Peptide receptor radionuclide therapy with somatostatin analogs beyond gastroenteropancreatic neuroendocrine tumors

First isolated by Brazeau et al. in 1972, somatostatin (SST) is a neuropeptide known for regulating various signaling pathways through its specific cell surface receptors. Somatostatin receptors (SSTRs) comprise a family of five G protein-coupled receptors that are widely distributed across the human body and are expressed by various tumor types. The growing understanding of their clinical potential led to the introduction of both cold and radiolabeled somatostatin analogs (SSAs), which have revolutionized the management of several cancers, especially neuroendocrine tumors. As a direct consequence, advances in peptide receptor radionuclide therapy (PRRT) over the last 30 years led to the approval of ¹⁷⁷Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors (GEPNETs). Theoretically, any cancer patients whose tumors express SSTR, as demonstrated in vivo through SSTR-based molecular imaging, could be candidates for PRRT, especially those with limited treatment options. However, evidence on the efficacy of PRRT in non-GEPNET SSTR-expressing tumors is limited, and mainly derived from small retrospective studies. Given the limited therapeutic options for advanced/metastatic patients, there is a clear need for randomized trials to formally approve PRRT with SSAs for patients who may benefit from this treatment, particularly in certain types of neuroendocrine neoplasms such as lung carcinoids, paragangliomas, and meningiomas, where high rates of disease control (up to 80%) can be achieved. In addition, emerging evidence supports the potential of combination therapies, alpha emitters, and non-SSTR-based radionuclide therapy in tumors beyond GEPNET. This review aims to provide a comprehensive overview of PRRT's role in cancers beyond GEPNET, exploring new possibilities and future directions for most SSTR highly expressing tumors.