Peptide Receptor Radionuclide Therapy Is Effective for Clinical Control of Symptomatic Metastatic Insulinoma: A Long-Term Retrospective Analysis.

Metastatic insulinoma is a rare malignant neuroendocrine tumor characterized by inappropriate insulin secretion, resulting in life-threatening hypoglycemia, which is often difficult to treat. There is currently very limited information about the efficacy of peptide receptor radionuclide therapy (PRRT) for clinical control of hypoglycemia. The aim of this long-term retrospective study was to evaluate the therapeutic efficacy of PRRT for improving hypoglycemia, to evaluate the change of medication after PRRT, and to calculate progression-free survival (PFS) and overall survival (OS). Methods: Inclusion criteria were histologically proven somatostatin receptor-positive metastatic malignant insulinoma and at least 2 cycles of [90Y]Y-DOTATOC or [177Lu]Lu-DOTATOC therapy from early 2000 to early 2022. A semiquantitative scoring system was used to quantify the severity and frequency of hypoglycemic episodes under background antihypoglycemic therapy (somatostatin analog, diazoxide, everolimus, corticosteroids): score 0, no hypoglycemic episodes; score 1, hypoglycemic events requiring additional conservative treatment with optimization of nutrition; score 2, severe hypoglycemia necessitating hospitalization and combined medication or history of hypoglycemic coma. Hypoglycemic score before and after PRRT was analyzed. Time of benefit was defined as a time range of fewer hypoglycemic episodes in the observation period than at baseline. Information on antihypoglycemic medication before and after therapy, PFS, and OS was recorded. Results: Twenty-six of 32 patients with a total of 106 [90Y]Y-DOTATOC/[177Lu]Lu-DOTATOC cycles were included. The average observation period was 21.5 mo (range, 2.3-107.4 mo). Before therapy, 81% (n = 21) of the patients had a hypoglycemia score of 2 and 19% (n = 5) had a score of 1. After PRRT, 81% of patients (n = 21) had a decreased score, and the remaining 5 patients showed a stable situation. There was temporary worsening of hypoglycemia just after injection of [90Y]Y-DOTATOC/[177Lu]Lu-DOTATOC in 19% of patients. The average time of benefit in the observation period was 17.2 mo (range, 0-70.2 mo). Antihypoglycemic medication reduction was achieved in 58% (n = 15) of patients. The median OS and PFS after the start of PRRT were 19.7 mo (95% CI, 6.5-32.9 mo) and 11.7 mo (95% CI, 4.9-18.5 mo), respectively. Conclusion: To our knowledge, our study included the largest cohort of patients with malignant insulinoma to be evaluated. Long-lasting symptom control and reduction of antihypoglycemic medications were shown in most patients after late-line PRRT.

90Y/177Lu-DOTATOC: From Preclinical Studies to Application in Humans.

The PRRT (Peptide Receptor Radionuclide Therapy) is a promising modality treatment for patients with inoperable or metastatic neuroendocrine tumors (NETs). Progression-free survival (PFS) and overall survival (OS) of these patients are favorably comparable with standard therapies. The protagonist in this type of therapy is a somatostatin-modified peptide fragment ([Tyr3] octreotide), equipped with a specific chelating system (DOTA) capable of creating a stable bond with ß-emitting radionuclides, such as yttrium-90 and lutetium-177. In this review, covering twenty five years of literature, we describe the characteristics and performances of the two most used therapeutic radiopharmaceuticals for the NETs radio-treatment: [90Y]Y-DOTATOC and [177Lu]Lu-DOTATOC taking this opportunity to retrace the most significant results that have determined their success, promoting them from preclinical studies to application in humans.