Peptide receptor radionuclide therapy with 177Lu-DOTA-TATE as a promising treatment of malignant insulinoma: a series of case reports and literature review.

INTRODUCTION: Insulinomas are a rare type of pancreatic neuroendocrine tumours characterized by insulin hypersecretion. They are considered malignant when metastases are present. Traditional therapies often promote only temporarily symptomatic relief and may be associated with severe adverse effects. There is scarce experience in treating malignant insulinomas with peptide receptors radionuclide therapy (PRRNT). PATIENTS AND METHODS: We describe PRRNT results in four patients with inoperable malignant insulinomas with poorly controllable hypoglycaemia. All patients received therapy with 177Lu-DOTA-TATE after conventional therapies failed in controlling disease progression and symptoms. The activity administered per cycle was 4.8-7.4 GBq. The interval between cycles was 10-16 weeks. Haematology, liver and kidney function tests were performed before treatment initiation and 5 and 10 weeks after each cycle. RESULTS: Patient 1 presented significant clinical benefit for 13 months after PRRNT, with imaging improvement. Patient 2 obtained reduction of the number and severity of hypoglycaemic episodes during 15 months after therapy. Patient 3 is asymptomatic since PRRNT first cycle performed 23 months ago and revealed significant imaging improvement. Patient 4 had resolution of hypoglycaemia only 3 days after PRRNT first cycle and today, 16 months after therapy, the disease seems to be in remission and the patient maintains euglycaemic state. PRRNT was well tolerated, with only hematologic grade 2 toxicity in patient 1 and mild kidney toxicity in patient 3. CONCLUSIONS: After the start of 177Lu-DOTA-TATE all patients achieved hypoglycaemia symptomatic control and had evident improvement of their quality of life. Three patients showed imagiological improvement suggesting reduced tumour load.

Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study.

Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1-2 (G1-G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21-54% (n = 125) vs Ki-67 ≥55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3-4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.

Lu-177-Based Peptide Receptor Radionuclide Therapy for Advanced Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) is a systemic cytotoxic radiation therapy using a compound of ß-emitting radionuclide chelated to a peptide for the treatment of tumor with overexpressed specific cell receptor such as somatostatin receptor subtype 2 (SSTR2) of neuroendocrine tumor (NET). Surgical resection should be performed for the curative treatment for NETs when it is feasible; however, a multi-disciplinary approach is needed when locally advanced or metastasized disease. PRRT with lutetium-177 (Lu-177)-labeled somatostatin analogues, as a new treatment modality targeting metastatic or inoperable NETs expressing the SSTR2, have been developed and successfully used for the past two decades. As Lu-177 emits both ß- and γ-radiation, it has the ability as a theragnostic agent for NETs compared with only ß-emitting yttrium-90 labeled PRRT. Several recent studies reported that Lu-177 gave an overall positive response and improved the patients' quality of life. To fully exploit its potential, large comparative studies are needed for the assessment of distinct efficacies of Lu-177 labeled PRRT. Additionally, for extending the indications and developing new regimens of Lu-177-based PRRT, more dedicated clinical research is required.