Peptide receptor radionuclide therapy after NETTER-1 clinical trial: what should not be left behind

Abstract

Peptide receptor radionuclide therapy (PRRT) is an established therapy that takes advantage of the over-expression of somatostatin receptors (SSTRs) on neuroendocrine tumor cell surface, to vehicle radioactivity on cancer tissues. Approximately 80% of neuroendocrine tumors (NETs) express SSTRs on cell surface, both in primary and in related metastases. PRRT exploits this peculiarity and consists in the systemic administration of a synthetic analog of somatostatin incorporating a suitable beta-emitting radionuclide, which, once internalized through a specific receptor, irradiates tumor tissue. Through the years, several radioactive compounds have been proposed for functional studies and therapy of NETs and they differ for radionuclide, somatostatin analog, chelator and, consequently, also for receptors’ affinity. Over the last decades it has been shown that PRRT has promising treatment results; PRRT has been studied in numerous single-arm clinical trials, until 2017, when the preliminary results of the first multicenter, stratified, open, randomized, controlled, two-arm, Phase III clinical trial were published. The NETTER-1 study counterposed PRRT plus best supportive care, including octreotide long-acting repeatable (LAR), versus the administration of high dose of the “cold” somatostatin analog octreotide (LAR) alone. NETTER-1 PRRT was performed using 177Lu-DOTA0Tyr3-Octreotate (DOTATATE) in a population with welldifferentiated, metastatic neuroendocrine tumors of the midgut. The interim analysis reported a markedly longer progression-free survival and significantly higher response rate with 177Lu-DOTATATE than high-dose octretide LAR. The overall survival improvement was associated with a significant benefit in terms of quality of life (QoL) compared with high-dose octreotide [1]. Following this publication, the international scientific community has developed increasing interest in PRRT and the therapy has been approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), and National Institute for Health and Care Excellence, initiating a paradigm shift in NET treatment. Particularly, 177LuDOTATATE (Lutathera—177Lu-oxodotreotide) administration has been approved in SSTRs-positive well-differentiated gastroenteropancreatic (GEP) NETs, at a recommended fixed dosage of 7.4 GBq (200 mCi) every 8 weeks, for a total of four cycles. Whereas this represents an important milestone in the field of radionuclide therapy, some crucial points must still be addressed.