Alpha therapies : where and when is the future in neuroendocrine tumours?

Abstract

Neuroendocrine tumors (NETs) represent a diverse group of neoplasms arising from neuroendocrine cells, treatable with various modalities including targeted radionuclide therapy. Traditional treatments such as surgery, somatostatin analogues, chemotherapy, target therapies and peptide receptor radionuclide therapy (PRRT) with beta-emitting isotopes like 177Lu-DOTATATE have shown good clinical efficacy. However, 177Lu-DOTATATE may be less effective in refractory or progressive cases, necessitating the transition to alpha-emitting therapies. The emergence of alpha therapies, leveraging the potent cytotoxicity of alpha-emitting isotopes, signifies a notable advancement in the therapeutic landscape for NETs. This review aims to provide an overview of the most significant developments and evidence for the use of targeted alpha therapies in neuroendocrine tumors. Alpha particles, with their high linear energy transfer (LET) and short range, offer distinct advantages over beta particles. Their potent cytotoxicity can cause double-strand DNA breaks, leading to higher tumor cell kill rates. Several alpha-emitting isotopes, including Actinium-225, Bismuth-213, and Lead-212, are currently being investigated for their therapeutic potential in NETs. These isotopes deliver lethal radiation doses to tumor cells while minimizing collateral damage to healthy tissues, even more targeted in hepatic disease when intraarterial administration is feasible. Despite challenges related to Ac-225 production, availability, costs, dosimetry, standardization, and sufficient long-term follow-up data, the clinical success in treating resistant and aggressive forms of NETs underscores the need for increased investment and research to optimize production and distribution processes. Developing reliable supply chains and comprehending the potential long-term effects of alpha emitters are essential steps. The time for Targeted Alpha Therapies is undeniably here and now, with continued advancements holding the potential to revolutionize the treatment of neuroendocrine tumors, providing hope and improved outcomes for patients globally.