Australasian Consensus Statement on the Identification, Prevention, and Management of Hormonal Crises in Patients with Neuroendocrine Neoplasms Undergoing Peptide Receptor Radionuclide Therapy.

Hormonal crises are a rare but increasingly recognized phenomenon following peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine neoplasms (NENs). Due to the paucity of published studies, approaches to the identification, prevention, and management of risk factors are inconsistent between different institutions. This consensus statement aimed to provide guidance for NEN patients undergoing PRRT. Our statement has been created on the basis of clinical demand and concerns regarding the precipitation of hormonal crises. A formal literature review was conducted to identify available studies. A total of 19 Australian and New Zealand experts in the fields of medical oncology, nuclear medicine, anaesthetics, and endocrinology collaborated on this consensus statement. The main focus is on carcinoid crises. Other hormonal crises seen in patients with functional pancreatic NENs are addressed briefly. These recommendations are relevant to PRRT centres internationally and should be tailored to local experience and available resources.

Simultaneous Pancreas-Kidney Transplant Complicated by Kidney Allograft Torsion and Pseudoaneurysms of the Y-Allograft: A Case Report and Review of the Literature.

Background: We report and review the literature of two rare complications of simultaneous pancreas-kidney transplantation (SPKT) occurring in one patient. Case Report. A 39-year-old man with dialysis-dependent kidney failure secondary to type 1 diabetes mellitus underwent successful SPKT in October 2018. Three months later, he presented with an acute kidney injury (AKI) and returned to dialysis. Kidney scintigraphy showed a central photopenic region, and angiograms showed absent flow in the kidney transplant artery without treatable thrombus and the incidental finding of two pseudoaneurysms of the pancreatic Y-graft. He remained dialysis-dependent for three weeks before spontaneous partial recovery of allograft function; repeat kidney scintigraphy showed significant improvement in perfusion. However, in April 2019 he was readmitted with a sudden deterioration in kidney allograft function again necessitating haemodialysis. Repeat imaging confirmed that the kidney allograft had shifted from the left iliac fossa to the midline. He underwent surgical exploration, during which torsion of the kidney allograft was confirmed and a nephropexy was performed. The kidney allograft was originally implanted in the left retroperitoneum via a midline transperitoneal approach, which likely predisposed it to torsion. The pseudoaneurysms of the pancreatic Y-graft were managed conservatively, and surveillance imaging demonstrated that they remained stable in size. The patient regained reasonable kidney allograft function (estimated glomerular filtration rate, eGFR, of 45 mL/min) and maintained normal pancreatic allograft function. Conclusion: Kidney allograft torsion should be considered post-SPKT in patients with AKI and absent arterial flow. Although most case reports describe surgical management of pseudoaneurysms post-SPKT, our case demonstrates successful conservative management.

Targeted alpha-particle therapy in neuroendocrine neoplasms: A systematic review.

Neuroendocrine neoplasms (NENs) are a very diverse group of tumors with a worldwide rise in incidence. Systemic therapy remains the mainstay treatment for unresectable and/or metastatic NENs. 177Lu-DOTATATE, a radiopharmaceutical which emits beta particles, has emerged as a promising therapy for metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, limited treatment options are available particularly after the failure of 177Lu-DOTATATE therapy. This review aims to identify and summarize the available evidence for, and potential adverse events of, targeted alpha-particle therapy (TAT) in the treatment of metastatic NENs, specifically GEP-NENs. The MEDLINE, EMBASE, SCOPUS, and Cochrane Library databases were searched. Two articles which met the inclusion criteria were identified and included in the review. Putative radiopharmaceuticals that can be considered for metastatic NEN treatment include 225Actinium (225Ac)-DOTATATE and 213Bismuth (213Bi)-DOTATOC. There was evidence of partial response using both radiopharmaceutical agents without significant hematological, renal, or hepatotoxicity. Future studies should consider longer term, randomized controlled trials investigating the role of TAT, in particular, 225Ac-DOTATATE, in the treatment of metastatic NENs.

Australian experience of peptide receptor radionuclide therapy in lung neuroendocrine tumours.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is an approved treatment modality for gastroenteropancreatic neuroendocrine tumours (GEP NETs), Although Phase III randomised clinical trial data is not available for NETs of other site of origin, in practice, PRRT is used more widely in clinical practice, based on its mechanism of targeting the somatostatin receptor. Use of PRRT for lung (bronchial) NET, specifically typical and atypical carcinoid (TC, AC), has been reported only in small retrospective case series. This multicentre study adds to the evidence regarding utility of PRRT for lung NETs. MATERIALS AND METHODS: A retrospective chart review of patients with TC and AC who received 177Lu-dotatate PRRT between January 2002 and June 2019 in six hospitals across Australia was undertaken. Data regarding demographics, efficacy and toxicity was evaluated at each site by the treating clinician. RESULTS: Forty-eight patients (32 AC, 15 TC, 1 unclassified) received a median of four 177Lu-dotatate treatments. There was a median of one prior line of systemic treatment (range: 0-3). The response rate to 177Lu-dotatate was 33%, with a median overall survival of 49 months (range of 3-91), at a median follow up of 33 months. This compares favourably with GEP NET. Overall toxicity was recorded as modest. CONCLUSIONS: 177Lu-dotatate PRRT in patients with lung NETs is used in real world practice, where it appears well-tolerated with some efficacy. Further evidence could be obtained through a global prospective clinical or registry trial.

Prevention and management of carcinoid crises in patients with high-risk neuroendocrine tumours undergoing peptide receptor radionuclide therapy (PRRT): Literature review and case series from two Australian tertiary medical institutions.

Peptide receptor radionuclide therapy (PRRT) is an important therapeutic option for somatostatin receptor (SSTR) positive metastatic and/or inoperable neuroendocrine tumours (NETs). However, in patients with poorly controlled carcinoid syndrome, it may lead to an acute flare of carcinoid symptoms or even carcinoid crisis. We report seven patients who received PRRT with (177Lu-DOTA0, Tyr3) octreotate (177Lu-octreotate-LuTate) across two Australian tertiary medical institutions who developed acute flare of carcinoid symptoms/carcinoid crisis during/after PRRT. Cases were identified as high-risk due to previous history of carcinoid crises, high tumour burden and markedly elevated tumour markers. We propose a protocol to prevent and manage severe carcinoid symptoms in high-risk patients treated with PRRT.

Systemic therapies for advanced gastroenteropancreatic neuroendocrine tumors.

INTRODUCTION: Neuroendocrine tumors are a heterogeneous group of malignancies, characterised by production of hormones and vasoactive peptides. The incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) is rising, and they have the highest prevalence amongst upper gastro-intestinal tumors. Diagnosis remains challenging due to wide variations in presentation and slow onset of symptoms. A multi-disciplinary approach is vital in appropriately managing the diverse spectrum of GEP-NET. Areas covered: Investigations in GEP-NET and biomarkers are described. Moreover, all available therapeutic options for GEP-NET including surgery, somatostatin analogues, targeted agents, Peptide Receptor Radionuclide Therapy and chemotherapy are also discussed. Expert commentary: The landscape of management has changed significantly in the last decade as a result of many practice-changing clinical trials. Long- acting somatostatin analogues are used not only for symptom control but also for their anti-proliferative effect. Targeted agents, such as everolimus and sunitinib, have improved PFS in GEP-NET. The recently presented NETTER-1 trial confirms the place of peptide receptor radionuclide treatment (PRRT) in treating NET. While chemotherapy remained an important option for high grade tumors. Despite promising results from recent trials, challenges include establishing the optimal sequencing of therapies to optimize outcome and preserve the quality of life.