13Peptide receptor radionuclide therapy (PRRT) for GEP-NETs
Introduction
In patients with inoperable metastasised gastroenteropancreatic neuroendocrine tumours (GEP-NETs), therapeutic options are limited. Treatment with somatostatin analogues such as octreotide and lanreotide reduces hormonal overproduction and can relieve symptoms in patients with GEP-NETs [1], [2], [3]. Furthermore, the long acting formula of the somatostatin Octreotide LAR significantly lengthens time to tumour progression in patients with metastatic midgut neuroendocrine tumours (NETs) [4].
The majority of GEP-NETs express somatostatin receptors, mainly somatostatin receptor subtype (sst) 2 and 5 [5]. These can be visualised using radiolabelled somatostatin analogues. The first commercially available diagnostic somatostatin receptor analogues were [111Indium-DTPA0]octreotide (111In-octreotide or Octreoscan) [6] and 99mTechnetium-depreotide (NEOSPECT or NEOTECT). Nowadays newer positron emission tomography (PET) radiopharmaceuticals have been developed, such as [68Ga-DOTA-Tyr3]octreotide [7] and [68Ga-DOTA-Tyr3]octreotate [8].
After the introduction of 111In-octreotide, the therapeutic application of high dose 111In-octreotide showed promising results on symptomatology in patients with neuroendocrine tumours [9]. However, the reported number of objective responses was rather disappointing with a relatively low percentage of patients with tumour shrinkage. In subsequent studies, severe haematological toxicity (myelodysplastic syndrome (MDS) or leukaemia) was observed in a few patients [10], [11].
The use of beta-emitters, such as Yttrium-90 (90Y) and Lutetium-177 (177Lu) was made possible with the introduction of the chelator DOTA (1,4,7,10-tetraazcyclodecane-1,4,7,10-tetraacetic acid). Newer, more efficient, radiolabelled somatostatin analogues were developed with high affinity to the somatostatin receptor, such as [90Y-DOTA0, Tyr3]octreotide (90Y-DOTATOC) and [177Lu-DOTA0, Tyr3]octreotate (177Lu-DOTATATE). The main focus of this review is on this next generation of somatostatin analogues, labelled with 177Lu and 90Y.
Section snippets
Chelator and peptides
The structure of somastostatin analogues that are used for diagnostic and therapeutic purposes consists of three parts: a radionuclide, a chelator and a cyclic octapeptide (Fig. 1).
DTPA (diethylene triamine penta-acetic acid) and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,20-tetra-acetic acid) are commonly used as chelators for PRRT. The most widely used combinations of peptide-chelators are [DOTA0,Tyr3]octreotide (DOTATOC) and [DOTA0,Tyr3]octreotate (DOTATATE). Other complexes include [DOTA0
Radionuclide characteristics
Over the past two decades, different radionuclides have been used for PRRT. Indium-111 (111In), with its auger electrons caused by gamma-emission, was used in early studies [10], [11]. Besides encouraging results with regard to symptom relief, the reported number of objective responses was rather disappointing. Furthermore, 111In-coupled peptides are not ideal for PRRT due to the small particle range and therefore low tissue penetration.
90Y has high tissue penetration (12 mm) due to
90Y-labelled somatostatin analogues
Early studies with 90Y labelled somatostatin analogues were done in Basel by Otte et al [16], [17]. In their pilot study, 29 patients with mostly neuroendocrine tumours were treated with 90Y-DOTATOC in a mean cumulative administered activity of 6120 ± 1347 MBq/m2 given in four or more single injections. Sixteen patients were diagnosed with inoperable or metastasised GEP-NETs. Disease stabilisation (SD) was reported in 14 (88%) GEP-NET patients and one (6%) patient had a partial remission (PR).
177Lu-labelled somatostatin analogues
De Jong et al [26] compared different radiolabelled somatostatin analogues in a preclinical setting. 111In-octreotide, 90Y-DOTATOC and 177Lu-DOTATATE were injected in rats bearing Somatostatin receptor subtype 2 (sst2) tumours. 177Lu-DOTATATE demonstrated the highest tumour uptake together with excellent tumour-to-kidney ratios.
Forrer et al [27] injected 222 MBq 111In-DOTATOC and 111In-DOTATATE within two weeks in five patients with metastatic neuroendocrine tumours. They examined whether one
Side effects
The kidneys are the dose-limiting organs for PRRT, when 90Y labelled somatostatin analogues are used. Valkema et al [34] compared the decline in creatinine clearance after treatment with 90Y-DOTATOC or 177Lu-DOTATATE. A median decline in creatinine of 7.3% per year was observed in 28 patients treated with 90Y-DOTATOC with a median follow-up of 2.9 years [35]. The median decline in creatinine was 3.8% per year in 37 patients treated with 177Lu-DOTATATE (cumulative administered activity of
Retreatment
Van Essen et al [39] reported successful retreatment with 177Lu-DOTATATE in 33 NET patients. All patients had benefit from prior therapy with 18.5–29.6 GBq of 177Lu-DOTATATE and later again experienced progressive disease, documented by CT or somatostatin receptor scintigraphy (SRS). Two additional cycles of 7.4 GBq 177Lu-DOTATATE were given. Tumour response was evaluated using SWOG criteria. Two (6%) patients had PR, six (18%) patients responded with MR, SD was reported in ten (30%) patients
Dosimetry
In the first PRRT biodistribution and therapy studies, it was found that the kidneys and bone marrow are the critical organs for PRRT. The current role of dosimetry is that of a guide with respect to safety, especially to prevent kidney damage.
In a recent 177Lu-DOTATATE dose escalating study of Bodei et al [33], evaluation of pharmakinetics, activity biodistribution and absorbed dose to normal organs and tumours was performed. Fifty-one patients with metastatic sst2-positive tumours (mainly
Combination of compounds
A preclinical study by de Jong et al [15] compared the antitumoral effects of the combination of 177Lu- and 90Y-labelled somatostatin analogues with either 90Y- or 177Lu-analogue alone in animals bearing tumours of various sizes. The combination of both compounds was best for tumour control of both large and small tumours and resulted in the longest survival of the animals. The tumour in this rat model was rapidly growing and this may led to necrosis in parts of the tumour, therefore causing a
Summary
Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues plays an increasing role in the treatment of patients with inoperable or metastasised gatroenteropancreatic neuroendocrine tumours (GEP-NETs). 90Y-DOTATOC and 177Lu-DOTATATE are the most used radiopeptides for PRRT with comparable tumour response rates (about 15–35%). The side effects of this therapy are few and mild. However, amino acids should be used for kidney protection, especially during infusion of 90
Conflict of interest
None.
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