Context Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE results in an increase of progression-free survival and quality of life in patients with progressive well-differentiated neuroendocrine neoplasms (NENs). Objective To study the effect of 177Lu-DOTATATE in patients with carcinoid syndrome and radiologically stable or newly diagnosed disease treated solely for the purpose of symptom reduction. Design Retrospective cohort study Setting Tertiary care hospital Patients 22 patients with a metastatic midgut NEN, elevated urinary 5-hydroxyindolacetic acid excretion and flushing and/or diarrhea despite treatment with a somatostatin analog, without documented disease progression Intervention PRRT with 177Lu-DOTATATE (intended cumulative dose: 29.6 GBq) with a primary aim to reduce symptoms. Results After PRRT, mean bowel movement frequency (BMF) decreased from 6.1 ± 3.4 to 4.6 ± 3.6 per day (p=0.009). Flushes decreased from 4.3 ± 2.9 to 2.4 ± 2.7 flushes per day (p=0.002). A decrease of BMF of more than 30% occurred in 47% of patients with baseline BMF of 4 or more (n=17). In patients with ≥2 episodes of flushing a day (n=15), 67% of patients had more than 50% decrease of daily flushing. A decrease in urinary 5-hydroxyindolacetic acid excretion of more than 30% was seen in 56% of patients. The EORTC-C30 diarrhea subscale score showed a trend towards improvement by an average of 16.7 ± 33.3 points (p=0.11). Conclusion PRRT with 177Lu-DOTATATE effectively reduced diarrhea and flushing in patients with carcinoid syndrome and can be considered for symptomatic treatment of carcinoid syndrome insufficiently controlled with somatostatin analogs.

Purpose Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE induces objective response in up to 57% of pancreatic neuroendocrine neoplasms (panNENs). Therefore, PRRT may comprise a downstaging option for panNEN patients who are not eligible for upfront curative surgery or are at high risk for recurrence. The aim of this study was to assess the potency of induction PRRT for locally advanced panNENs and to evaluate the effect of surgery after PRRT on overall survival (OS). Methods Retrospective cohort study of panNEN patients treated with induction 177Lu-DOTATATE. Results After PRRT, 26 out of 49 patients underwent pancreatic surgery with curative intent (PRRT + surgery). Partial objective response was obtained in 62% of the PRRT + surgery group versus 26% of the patients not undergoing panNEN surgery (PRRT-only group, p = 0.02). Downstaging in tumour-vessel interface was observed in 38% of all patients with at least one involved vessel. Median OS was 14.7 years (95% CI 5.9–23.6) for the PRRT + surgery group compared to 5.5 years (95% CI 4.5–6.5) for the PRRT-only group (p = 0.003). In the Cox proportional hazards analysis, surgery was not significantly associated with OS after propensity score adjustment with cumulative activity, performance status, tumour size after PRRT, and tumour grade. Median progression-free survival was 5.3 years (95% CI 2.4–8.1) for the PRRT + surgery group and 3.0 years (95% CI 1.6–4.4) for the PRRT-only group (p = 0.02). Conclusion Early administration of PRRT followed by surgery is associated with favourable long-term outcomes in patients with locally advanced or oligometastatic panNEN and can be considered for selected patients with vascular involvement and/or increased risk of recurrence.

Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-[DOTA0,Tyr3]-octreotate (177Lu-DOTATATE) has become an established second- or third-line treatment option for patients with somatostatin receptor (SSTR)-positive advanced well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). Clinical evidence of the efficacy of PRRT in tumor control has been proven and lower risks of disease progression or death are seen combined with an improved quality of life. When appropriate patient selection is performed, PRRT is accompanied by limited risks for renal and hematological toxicities. Treatment of NET patients with PRRT requires dedicated clinical expertise due to the biological characteristics of PRRT and specific characteristics of NET patients. This review provides an overview for clinicians dealing with NET on the history, molecular characteristics, efficacy, toxicity and relevant clinical specifics of PRRT.

Purpose of Review Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3] octreotate is an effective and safe second- or third-line treatment option for patients with low-grade advanced gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). In this review, we will focus on possible extensions of the current use of PRRT and on new approaches which could further improve its treatment efficacy and safety. Recent Findings Promising results were published regarding PRRT in other NENs, including lung NENs or high-grade NENs, and applying PRRT as neoadjuvant or salvage therapy. Furthermore, a diversity of strategic approaches, including dosimetry, somatostatin receptor antagonists, somatostatin receptor upregulation, radiosensitization, different radionuclides, albumin binding, alternative renal protection, and liver-directed therapy in combination with PRRT, have the potential to improve the outcome of PRRT. Also, novel biomarkers are presented that could predict response to PRRT. Summary Multiple preclinical and early clinical studies have shown encouraging potential to advance the clinical outcome of PRRT in NEN patients. However, at this moment, most of these strategies have not yet reached the clinical setting of randomized phase III trials.

PurposePeptide receptor radionuclide therapy (PRRT) can cause dose-limiting toxicities (DLTs) of the bone marrow, liver, and kidneys. It is yet unknown whether women and men are equally at risk of these DLTs.MethodsNeuroendocrine tumor patients treated with 177Lu-DOTATATE between 2000 and 2015 in our phase II trial with available laboratory data were included. For all DLTs, the highest Common Terminology Criteria for Adverse Events (version 4.03) grades that occurred from the start of PRRT until 3 months after the last cycle were scored.ResultsAt baseline, women (n = 439) had a significantly lower body mass index, Karnofsky Performance Score, hemoglobin level, and creatinine clearance and a significantly higher platelet level than men (n = 534). Both groups received a median activity of 29.6 GBq (800 mCi). After the start of PRRT, women more frequently developed grade ≥2 thrombocytopenia compared with men (25% vs 18%, P = 0.004) due to a significant increase in grade ≥3 thrombocytopenia (11% vs 6%, P = 0.008). Furthermore, the incidence of grade ≥3 anemia was higher in women (7% vs 3%, P = 0.002). In the multivariable regression model, female sex (odds ratio, 2.50; 95% confidence interval, 1.67–3.74) was confirmed to be an independent risk factor for grade ≥2 thrombocytopenia, among baseline platelet count, bone metastases, uptake on 111In-DTPA-octreotide scan, Karnofsky Performance Score, alkaline phosphatase, lymphocytes, albumin, and renal function.ConclusionsFemale neuroendocrine tumor patients more often experienced PRRT-induced toxicities of platelets and hemoglobin than males, but this did not lead to a lower cumulative activity.

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Objective: Hyponatremia and hypernatremia are common electrolyte abnormalities in patients with malignancy and have been independently associated with worse survival outcomes. To date, there are no data on the impact of dysnatremia on survival outcome in patients with neuroendocrine neoplasms (NENs). Design: Retrospective cohort analysis from a tertiary care center of NEN patients treated with peptide receptor radionuclide therapy (PRRT) with a cumulative activity of at least 3.7 GBq 177Lu-DOTATATE between the years 2000 to 2015 Methods: Comparison of overall survival of patients with the occurrence of hyponatremia (serum sodium <135mmol/L) or hypernatremia (serum sodium >145mmol/L) before start or during PRRT. Results: A total of 649 patients were included. Hyponatremia occurred in 57 patients during the observation period and was associated with a shorter median overall survival (95% CI) of 25 months (14-36) compared to 55 months (48-61) of the 512 normonatremic patients (p<0.001), adjusted hazard ratio (HR) 1.48 (95% CI: 1.04-2.12). Overall survival time was reduced regardless of whether hyponatremia was present at baseline or during PRRT. In contrast, hypernatremia occurred in 80 patients and was associated with a longer median overall survival (95% CI) of 94 months (47-140) compared with the 512 normonatremic patients (p=0.018), adjusted HR 0.61 (95% CI: 0.40-0.92). This association was driven by the patients with hypernatremia during PRRT. No association between dysnatremia and progression-free survival after PRRT was observed. Conclusions: The occurrence of hypo- or hypernatremia in PRRT-treated NET patients is associated with opposing outcomes with regard to overall survival. Sodium levels might have a prognostic role in these patients.