Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms characterised by their endocrine metabolism and histological pattern, originating mainly from the gastroenteropancreatic tract (GEP NETs). As opposed to other tumour entities GEP NETs are relatively rare tumours and their diagnosis requires a high index of suspicion. NETs characteristically synthesise, store and secrete a variety of peptides and neuroamines which may lead to clinical syndromes such as the carcinoid syndrome, the Zollinger Ellison syndrome, or the Verner Morrison syndrome [1, 2]. However, most GEP NETs are clinically silent until late presentation with metastases. In fact, a delayed diagnosis of NET is typical, resulting in excessive morbidity and mortality and increased probability of metastatic disease. A multidisciplinary approach for therapeutic intervention is necessary. On initial clinical presentation, NETs may be difficult to diagnose because of the large variability in tumour location and the high frequency of small lesions. The proliferation marker Ki-67 (MIB-1) is important in determining tumour grade and prognosis. Once metastasised, the therapeutic options for patients with NETs are limited. Treatment with long-acting somatostatin (SST) analogues results in reduced hormonal (over)production, and thus, relief of symptoms. Surgery is the therapy of choice in localised disease. Chemoembolisation of primary tumour/liver metastases can be attempted in order to reduce the tumour mass for subsequent therapy with radiolabelled peptide analogues in patients with slow-growing tumours. In patients with poorly differentiated tumours chemotherapy may be considered [3]. However, the management options are manifold, and there are only a few evidence-based controlled studies available. Furthermore, formal guidelines are required. One should be aware that not all centres have the same treatment approach. For example, some believe that the long-acting SST analogues exert a beneficial effect even when the patient does not have symptoms. Positive effects of long-acting octreotide on tumour progression were assessed in the PROMID study recently [4]. In addition, there is not a general agreement as to the scope and timing of tumour debulking surgery and/or chemoembolisation [1].

The assessment of the location and extent of NETs is crucial for clinical management. Although being a heterogeneous group of neoplasms, NETs are characterised by their ability to over-express SST receptors (SSTR) at the cell surface. For localisation, conventional SSTR scintigraphy/positron emission tomography (PET), computed tomograhpy (CT)/magnetic resonance imaging (MRI), fused PET/CT or PET/MRI imaging, endoscopic ultrasound, arterial stimulation and venous sampling are used [5, 6, 7, 8]. Other nuclear medicine techniques are also available for rare NETs. Here, we give an overview of the clinical value of radiopharmaceuticals used for diagnosis and treatment of NET patients.

Section snippets

Peptide receptor (R) expression on NETs as possible targets

In initial studies we have shown that the expression of peptide receptors on NET cells is significantly higher as compared to normal tissues and cells [9, 10]. Over the past decade such receptors have become recognised targets for molecular imaging and therapy, because they are expressed on the cell surface and, upon binding of a ligand, the R-receptor-ligand complex is partly internalised [11]. SST and its analogues inhibit the growth of normal as well as malignant cells [12, 13]. These

Peptide radiopharmaceuticals as molecular agents

On the basis of SSTR-expression, a variety of SST-based radiopharmaceuticals have been synthesised and comparatively investigated for their in vitro binding properties to the five SSTR subtypes (Table 1).

111In-DTPA-D-Phe1-octreotide, which binds preferentially to the SSTR subtype 2, was the first radiopharmaceutical available on the market (OctreoScan®). This radiopharmaceutical was further improved to yield 111In-DOTA-D-Phe1-Tyr3-octreotide (111In-DOTA-TOC), which shows a similar in vitro and

Non-peptide molecular targets

Metaiodobenzylguanidine (mIBG) is the combination of the benzyl group of bretylium and the guanidine group of guanethidine. Since mIBG structurally resembles norepinephrine, it enters neuroendocrine cells by an active uptake mechanism and is stored in the neurosecretory granules [57]. Radioiodinated (123I, 131I) mIBG is used to image and treat NETs, particularly those of the sympatho-adrenal system (pheochromocytomas, paragangliomas and neuroblastomas), although other NETs (e.g. carcinoids,

Peptide radiopharmaceuticals

Today, SSTR scintigraphy using the above mentioned radiolabelled peptide radiopharmaceuticals, in particular long-acting octreotide analogues, is established in clinical practice. Since its implementation in the late 1980s [65, 66], SSTR scintigraphy has improved the ability to diagnose, detect, stage and review the response to therapy in patients with NETs. Clinical studies with 111In-DTPA-OC have clearly shown that this radiopharmaceutical is effective in diagnosing and staging tumours and

General approaches

Evaluation of the type of peptide radiopharmaceutical used for SSTR-targeted therapy, based on the scintigraphic pattern and dosimetric studies, should always be performed for the individual NET patient because of the above mentioned discrepancies concerning both tumour uptake and detection of tumour lesions between the different radiopharmaceuticals.

Patient selection and timing

In principle, all patients with NETs known to express SSTR are eligible for high-dose therapy, provided that the tumours demonstrate sufficient

Non-somatostatin receptor-based peptide receptor radionuclide therapy

Besides SSTR, receptors for other regulatory peptides are also frequently over-expressed in NETs [114]. Among them gastrin/CCK analogues binding to CCK receptors are garnering increasing interest especially in the diagnosis and therapy of metastatic MTC. Gastrin analogues showing a superior selectivity and affinity for CCK-2 receptors, the receptor subtype mainly expressed in tumours, have been extensively investigated for possible applications in nuclear medicine [115].

The first generation of

Non-peptide molecular targets (131I-mIBG)

Radioiodinated mIBG is indicated for the treatment of neural crest tumours such as inoperable malignant pheochromocytoma, paraganglioma, carcinoid tumour, Stage II or IV neuroblastoma and MTC following whole body and tumour dosimetry [125]. In general, several therapeutic doses (3.7–11.2 GBq) may be required to achieve an objective response to treatment. Treatment may be repeated in 4–6 week intervals, and activity reduction should be considered in patients with myelosuppression and impaired

Combination of different radiopharmaceuticals

Because of the differences in biodistribution and critical organs, targeted therapy in NET patients such as combined therapy could provide a significant increase in the delivered tumour dose over either agent alone. The magnitude of increase depends on the relative dose delivered by each agent.

Therapy might be improved by a combination of 177Lu- and 90Y-labelled SST radiopharmaceuticals. The 90Y gives a high dose to the tumour lesions and also to areas with low SSTR expression, in heterogeneous

Conclusions

The highly variable natural course of the disease should always be considered. According to the results obtained so far, there can be no doubt about the wide therapeutic index and the high efficacy of SST analogues in the symptomatic management of NETs. In addition, the results of PRRT with long-acting SST analogues indicate that these molecular therapies have their place in the treatment of patients with SSTR-positive NETs for size reduction, improvement of quality of life and overall

Conflict of interest statement

None declared.

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