¹¹¹In- and ⁹⁰Y-DOTA-Lanreotide: Results and implications of the MAURITIUS trial1

The high-level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled peptide analogues as tumor tracers in nuclear medicine. The vast majority of human tumors seem to overexpress one or the other of 5 distinct hSSTR subtype receptors. Whereas neuroendocrine tumors frequently overexpress human(h) SSTR2, intestinal adenocarcinomas frequently express hSSTR3 or hSSTR4, or both of these hSSTRs. In contrast to ¹¹¹In-diethylenetriamine pentaacetic acid (DTPA)-_DPhe¹-octreotide (OctreoScan^®; Mallinckrodt, Petten, NL), which binds to hSSTR2 and 5 with high affinity (K_d 0.1–5 nmol/L), to hSSTR3 with moderate affinity (K_d 10–100 nmol/L), and does not bind to hSSTR1 and hSSTR4, ¹¹¹In/⁹⁰Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (K_d 200 nmol/L). Based on its unique hSSTR binding profile, ¹¹¹In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and ⁹⁰Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. When directly compared with ¹¹¹In-DTPA-_DPhe¹-octreotide and ¹¹¹In-DOTA-_DPhe¹-Tyr³-octreotide, discrepancies in the scintigraphic imaging pattern are seen in about one third of tumor patients concerning both the tumor uptake as well as the detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a higher high-affinity binding affinity of ¹¹¹In-DOTA-_DPhe¹-Tyr³-octreotide for hSSTR2 (K_d 0.1–1 nmol/L). Beneficial results of receptor-mediated experimental radionuclide therapy were first reported for high-dose treatment with ¹¹¹In-DTPA-_DPhe¹-octreotide, based on the emission of Auger electrons. Phase lla of the Multicenter Analysis of a Universal Receptor Imaging and Treatment Initiative, a European Study (MAURITIUS), shows in progressive cancer patients (therapy entry criteria) with a calculated tumor dose > 10 Gy/GBq ⁹⁰Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with peptide receptor imaging agents. In the MAURITIUS study, cumulative treatment doses up to 232 mCi ⁹⁰Y-DOTA-lanreotide were given as short-term intravenous infusion. Preliminary treatment results in 154 patients indicate stable tumor disease in 41% (63 of 154) of patients and regressive tumor disease in 14% (22 of 154) of tumor patients with different tumor entities expressing hSSTR. No severe acute or chronic hematologic toxicity, change in renal or liver function parameters caused by ⁹⁰Y-DOTA-lanreotide treatment were reported for patients in the MAURITIUS trial. In two thirds of patients with neuroendocrine tumor lesions, ⁹⁰Y-DOTA-_DPhe¹-Tyr³-octreotide showed a higher tumor uptake and should therefore be considered the first choice for experimental receptor-based therapy. Potential indications for ⁹⁰Y-DOTA-lanreotide treatment are radioiodine-negative thyroid cancer, hepatocellular cancer, lung cancer, some brain tumors, and possibly melanomas. In conclusion, preclinical data and clinical studies confirm the potential usefulness of radiolabeled lanreotide for tumor diagnosis and therapy. However, careful consideration of the type of radiotracer used for receptor-mediated therapy should be made for the individual patient. Whole-body dosimetry should always be performed to predict doses for tumors and the critical organs, which are kidney and bone marrow.

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