Radiolabeled somatostatin analogs are used for the localization and treatment of sst-positive tumors, mostly of neuroendocrine origin. A large variety of radiolabeled somatostatin derivatives has been prepared for radionuclide therapy and visualization of these tumors and metastases, and some are in various stages of preclinical and clinical investigation. 90Y-DOTA-Tyr3-octreotide (OctreoTher; Novartis) is an example of a somatostatin analog radiolabeled with the high-energy ß-emitter 90Y. More recent is the peptide 177Lu-DOTA-Tyr3-octreotate, which is a further improved targeted radiopharmaceutical because of its high rate of uptake and increased retention in sst2-positive tumors.
Despite differences between the several protocols used, most of the studies using 90Y-DOTATATE have demonstrated tumour responses of 10–30% (mean 25%), considerably higher than those obtained with 111In-DTPA
In contrast to 111In-DTPA-D-Phe1-octreotide, which binds to SSTR2 and SSTR5 with high affinity, binds to SSTR3 with moderate affinity, and does not bind to SSTR1 and SST4, 111In- and 90Y-DOTA-lanreotide was found to bind to SSTR2–4 and SST5 with high affinity, and to SSTR1 with low affinity. Leimer et al.(1998) initially reported a 25% regression of liver metastasis and substantial symptomatic improvement in a patient with a malignant gastrinoma after four infusions of 1 GBq 90Y-lanreotide. Following that observation, the phase IIa Multicentre Analysis of a Universal Receptor Imaging and Treatment Initiative (MAURITIUS) European study was organized, in which 39 patients with GEP tumours (34 carcinoid tumours) were included. After two cycles of 90Y-DOTA-lanreotide, the treatment was discontinued in the presence of progressive disease; otherwise, a further two cycles were given. Over a 3-year follow-up period, 20.5% of patients achieved regression of their disease, whereas 43.6% demonstrated stable disease. A few patients with malignant chromaffin cell tumours have been treated with 111In-DTPA-octreotide and 90Y-DOTATOC, some obtaining disease stabilization; initial results were encouraging.
From these studies, where several different radio-pharmaceuticals have been used for the treatment of NETs, it seems that 177Lu-DOTA-Tyr3-octreotate represents a major advance in the field of treatment with radiopeptides. However, it must be emphasized that direct, randomized, comparative studies of the various forms of radiopharmaceuticals used are lacking.
Treatment with radiolabelled SST analogues is an evolving therapeutic modality for the management of patients with inoperable or metastasized neuro-endocrine, particularly GEP, tumours. Prerequisities for treatment success include demonstration of high tumour uptake relative to non-target tissues on quantitative, diagnostic radionuclide imaging (e.g. OctreoScan) and stable haematological and biochemical function. Targeted therapies are better tolerated than other systemic treatments and deliver higher absorbed radiation doses to the tumour than can be achieved by external beam irradiation. The results obtained with [90Y-DOTA0,Tyr3]-octreotide and [177Lu-DOTA0,Tyr3]-octreotate have also exhibited substantial tumour regression, whereas the combination of these two radiopeptides may be even more effective than either alone. Future directions for improving this type of therapy include multireceptor targeting, attempts to upregulate SSTR expression on tumours and the use of radiosensitizers. At the present time this promising treatment remains experimental.
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