Abstract
BackgroundLow-grade neuroendocrine tumors (NETs) are characterized by an abundance of somatostatin receptors (SSTR) that can be targeted with somatostatin analogs (SSA). When activated with a single dose of SSA, the receptor-ligand complex is internalized, and the receptor is by default recycled within 24 h. Ongoing medication with long-acting SSAs at 68Ga-DOTA-SSA-PET has been shown to increase the tumor-to-normal organ contrast. This study was performed to investigate the time-dependent extended effect (7 h) of a single intravenous dose of 400 µg short-acting octreotide on the tumor versus normal tissue uptake of 68Ga-DOTATOC.MethodsPatients with small-intestinal NETs received a single intravenous dose of 400 µg octreotide and underwent dynamic abdominal 68Ga-DOTATOC-PET/CT at three sessions (0, 3 and 6 h) plus static whole-body (WB) PET/CT (1, 4 and 7 h), starting each PET/CT session by administering 167 ± 21 MBq, 23.5 ± 4.2 µg (mean ± SD, n = 12) of 68Ga-DOTATOC. A previously acquired clinical whole-body 68Ga-DOTATOC scan was used as baseline. SUV and net uptake rate Ki were calculated in tumors, and SUV in healthy organs.ResultsTumor SUV decreased significantly from baseline to 1 h post-injection but subsequently increased over time and became similar to baseline at 4 h and 7 h. The tumor net uptake rate, Ki, similarly increased significantly over time and showed a linear correlation both with SUV and tumor-to-blood ratio. By contrast, the uptake in liver, spleen and pancreas remained significantly below baseline levels also at 7 h and the receptor turn-over in tumors thus exceeded that in the normal tissue, with restitution of tumor 68Ga-DOTATOC uptake mainly completed at 7 h. These results however differed depending on tumor size, with significant increases in Ki and SUV between the 1st and 2nd PET, in large tumors (≥ 4 mL) but not in small (> 1 to < 4 mL) tumors.ConclusionSSTR recycling is faster in small-intestinal NETs than in liver, spleen and pancreas. This opens the possibility to protect normal tissues during PRRT by administering a single dose of cold peptide hours before peptide receptor radionuclide therapy (PRRT), and most likely additionally improve the availability and uptake of the therapeutic preparation in the tumors.
Highlights
Low-grade neuroendocrine tumors (NETs) are characterized by an abundance of somatostatin recep‐ tors (SSTR) that can be targeted with somatostatin analogs (SSA)
The SI-NETs mainly express somatostatin receptor (SSTR) subtype 2 to about 80% [5,6,7,8], and to a lesser extent subtypes 3 and 5 of the G-protein-coupled (GPCR) trans-membrane type, that are encoded on separate genes (SSTR2/17, SSTR3/22, and SSTR5/16) [9,10,11]
At WB 2 and WB 3, the tumors demonstrated a significant recovery of SSTR activity back to the baseline values, or even above, at the last time point after the 400 μg Octreotide injection (Fig. 2)
Summary
Low-grade neuroendocrine tumors (NETs) are characterized by an abundance of somatostatin recep‐ tors (SSTR) that can be targeted with somatostatin analogs (SSA). Dörr et al reported that SSA medication did not change the diagnostic accuracy of a somatostatin receptor scintigraphy, but quite the opposite; by internalizing the receptors to a relatively greater extent in the normal tissues than in the tumors, the tumor-to-normal tissue contrast, and thereby the tumor detection, was improved [18]. Based on their finding, they further suggested, in the context of peptide receptor radionuclide therapy (PRRT), that administration of cold peptide might even improve the tumor uptake of the therapeutic preparation [18]. In a previous study from our group, intravenous injection of 50 μg SSA decreased the normal tissue uptake and increased the tumor uptake of 68Ga-DOTATOC, increasing the tumor-to-normal tissue contrast, whereas 500 μg of intravenous SSA further decreased the normal tissue uptake, and that in the tumors, except in a large pancreatic NET with very high SSTR expression [23]
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