Somatostatin receptor radionuclide therapy in neuroendocrine tumors

Abstract

Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE has been approved for the treatment of gastroenteropancreatic NETs. An understanding of benefits and risks is important for the appropriate implementation of this therapy. This review summarizes study data supporting the use of radiolabeled somatostatin analogs for the treatment of advanced NETs and highlights risks, including potential toxicities in specific populations. Key ongoing clinical trials, including randomized studies, are designed to better define the position of PRRT within the broader therapeutic landscape. Preclinical and early-phase human studies are focused on the development of novel somatostatin-receptor agonists and antagonists, new radionuclides, and radiosensitizing combination therapies.

Bombesin Receptor Family Activation and CNS/Neural Tumors: Review of Evidence Supporting Possible Role for Novel Targeted Therapy

“…Second, the BnR ectopic expression/ overexpression by these tumors can be used for PRRT using cytotoxic radiolabeled Bn compounds, in a similar manner to the use of radiolabeled somatostatin receptor ligands, which are currently now widely used in the treatment of malignant neuroendocrine tumors over-/ectopically expressing somatostatin receptors, and is being increasingly examined in other non-endocrine tumors (prostate, breast, etc.) (2,10,11,13,16,20,92,102,135,245,262). In studies on non-CNS tumors, PRRT has been successful both when used alone (4,11,20,21,42,73,74) and in combination with other cytotoxic therapies, including chemotherapy (284,(305)(306)(307)(308)(309).…”

“…Third, the BnR ectopic expression/overexpression by these tumors can be used also for targeted delivery of cytotoxic non-radiolabeled compounds including chemotherapeutic agents, which is increasingly being studied in other malignant tumors ( 4 , 10 , 13 , 42 , 74 , 78 , 79 ). Fourth, studies with NETs using ectopic expression/overexpression of somatostatin receptors to image the tumor is now the most sensitive method to localize these tumors ( 242 , 246 , 262 ). Using a similar strategy with BnR ectopic expression/overexpression by these CNS/neural tumors may allow better definition of infiltrative tumor margins at surgery ( 173 , 174 ), which can be a major problem with gliomas, as well as allowing better definition of the extent of remaining tumor, which can affect the therapeutic approach.…”

“…However, a number of points suggest that it is very likely this will change in the near future and will become an increasingly studied area in patients with advanced disease from these tumors. First, the prototypical overexpressed GPCR that is now widely clinically used for antitumor treatment is the somatostatin receptor (primarily sst2 subtype), for the treatment of malignant neuroendocrine tumors (NETs), using radiolabeled (primarily 177 Lu-, and to a lesser extent 90 Y) somatostatin receptor ligands for Peptide Radio-Receptor Therapy (PRRT), in patients with advanced disease (253)(254)(255)(256)(257)(258)(259)(260)(261)(262)(263). The FDA approval of this was based on results of a double-blinded, control phase 3 trial (NETTER-1) (264) in patients with advanced unresectable, midgut carcinoid NETs, which demonstrated with PRRT treatment with a 177 Lu-labeled somatostatin agonist analogue, PFS was significantly prolonged (from 8.4 to >40 months, p<0.0001), with an increased overall survival from 3 to 18%, combined with the results of treatment of 510 patients with advanced panNETs and NETs in other locations, treated in Rotterdam (265).…”

“…In a recent meta-analysis of 22 PRRT studies in patients (1,758 patients) with various advanced NETs treated with PRRT, the pooled disease response rate (complete/partial tumor response) was 33% with RECIST criteria, and the pooled disease control rate (compete/partial response or stable disease) was 79% (267). As result of these studies in patients with advanced NETs, PRRT has become one of the main antitumor approaches now widely used in patients with advanced neuroendocrine disease (253)(254)(255)(256)(257)(258)(259)(260)(261)(262)(263). Second, with the PRRT success with radiolabeled somatostatinanalogues in treating malignant neuroendocrine tumors, this approach is being either applied or increasingly considered for use in other overexpressing somatostatin receptor-expressing malignant tumors (4,10,74,235).…”

“…Because of the success of PRRT in NETs using radiolabeled somatostatin receptor ligands for administering targeted cytotoxicity to the tumor (reviewed in the previous paragraph), coupled with the lack of overexpressed somatostatin receptors in most common tumors, there is a marked increase in the possibility of also developing this therapeutic approach with other GPCRs in which the active ligand contains cytotoxic non-radioactive moieties that would result in receptor-mediated tumor cytotoxicity (RMT) on various malignant tumor cells ( 4 , 10 , 42 , 74 , 90 , 262 , 278 ).…”