Clinical Experience with Targeted Alpha-Emitter Peptide Receptor Radionuclide Therapy (α-PRRT) for Somatostatin Receptor-Positive Neuroendocrine Tumors

Background: α-emitting Peptide Receptor Radionuclide Therapy (α-PRRT) is emerging as a promising new generation of PRRT for neuroendocrine tumors (NETs), providing enhanced tumor cell cytotoxicity and reduced irradiation of adjacent healthy tissues due to its high linear energy transfer (LET) and short particle range. This review summarizes available clinical evidence on α-PRRT using different α-emitting isotopes, including actinium-225, lead-212, and bismuth-213, in somatostatin receptor (SSTR)-positive NETs. Methods: A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov, as well as major oncology congress abstracts (ENETS, ESMO, ASCO). Eligible studies included clinical trials evaluating α-PRRT in patients with advanced SSTR-positive NETs, reporting therapeutic response and adverse events. The primary endpoint was the objective response rate (ORR); secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: Seven studies encompassing 150 patients were included. Treatment with 225AcAc-DOTATATE yielded a pooled ORR of 50% and a DCR of 81.3% across 121 evaluable patients. The best responses were observed in patients who had previously responded to β-PRRT (ORR 70.4%, DCR 96.3%), while one-third of β-PRRT–refractory patients achieved partial or complete responses. 212PbPb-DOTAMTATE demonstrated an ORR of 56.8% and DCR of 100% in preliminary phase II results, though dysphagia was noted in 34% of patients. 213BiBi-DOTATOC and 212PbPb-VMT-α-NET studies also showed promising disease control with minimal grade ≥ 3 hematologic or renal toxicities. Across all studies, α-PRRT was well tolerated, with predominantly low-grade hematologic adverse events and no significant hepatic or renal toxicity. Conclusions: Clinical data to date indicate that α-PRRT offers meaningful therapeutic benefit in patients with metastatic or treatment-refractory NETs, achieving favorable response rates with manageable toxicity. Early results support α-PRRT as a potential first- or second-line therapeutic option. Ongoing phase III trials will be critical to confirm its long-term safety, survival outcomes, and role in routine clinical practice.