Neuroendocrine neoplasms are tumors that arise from diffuse neuroendocrine system cells. They are most commonly found in the gastrointestinal tract, pancreas and lungs. Neuroendocrine neoplasms are fairly rare diseases, but their incidence and prevalence have increased substantially in recent decades. The majority of neuroendocrine tumors overexpress somatostatin receptors (SSTRs), which are targeted for imaging and treatment.
Somatostatin receptor (SSTR) alogues, which are used for imaging of neuroendocrine tumors (NETs), can also be used for therapy by replacing the imaging isotope with a therapeutic isotope. This general field is referred to as peptide receptor radionuclide therapy (PRRT). PRRT is not specific to NETs, but NET therapy is currently the most advanced and only U.S. Food and Drug Administration (FDA)-approved example of it. Furthermore, this combination of imaging and therapeutic isotopes with the same target is a good example of theranostics, which is a portmanteau word consisting of “therapy” and“diagnostics.” The term “theranostics” is fairly new, but the best example of it is one of the oldest isotopes, essentially originating
the field of nuclear medicine, 131, which is used for simultaneous imaging and therapy.
Development of Peptide Receptor Radionuclide Therapy
NETs are well known for being heterogeneous. They can arise from a variety of different organs; can be benign or malignant; are well, moderately, or poorly differentiated, as in grade; have variable metastatic potential; and are either functional or nonfunctional (i.e., produce hormones and symptoms or do not) . Symptoms can markedly reduce quality of life and are an important consideration for therapy. NETs have a low incidence but a high prevalence given the lower mortality associated with these tumors.
One commonality among NETs is expression of the G protein–coupled SSTRs,of which there are five subtypes in humans. The human somatostatin molecule, composed of 14 amino acids, is a hormone used by neuroendocrine cells for neurotransmission and cell proliferation. An abbreviated version of the human somatostatin molecule,
composed of eight amino acids, is octreotide (Sandostatin, Novartis). Octreotide was FDA-approved in 1988 for symptom control in patients with functional NETs (package
insert, Novartis). However, it is also known to have antiproliferative effects and is practically used in that way for patients with lowor intermediate-grade metastatic inoperable NETs.
"Over the past two decades, SSTR-targeted imaging using radiolabeled somatostatin agonists followed by PRRT has been remarkably successful in managing neuroendocrine tumors," said Jingjing Zhang, MD, Ph.D., assistant professor in the Department of Diagnostic Radiology at the Yong Loo Lin School of Medicine at the National University of Singapore in Singapore. "However, potent SSTR antagonists—which only poorly internalize into tumor cells if at all—have surprisingly been shown to be even superior to agonists for such purposes."
To further investigate the role antagonists can play in treating neuroendocrine tumours researchers developed a study to determine the safety, biodistribution and efficiency of a new type of SSTR antagonist, 177Lu-DOTA-LM3. Fifty-one patients with progressive, heavily pretreated neuroendocrine neoplasms underwent PRRT with 177Lu-DOTA-LM3. Treatment-related adverse events were graded for all participants, and dosimetry was performed for 11 patients.
177Lu-DOTA-LM3 was administered without severe adverse effects and was well tolerated by most patients. Disease control was reached in 40 out of 47 patients (85 percent) who were monitored after 177Lu-DOTA-LM3 therapy. Two patients achieved complete remission by the European Organization for Research and Treatment of Cancer criteria.
Of note, the uptake and dosimetry of the antagonist 177Lu-DOTA-LM3 were compared with those of the commonly used SSTR agonist 177Lu-DOTATOC in patients undergoing treatment on the same dosimetry protocol. 177Lu-DOTA-LM3 demonstrated higher uptake and a longer effective half-life in tumor lesions, resulting in higher tumor radiation doses than for agonist 177Lu-DOTATOC.
"These encouraging findings demonstrate the feasibility and superiority of SSTR antagonist 177Lu-DOTA-LM3 as compared to SSTR agonists. Furthermore, antagonist PRRT can be performed under concurrent treatment with somatostatin analogs without the need for interrupting these medications. This is especially important for patients suffering from carcinoid syndrome or even carcinoid crisis,". "The results are very encouraging for theranostic applications of SSTR antagonists to further improve outcomes in patients with neuroendocrine neoplasms in the future."
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