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Peptide receptor radionuclide therapy

https://doi.org/10.1016/j.beem.2007.01.007Get rights and content

Peptide receptor radionuclide therapy with radiolabelled somatostatin analogues is an emerging and convincing treatment modality for patients with unresectable, somatostatin-receptor-positive neuroendocrine tumours. Using radiolabelled somatostatin analogues for imaging became the gold standard for staging of neuroendocrine tumours. The somatostatin receptor is strongly over-expressed in most tumours, resulting in high tumour-to-background ratios. Consequently, the next step was to try to treat these patients by increasing the radioactivity of the administered radiolabelled somatostatin analogue in an attempt to bring about tumour cure. Many patients have been treated successfully with this approach, roughly 25% of them achieving objective tumour shrinkage >50%. Serious side-effects have been rare. This article reviews the effectiveness and safety of the different radiolabelled somatostatin analogues used. Furthermore, clinical issues – including indication and timing of therapy – are discussed. Finally, important directions for future research are mentioned to illustrate new strategies for increasing therapy efficacy.

Section snippets

Development of peptide receptor radionuclide therapy

Somatostatin receptor scintigraphy was introduced in the late 1980s, and after the development of [indium-111-DTPA0] octreotide ([111In-DTPA0]octreotide) this radiolabelled hormone analogue became the gold standard for staging sst-positive neuroendocrine tumours.4, 5 Since then many improvements concerning the peptide and the radiolabelling were made. Nowadays, somatostatin analogues labelled with positron emitters are available. The use of these compounds with an integrated positron emission

Radionuclides

Over the past decade, the most frequently used radionuclides in PRRT with somatostatin analogues were indium-111 (111In), yttrium-90 (90Y), and lutetium-177 (177Lu). These radionuclides have different physical characteristics which will influence the effects of the therapy, i.e., different particles are emitted at different energies, resulting in various tissue penetration ranges. The peptide is conjugated with a chelator which forms a stable complex with these three radionuclides. Beside the

Somatostatin analogues used for PRRT

There are two known natural somatostatins, one consisting of 14 amino acids, the other 28 amino acids. They act as neurotransmitters with endocrine and paracrine functions in vivo, and are rapidly degraded by peptidases. The serum half-life of these peptides in blood is approximately 2 minutes, which is too short to qualify natural somatostatins as radiopharmaceuticals.26

The breakthrough in somatostatin receptor imaging and subsequently in therapy was made when the octapeptide octreotide was

Clinical studies

A number of phase-I and phase-II therapy studies using different somatostatin analogues, different radionuclides, and different treatment protocols has been published to date. The numerous variables, including different patient characteristics, make it nearly impossible to compare the results of these studies properly. However, it has become evident that the kidneys and/or the bone marrow are the major dose-limiting organs for this treatment.

Side-effects and toxicity

Generally PRRT can be regarded as a relatively safe treatment, and severe side-effects are rare, especially when compared with side-effects in studies using chemotherapy.46, 47, 48 The side-effects in PRRT can be divided into acute side-effects and more delayed effects caused by radiation toxicity.

The acute effects occurring at the time of injection up to a few days after therapy include nausea, vomiting, and increased pain at tumour sites (approximately 30% of the patients), symptoms that were

Current clinical practice

In symptomatic patients at the time of diagnosis metastatic disease is present in 90% and surgical cure is not possible68; nevertheless surgery remains an important cornerstone in the management of these tumours. Beside surgery, radiofrequency ablation (RFA) or chemo-embolization are minimal invasive treatment options when the disease is limited to the liver or when the tumour load in the liver is very high. Several small series have shown good responses.69, 70, 71 However, RFA and

Future developments

There are five main directions for future research to improve PRRT with radiolabelled somatostatin analogues. Improving the vehicle (i.e. the peptide) is highly interesting. Many new somatostatin analogues with a higher affinity for sst2 or with a wider affinity for several sst subtypes have already been introduced into the preclinic.75 Simultaneously, investigations have been made to improve the delivery of the radiopharmaceutical to the target. This includes the method of application (e.g.

Summary

PRRT has been proven to be an effective and safe treatment alternative for sst-positive, unresectable neuroendocrine tumours. Currently the maximum tolerated dose is defined by the dose to the critical organs, kidney and bone marrow. It is likely that the dose can be increased in future by the introduction of new protective agents and different treatment schemes and radionuclides.

The present data in the literature do not allow definition of the most suitable peptide and radionuclide for the

Acknowledgements

Flavio Forrer received a personal research grant from the Swiss National Science Foundation and the Novartis Foundation.

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