Peptide receptor radionuclide therapy for GEP-NET: consolidated knowledge and innovative applications

Purpose: Aim of the present review is to analyze the most relevant achievements of peptide receptor radionuclide therapy (PRRT) in neuroendocrine neoplasms (NENs) management, focusing on treatment efficacy as well as toxicity and taking into account the innovative applications and future perspectives. Methods: A comprehensive literature review of PubMed/Medline (last updated January 2021) was performed using a combination of the following keywords: PRRT, NEN/NET treatment, somatostatin analogues, PET/CT [⁶⁸Ga]Ga-DOTA-peptides (DOTATATE, DOTATOC, DOTANOC), [18F]FDG. Case reports, editorials, letters to the editor and articles not specifically addressing PRRT achievements were excluded. Only papers in English were considered. Results: Published data showed that PRRT has been increasingly used for treatment of well-differentiated neuroendocrine tumours (NETs). Preliminary results from early studies were difficult to compare due to different treatment regimens in often small and heterogeneous patients’ populations. Recently, the regulatory agencies approved [¹⁷⁷Lu]Lu-DOTA-TATE for treatment of well-differentiated gastro-entero-pancreatic neuroendocrine tumours G1-G2 (GEP-NET). Patients treated with PRRT show good response rates (range 66–95% considering total objective response and stable disease). Regarding toxicity, a significant reduction of renal absorbed dose (ranging from 9 to 53%) has been reported using kidney protection strategies. Moreover, the incidence of haematological long-term toxicity has been reported in many studies but toxicity is mild and transient in most patients while severe toxicity, such as acute leukemia (AL) and myelodysplastic syndrome (MDS), were reported in less than 3% of patients. However, several issues are still under debate including dose schemes personalization, selection of eligible patients, evaluation of treatment response and treatment sequencing. Conclusion: PRRT is now recognized as an effective treatment strategy for well-differentiated SSTR-positive NETs with a very high disease control and overall limited toxicity. Further optimization of PRRT employment is warranted to further increase efficacy and reduce toxicity.