Evidence and clinical practice of peptide receptor radionuclide therapy for unresectable neuroendocrine tumors

Peptide receptor radionuclide therapy (PRRT) is a promising treatment option for unresectable neuroendocrine tumors (NETs). In June 2021, PRRT with 177Lu-DOTA0-Tyr3-octreotate (177Lu-oxodotreotide) was approved for somatostatin receptor (SSTR)- positive unresectable NETs in Japan. Persistently, SSTR has been investigated as the most important diagnostic and treatment target for NETs. Radioisotope (RI)-labeled somatostatin analogues are important imaging and therapeutic agents; therefore, somatostatin-based PRRT was introduced in the 1990s. PRRT with 177Lu- oxodotreotide was shown to be useful in an international phase III study (NETTER-1) and became the standard treatment for unresectable NET. This study has demonstrated significant outcomes regarding longer progression free survival (PFS) after PRRT with 177Lu- oxodotreotide plus octreotide LAR compared with that of those after high dose octreotide LAR in patients with midgut NETs. According to the NETTER-1 study and a large cohort study for SSTR-positive gastroenteropancreatic and lung NETs, PRRT with 177Lu- oxodotreotide was approved for foregut, midgut, and hindgut NETs in European countries and the United States. In Japan, prospective clinical trial was performed. Moreover, PRRT with 177Lu- oxodotreotide was proven to be an effective and safe treatment for Japanese patients with NETs. According to prospective and large retrospective studies, the response rate after PRRT was 9–50% and PFS was 22–53 months. Severe hematological toxicities and secondary hematological malignancy occurred approximately 10% and 1–5% after PRRT, respectively. Somatostatin receptor scintigraphy (SRS) with 111In-pentetoreotide was the most important inclusion criteria and SRS uptake could be a predictive marker of PRRT. Relationship SRS with 111Inpentetoreotide and PRRT with 177Lu- oxodotreotide should be the most innovative clinical model of RI theranostics.