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Purpose of Review: Gastroenteropancreatic NEN (GEP-NEN) are group of malignancies with significant clinical, anatomical and molecular heterogeneity. High-grade GEP-NEN in particular present unique management challenges., Recent Findings: In the current era, multidisciplinary management with access to a combination of functional imaging and targeted molecular profiling can provide important disease characterisation, guide individualised management and improve patient outcome. Multiple treatment options are now available, and combination and novel therapies are being explored in clinical trials. Precision medicine is highly relevant for a heterogenous disease like NEN. The integration of dual-tracer functional PET/CT imaging, molecular histopathology and genomic data has the potential to be used to gain a more comprehensive understanding of an individual patient's disease biology for precision diagnosis, prognostication and optimal treatment allocation., (© 2023. Crown.)

Merkel cell carcinoma is a rare, aggressive skin malignancy, also known as neuroendocrine carcinoma of the skin, with high rates of recurrence and distant metastasis. In refractory metastatic Merkel cell carcinoma (mMCC), besides immunotherapy, chemotherapy, and radiation, peptide receptor radionuclide therapy (PRRT) may be a viable option since this type of tumor can express somatostatin receptors. Methods: We performed a comprehensive review of the literature to evaluate the efficacy of PRRT in mMCC patients. Results: Thirty-seven patients with mMCC received PRRT (1-5 cycles) with 177 Lu- or 90 Y-labeled somatostatin analogs (cumulative activity, 1.5-30 GBq). Radiographic response was available for 19 of 28 patients who received PRRT alone. Six (31.6%) of 19 patients showed objective responses, from partial to complete, and no severe adverse events were reported. Conclusion: Our analysis supports the use of PRRT in mMCC with sufficient somatostatin receptor uptake, although the quality of the available evidence is low. Prospective clinical trials are already in development and have started accruing in some parts of the world., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

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., (© 2022 S. Karger AG, Basel.)

Peptide receptor radionuclide therapy (PRRT) is a widely accepted treatment for progressive grade 1 and 2 (G1-2) gastroenteropancreatic neuroendocrine tumors (NET). There is increasing evidence that PRRT is effective for selected patients with well-differentiated (WD) G3 NET, which are now separated from neuroendocrine carcinoma (NEC). These preliminary data have led to prospective PRRT trials currently in progress. This article provides an update of the current role of PRRT for patients with WD-G3 NET, highlighting the importance of patient selection based on molecular imaging phenotype, as well as outlining some potential future directions in this field. Upcoming prospective trials will help define the role, sequencing, and optimization of PRRT to improve outcomes of patients with WD-G3 NET., Competing Interests: Conflict of interest statement None for Grace Kong. Although not relevant to any material in this manuscript, Professor Hicks is a shareholder of Telix Pharmaceuticals and Founder and Shareholder of PreMIT Pty Ltd., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Neuroendocrine neoplasms (NENs) encompass a broad spectrum of tumors throughout the body and range in biologic behavior from indolent to aggressive. Consequently, a wide spectrum of treatment options are available for NENs, including observation, somatostatin analogues, targeted therapy, chemotherapy, surgical resection, liver-directed therapy (embolization and ablation), and peptide receptor radionuclide therapy. Given the wide variety of tumor behaviors and treatments, precise criteria for treatment response in NENs are lacking. Though conventional anatomic imaging with CT and MRI remains important for NEN response assessment, the use of somatostatin receptor (SSR) PET is increasing and often provides synergistic and complementary information. Additionally, in certain clinical scenarios, a particular imaging strategy may prove superior or inferior to others for the detection of metastatic disease and evaluation of therapy response. A strong need exists to further define appropriate and standardized assessment criteria for tumor response and progression in NEN. This article presents the strengths and weaknesses of individual imaging modalities for evaluating NEN therapy response, including conventional anatomic imaging, SSR PET, FDG PET, dual-tracer PET, and PET/MRI. Ongoing challenges and unmet needs in the use of imaging for NEN response evaluation are explored.

The purpose of this study was to assess the efficacy and safety of 177 Lu-DOTATATE in patients with somatostatin receptor (SSR)-positive lung neuroendocrine tumors (NETs). Methods: This is a retrospective review of the outcome of patients with typical carcinoid (TC) and atypical carcinoid (AC), treated with 177 Lu-DOTATATE at 2 ENETS Centers of Excellence. Morphologic imaging (RECIST 1.1) and 68 Ga-DOTATATE PET/CT responses were assessed at 3 mo after completion of 177 Lu-DOTATATE. Concordance between 2 response assessment methods was evaluated by κ statistics. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and compared by Log-rank test. Treatment-related adverse events (AEs) were graded based on Common Terminology Criteria for Adverse Events, version 5. Results: Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68 Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of 177 Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68 Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68 Ga-DOTATATE PET/CT, weighted κ of 0.51 (95% CI, 0.21-0.68). Of patients with stable disease by RECIST, those with partial response on 68 Ga-DOTATATE PET/CT had a longer OS than those with no response, NR versus 52 mo (95% CI, 28-64), hazard ratio 0.2 (95% CI, 0.1-0.6), P  < 0.001. Most grade 3/4 AEs were reversible and the most common was lymphopenia (14%) with no incidence of myelodysplasia or leukemia. Conclusion: In patients with advanced progressive lung NET and satisfactory SSR expression, 177 Lu-DOTATATE is effective and safe with a high disease control rate and encouraging PFS and OS., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: This study aimed to analyse the molecular imaging (MI) phenotype of typical carcinoid (TC) and atypical carcinoid (AC) by 68 Ga-DOTATATE (GaTATE) and 18 F-FDG (FDG) PET/CT with the emphasis on its potential theranostic implications for peptide receptor radionuclide therapy (PRRT)., Methods: Retrospective review of patients with biopsy-proven TC or AC undergoing both GaTATE and FDG PET/CT at presentation. Based on correlative CT or MRI, positive lesions on either scan were defined by uptake above liver parenchyma. Per patient MI phenotypic pattern was classified as score 1, if all lesions were negative on both scans; score 2, if all were GaTATE positive/FDG negative; score 3, if all lesions were GaTATE positive but some or all were also FDG positive and score 4, if there were any GaTATE negative/FDG positive lesions. Scores 1 and 4 were deemed unsuitable for PRRT., Results: Of 56 patients (median age 66.5 years, 32 female), 22 had TC, and 34 had AC. Distant metastases were seen in 32% of TC and 94% of AC. At a median follow-up of 37 months for TC and 38 months for AC, 100% and 63% were alive, respectively. Median OS for AC was 56 months (95% CI 43, not reached [NR]), and TC was NR. On inter-patient dual-tracer analysis, scores 1, 2, 3 and 4 were 23%, 18%, 36% and 23% in TC and 3%, 15%, 32% and 50% in AC, respectively. In 16 patients (score 2, N = 3; score 3, N = 12; score 4, N = 1) who were treated with PRRT, disease control rate at 3 months and OS were, 85% and 54.6 months (95% CI 44-70), respectively., Conclusions: TC and AC showed a wide inter-patient phenotypic heterogeneity on GaTATE and FDG with around half of patients (46% TC and 53% AC) having an unsuitable phenotype for PRRT. Dual-tracer MI phenotype can be used to select the most suitable patients for PRRT.

Peptide receptor radionuclide therapy (PRRT) is an established treatment for grade 1 and 2 gastroenteropancreatic neuroendocrine tumors with an increased uptake on somatostatin receptor imaging (SRI). Patients with metastatic high-grade (WHO G3) gastroenteropancreatic neuroendocrine neoplasms (NET G3 and NEC) represent a heterogeneous subgroup with poor prognosis and standard platinum-etoposide chemotherapy have limited therapeutic benefit. However, there is promising emerging evidence supporting the effectiveness of PRRT in SRI-positive G3 disease. A review search for studies reporting on PRRT in gastroenteropancreatic neuroendocrine neoplasms G3 was performed: four studies with more than ten cases were found. PRRT was mainly given as second- or third-line treatment in patients with progressive disease. Most patients had a pancreatic primary, 50% had well-differentiated tumors, and most had a Ki-67 <55%. Three studies showed similar results with promising response rates (31-41%) and disease control rates (69-78%). Progression-free survival (11-16 months) and survival (22-46 months) were best concerning patients with a Ki-67 <55%. Progression-free survival was 19 months in NET G3, 11 months for lowNEC (Ki-67 ≤55%) and 4 months for highNEC (Ki-67 >55%). PRRT should be considered for patients with increased uptake on SRI, both in gastroenteropancreatic NET G3 cases and as well as in NEC cases with a Ki-67 21-55%. PRRT for NEC with a Ki-67 >55% is less defined, but could be considered in highly selected cases after response to initial chemotherapy where all residual disease have high uptake on SRI. Dual tracer using 18F-FDG PET/CT and SRI provides important information for patient selection for PRRT in this heterogeneous complex high-grade disease.

Opinion Statement: Neuroendocrine neoplasia (NEN) represents a heterogenous group of tumours. Guidelines regarding treatment choice and sequencing remain complex given varied primary sites, hormone-secretory status, tumour grade, disease heterogeneity, and paucity of rigorous comparative trials due to rarity of this condition. However, there is increasing evidence that peptide receptor radionuclide therapy (PRRT) is an effective treatment, especially for grade 1 and 2 NEN. Primary indications for treatment include oncologic control in patients with progressive disease and symptomatic control in the context of hormone-secretory syndromes or tumour-related pain. However, strategies are needed to further optimize efficacy and outcomes, and to expand treatment indications. Important considerations could include personalized PRRT regimens based on better characterization of the disease in an individual patient. Future directions should also focus on strategies to further enhance the efficacy of PRRT including combination treatments with other systemic therapies, such as radiosensitising chemotherapy, DNA repair-modifying agents and immunotherapy. Further evolution of therapeutic radiopharmaceuticals also offers promise.

Purpose: Peptide receptor radionuclide/chemoradionuclide therapy (PRRT/PRCRT) is an effective therapy for metastatic neuroendocrine neoplasia (NEN), but therapy-related myeloid neoplasms (t-MN) remain of concern. The study reviewed the clinicopathological features and outcomes of patients who developed t-MN., Methods: Retrospective analysis of all patients diagnosed with t-MN by 2016 WHO classification, from a cohort of 521 patients who received PRRT/PRCRT over a 12-year period. Molecular next-generation sequencing using an in-house 26-gene panel was performed., Results: Twenty-five of 521 (4.8%) patients were diagnosed with t-MN, including six acute myeloid leukaemia (AML) and 19 myelodysplastic syndrome (MDS). The median time from first cycle PRRT/PRCRT to diagnosis of t-MN was 26 months (range 4-91). Twenty-two of 25 (88%) patients had grade 1-2 pancreatic or small bowel NEN with moderate metastatic liver burden. Six patients (24%) had prior chemotherapy. Median number of PRRT cycles = 5 (22/25 (88%) with concomitant radiosensitising chemotherapy). All 25 patients achieved disease stabilisation (68%) or partial response (32%) on RECIST 1.1 at 3 months post-PRRT. At t-MN diagnosis, all patients presented with thrombocytopenia (median nadir 33 × 10 9 /L, range 3-75) and 17 (68%) remained NEN progression-free. Marrow genetic analysis revealed unfavourable karyotype in 16/25 (66%) patients with tumour protein 53 (TP53) mutation in nine (36%). Azacitidine therapy was utilised in ten eligible patients, while four received induction chemotherapy for AML. The median overall survival from first PRRT was 62 months (19-94), but from t-MN diagnosis was only 13 months (1-56), with death due primarily to haematological disease progression., Conclusions: The diagnosis of t-MN after PRRT/PRCRT is an infrequent but serious complication with poor overall survival. Most patients present with thrombocytopenia; unfavourable genetic mutations have a poor response to t-MN treatment. Prospective data are needed to explore potential pre-existing genetic factors and predictive biomarkers to minimise the risk of t-MN.

Imaging of somatostatin receptor expression is an established technique for staging of neuroendocrine neoplasia and determining the suitability of patients for peptide receptor radionuclide therapy. PET/CT using 68 Ga-labeled somatostatin analogs is superior to earlier agents, but the rapid physical decay of the radionuclide poses logistic and regulatory challenges. 64 Cu has attractive physical characteristics for imaging and provides a diagnostic partner for the therapeutic radionuclide 67 Cu. Based on promising preclinical studies, we have performed a first-time-in-humans trial of 64 Cu-MeCOSar-Tyr 3 -octreotate ( 64 Cu-SARTATE) to assess its safety and ability to localize disease at early and late imaging time-points. Methods: In a prospective trial, 10 patients with known neuroendocrine neoplasia and positive for uptake on 68 Ga-DOTA-octreotate ( 68 Ga-DOTATATE) PET/CT underwent serial PET/CT imaging at 30 min, 1 h, 4 h, and 24 h after injection of 64 Cu-SARTATE. Adverse reactions were recorded, and laboratory testing was performed during infusion and at 1 and 7 d after imaging. Images were analyzed for lesion and normal-organ uptake and clearance to assess lesion contrast and perform dosimetry estimates. Results: 64 Cu-SARTATE was well tolerated during infusion and throughout the study, with 3 patients experiencing mild infusion-related events. High lesion uptake and retention were observed at all imaging time-points. There was progressive hepatic clearance over time, providing the highest lesion-to-liver contrast at 24 h. Image quality remained high at this time. Comparison of 64 Cu-SARTATE PET/CT obtained at 4 h to 68 Ga-DOTATATE PET/CT obtained at 1 h indicated comparable or superior lesion detection in all patients, especially in the liver. As expected, the highest early physiologic organ uptake was in the kidneys, liver, and spleen. Conclusion: 64 Cu-SARTATE is safe and has excellent imaging characteristics. High late-retention in tumor and clearance from the liver suggest suitability for diagnostic studies and for prospective dosimetry for 67 Cu-SARTATE peptide receptor radionuclide therapy, and the half-life of 64 Cu would also facilitate good-manufacturing-practice production and distribution to sites without access to 68 Ga., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Rectal neuroendocrine neoplasia (NEN) is more common than other NEN origins, but is less commonly metastatic. However, when present, distant disease carries a particularly poor prognosis. Evidence guiding optimal treatment of such patients is lacking. We assessed PRRT outcomes in patients with somatostatin receptor (SSTR) positive metastatic rectal NEN from two referral centres., Methods: Patients treated with PRRT were retrospectively reviewed. Morphologic (RECIST 1.1), SSTR imaging responses and toxicity were assessed 3 months post-PRRT. Kaplan-Meier estimate was used to determine progression-free survival (PFS) and overall survival (OS) from start of PRRT., Results: Twenty-seven consecutive patients (M = 20, age 31-81 years) were reviewed. The majority (70%) had ENETs grade 2 disease (19 patients), three had Grade 3, one Grade 1, and four not documented. Overall, 63% (10/16 patients with available FDG PET/CT) had FDG avid disease. Twenty-six patients were treated for disease progression. Most had 177 Lu-DOTA-octreotate with median cumulative activity of 30 GBq, median four cycles. 14 patients had radiosensitising chemotherapy (5FU or capecitabine). At 3 months post-PRRT, CT disease control rate (DCR) was 96%: partial response was observed in 70% (19/27) and stable disease in 26%. All but one had partial SSTR imaging response. The median PFS was 29 months. Ten patients died, with median overall survival 81 months with a median follow-up of 67 months. Seventeen patients had further treatments after initial PRRT (10 had further cycles of PRRT). Three patients had grade 3 lymphopenia, without significant renal toxicity, MDS or leukaemia., Conclusion: Our results indicate high efficacy and morphologic responses with minimal toxicity and very encouraging survival from PRRT in patients with metastatic rectal NEN despite the adverse prognostic features of this cohort. Further prospective PRRT trials are warranted in this subgroup.

There is no consensus on optimal follow-up for completely resected gastroenteropancreatic neuroendocrine tumors. Published guidelines for follow-up are complex and emphasize closer surveillance in the first 3 years after resection. Neuroendocrine tumors have a different pattern and timescale of recurrence, and thus require more practical and tailored follow-up. The Commonwealth Neuroendocrine Tumour Collaboration convened an international multidisciplinary expert panel, in collaboration with the North American Neuroendocrine Tumor Society, to create patient-centered follow-up recommendations for completely resected gastroenteropancreatic neuroendocrine tumors. This panel used the RAND/UCLA (University of California, Los Angeles) Appropriateness Method to generate recommendations. A large international survey was conducted outlining current the surveillance practice of neuroendocrine tumor practitioners and shortcomings of the current guidelines. A systematic review of available data to date was supplemented by recurrence data from 2 large patient series. The resultant guidelines suggest follow-up for at least 10 years for fully resected small-bowel and pancreatic neuroendocrine tumors and also identify clinical situations in which no follow-up is required. These recommendations stratify follow-up strategies based on evidence-based prognostic factors that allow for a more individualized patient-centered approach to this complex and heterogeneous malignant neoplasm.

Purpose: Grade 3 NENs are aggressive tumours with poor prognosis. PRRT+/- radiosensitising chemotherapy is a potential treatment for disease with high somatostatin receptor (SSTR) expression without spatially discordant FDG-avid disease. We retrospectively evaluated the efficacy of PRRT in G3 NEN., Methods: Kaplan-Meier estimation was used to determine progression-free survival (PFS) and overall survival (OS) defined from start of PRRT. Subgroup analysis was performed for patients with Ki-67 ≤ 55% and >55%. Anatomical response (RECIST 1.1) and toxicity 3 months after PRRT was determined. Disease control rate (DCR) was defined as complete response (CR), partial response (PR) and stable disease (SD) of those with prior progression., Results: 28 patients (M = 17; age 16-78 years; Ki-67 ≤ 55% = 22) were reviewed. 17 patients had pancreatic, 5 small bowel, 3 large bowel, 2 bronchial and 1 unknown primary disease. 25/28 had significant FDG-avid disease prior to treatment. Most had 177 Lu-DOTA-octreotate (median cumulative activity 24.4 GBq, median 4 cycles). Twenty patients had radiosensitising chemotherapy. 89% were treated for disease progression; 79% after prior chemotherapy. Median follow-up was 29 months. The median PFS was 9 months for all patients. 16 patients died (Ki-67 ≤ 55% = 11; Ki-67 > 55% = 5) with median OS of 19 months. For Ki-67 ≤ 55% (N = 22), the median PFS was 12 months and median OS 46 months. For Ki-67 > 55% (N = 6), the median PFS was 4 months and median OS 7 months. On CT imaging, DCR at 3 months post-PRRT was 74%, 35% (8/23) PR and 39% (9/23) SD. Eleven patients received further PRRT due to recrudescent disease after response. Five patients developed progression of discordant FDG-avid disease and were referred for targeted therapy/chemotherapy. Grade 3 and 4 lymphopenia and thrombocytopenia occurred in five and five patients, respectively. No renal or liver toxicity related to treatment was seen., Conclusions: PRRT achieves clinically relevant disease control with acceptable toxicity in G3 NENs.

Background: To evaluate the effects of long-acting somatostatin analogue (SSA) therapy on 68 Ga-DOTA-octreotate (GaTate) uptake at physiological and metastatic sites in neuroendocrine tumour (NET) patients., Methods: Twenty-one patients who underwent GaTate PET/CT before and after commencement of SSA therapy were reviewed. Maximum standardized uptake values (SUVmax) were measured in normal organs. Changes in uptake of 49 metastatic lesions in 12 patients with stable disease were also compared. Serum chromogranin-A (CgA) levels were available for correlation between scans in 17/21 patients., Results: Mean thyroid, spleen and liver SUVmax decreased significantly following SSA therapy from a baseline of 5.9 to 3.5, 30.3 to 23.1 and 10.3 to 8.0, respectively (p = < 0.0001 for all). Pituitary SUVmax increased from 10.2 to 11.0 (p = 0.004) whereas adrenal and salivary gland SUVmax did not change. Tumour SUVmax increased in 7 of 12 patients with stable disease; CgA was stable or decreasing in 5 of these patients. 30/49 (61%) metastatic lesions had an increase in SUVmax and lesion-to-liver uptake ratio increased in 40/49 (82%) following SSA therapy., Conclusion: Long-acting SSA therapy decreases GaTate uptake in the thyroid, spleen and liver but in most cases increases intensity of uptake within metastases. This has significant implications for interpretation of GaTate PET/CT following commencement of therapy as increased intensity alone may not represent true progression. Our findings also suggest pre-dosing with SSA prior to PRRT may enable higher doses to be delivered to tumour whilst decreasing dose to normal tissues.

Purpose: Bulky disease is an adverse prognostic factor for 177 Lu-DOTA-octreotate ( 177 Lu-DOTATATE) peptide receptor radionuclide therapy (PRRT). 90 Y-DOTA-octreotate ( 90 Y-DOTATATE) has theoretical advantages in this setting but may less effectively treat co-existent smaller deposits and have higher toxicity than 177 Lu-DOTATATE. The aim of this study was to assess the efficacy and safety of using these agents sequentially., Methods: We reviewed patients (pts) with at least one lesion of a transaxial diameter >4 cm who completed 1-2 cycles of 90 Y-DOTATATE followed by 2-3 cycles of 177 Lu-DOTATATE, with treatment empirically adapted to disease size and burden in individual patients. Data collected included morphological and molecular imaging response, toxicity, and progression-free and overall survival., Results: Twenty-six pts (17 men; aged 27-74 years) received a median cumulative activity of 6.5 GBq 90 Y-DOTATATE, and 21 GBq 177 Lu-DOTATATE. All but one received radiosensitising chemotherapy. Adverse prognostic factors included ENETS grade 2 or 3 in 58 %, and FDG-avid disease in 73 %. Nineteen pts treated for progressive disease had stabilisation (37 %) or regression on CT (42 % partial response, 21 % minor response), with a mean 59 % (8-99 %) reduction in disease burden. All seven pts treated for uncontrolled symptoms reported improvement during PRRT with 4/7 having complete symptom resolution at 3 months. Eight patients had grade 3/4 lymphopaenia, and two patients grade 3/4 thrombocytopaenia without significant hepatic or renal toxicity. Median survival was not reached after a median follow-up of 35 months. Median progression-free survival was 33 months., Conclusion: PRCRT with 90 Y -DOTATATE followed by 177 Lu-DOTATATE in individualised regimens achieved high clinical and morphological response in patients with bulky tumours. Despite lack of a control arm, the efficacy of this treatment approach appears higher than reported results with either agent used alone or other approved treatments, particularly given the adverse prognostic features of this cohort.

Purpose: Increased glycolytic activity on FDG PET/CT defines a subgroup of patients with metastatic gastroenteropancreatic neuroendocrine tumour (NET) with a poor prognosis. A limited range of systemic treatment options exist for more aggressive NET. The role of peptide receptor chemoradionuclide therapy (PRCRT) in such patients is, however, unclear. This retrospective study assessed the outcomes of patients with FDG-avid NET treated with PRCRT., Methods: Clinical, biochemical and imaging response was assessed after completion of induction treatment of PRCRT with 5-fluorouracil in 52 patients selected for treatment on the basis of somatostatin-receptor imaging without spatially discordant FDG-avid disease. Of the cohort, 67% had received prior chemotherapy. Overall survival (OS) and progression-free survival (PFS) were also analysed., Results: PRCRT was well tolerated with negligible grade 3/4 toxicities. After a median follow-up period of 36 months, the median OS was not achieved with a median PFS of 48 months. At 3 months after completion of PRCRT 2% of patients showed a complete anatomical response, 28% a partial response, 68% stable disease, and only 2% progression. On FDG PET/CT, 27% achieved a complete metabolic response during the follow-up period. A biochemical response (>25% fall in chromogranin-A levels) was seen in 45%., Conclusion: PRCRT is an effective treatment in patients with FDG-avid NET, even in patients who have failed conventional therapies. Given apparently higher response rates than with alternative therapeutic options and low toxicity, further research is needed to establish whether PRCRT should be used as a first-line treatment modality in this patient population.

Introduction: Ga-68 DOTATATE (Ga-octreotate, GaTate) positron emission tomography (PET)/CT has multiple advantages compared with conventional and In-111 octreotide imaging for neuroendocrine tumours and other somatostatin-receptor expressing tumours. This study assesses the management impact of incremental diagnostic information obtained from this technique compared with conventional staging., Methods: Fifty-nine GaTate PET/CT studies were performed over an 18-month period (52 proven or suspected gastro-entero-pancreatic or bronchial neuroendocrine tumours and seven neural crest/mesenchymal tumours). A retrospective blinded review was performed on the number of abnormalities (1, 2-5 or >5) within defined regions with comparison to conventional imaging to assess incremental diagnostic information. Subsequent management impact (high, moderate or low) was determined by clinical review and follow up to assess pre-PET stage, treatment intent and post-PET management change., Results: Eighty-eight percent of GaTate studies were abnormal. Compared with conventional and In-111 octreotide imaging, additional information was provided by GaTate PET/CT in 68 and 83% of patients, respectively. Management impact was high (inter-modality change) in 47%, moderate (intra-modality change) in 10% and low in 41% (not assessable in 2%). High management impact included directing patients to curative surgery by identifying a primary site and directing patients with multiple metastases to systemic therapy., Conclusion: GaTate PET/CT imaging provides additional diagnostic information in a high proportion of patients with consequent high management impact. GaTate PET/CT could replace (1)In-111 octreotide scintigraphy at centres where it is available given its superior accuracy, faster acquisition and lower radiation exposure. Rapid implementation could be achieved by allowing substitutional funding in the Medicare Benefit Schedule., (© 2012 The Authors. Journal of Medical Imaging and Radiation Oncology © 2012 The Royal Australian and New Zealand College of Radiologists.)

Purpose: Tumour sequestration of radiotracer may lead to decreased bioavailability in healthy tissue resulting in lower absorbed radiation dose to critical organs. This study aims to assess the impact of disease burden, body habitus and urinary excretion on the biodistribution of (68)Ga-DOTA-octreotate., Methods: Ten patients with highly varied burden of somatostatin receptor-positive neuroendocrine tumour on (68)Ga-DOTA-octreotate positron emission tomography (PET)/CT were selected. Volumes of interest were drawn to derive the average uptake of renal parenchyma, spleen and body background, as well as to compute the fraction of injected activity sequestered in tumour and excreted in urine. Uptake values were assessed for correlation with tumour sequestration, weight, lean body weight, body surface area and urinary excretion., Results: There was a trend for tumour sequestration, body habitus and urinary excretion to inversely influence all healthy tissue uptake values. In particular, renal uptake, splenic intensity and background soft tissue activity were all significantly correlated to composite factors combining tumour sequestration with body habitus and renal excretion. When combined with body habitus index or a body habitus index and renal excretion, tumour sequestration was strongly and significantly correlated inversely with renal uptake., Conclusion: Our results suggest that tumour sequestration of (68)Ga-DOTA-octreotate is a major factor leading to a sink effect that decreases activity concentration in healthy organs such as the kidney. However, body habitus and renal function also influence tissue biodistribution, in a synergistic fashion. Compared with a fixed-dose peptide receptor radionuclide therapy protocol, an adjusted-dose regimen tailored to tumour burden, body habitus and renal function may allow greater radiation dose to individual lesions without substantially adding to toxicity in normal tissues.

Purpose: The aim of this retrospective study was to determine whether patients with previous peptide receptor radionuclide therapy using high-activity (111)In-pentetreotide can be safely treated with (177)Lu-octreotate and whether addition of radiosensitising chemotherapy increases the toxicity of this agent., Methods: Records of 27 patients (aged 17-75) who received 69 (median 3 per patient) (177)Lu-octreotate administrations, including 29 in conjunction with radiosensitising infusional 5-fluorouracil (5-FU) (n = 27), or capecitabine (n = 2), between October 2005 and July 2007 subsequent to 1-8 prior cycles of (111)In-pentetreotide therapy were analysed. Toxicity was assessed during and at 8-12 weeks post-treatment, with further long-term assessments including survival status reviewed till death or study close-out date of 1 November 2009., Results: Reduction in blood counts was most marked following the first dose of (177)Lu-octreotate but at early follow-up the only major haematological toxicity was a single case of grade 4 lymphopaenia. Both the presence of bone metastases and the administration of chemotherapy tended to result in greater reduction in blood counts, but these differences did not reach statistical significance. On long-term follow-up, 16 patients (59%) are alive with median overall survival of 36 months (32-44 months from first (177)Lu-octreotate therapy). None of the recorded deaths was directly related to treatment toxicity. One patient had late grade 4 anaemia and thrombocytopaenia secondary to bone marrow failure from progressive infiltration by tumour. No other significant long-term haematological toxicities were recorded and no leukaemia was observed. No renal toxicity was observed on serial serum creatinine or radionuclide glomerular filtration rate (GFR) determination on initial or long-term follow-up., Conclusion: (177)Lu-octreotate is a safe and well-tolerated therapy for patients who have previously been treated with (111)In-pentetreotide and can be safely combined with radiosensitising chemotherapy. However, caution is recommended in patients with bone metastases. Significant late toxicities including bone marrow or renal failure, or leukaemia directly related to radionuclide therapy, did not occur in our series.

Introduction: High-administered activity In-111 octreotide (HA-Oc) therapy has been used for patients with disseminated neuroendocrine tumors (NET) with high somatostatin receptor (SSR) expression. Combining HA-Oc with radiosensitizing 5-fluorouracil (5FU) chemotherapy could enhance efficacy. Our other aim was to assess whether concomitant 5FU would contribute to significant additional toxicity., Methods: Fifteen (15) consecutive patients who received 3 cycles of HA-Oc+5FU were evaluated. Symptomatic, octreoscan, computed tomography (CT), hormonal responses, and toxicity were reviewed at 3 months post-last treatment. Long-term follow-up was performed to death or April 2008 to assess late toxicity and time to progression requiring retreatment., Results: At 3 months post-treatment, 67% of patients had symptomatic improvement, with 20% experiencing a complete resolution of symptoms. Overall, 90% achieved stabilization or a decrease in hormone levels. Octreoscan improvement/stabilization occurred in 95% and CT stabilization in 80% of patients with previously progressive disease, but no partial or complete regression by Response Evaluation Criteria in Solid Tumors criteria. Transient lymphopenia and nausea were the most common side-effects, and there was no significant renal or grade 4 hematologic toxicity. Subacute side-effects included a peripherally inserted central catheter line thrombosis (1 patient), discomfort/pain associated with lesion necrosis, and 1 lymph node swelling. Median time to retreatment was 23 months (range, 6-34) for 10 patients. Six (6) patients deceased (no deaths directly related to 5FU); 9 patients (60%) are alive at 36-139 months., Conclusions: HA-Oc+5FU achieve a high rate of symptomatic response associated with stabilization/improvement in hormonal and functional scan abnormalities. Combination treatment achieved disease stabilization in the majority of patients with previously progressive disease. There was no significant observed increase in toxicity with additional 5FU, making it a promising adjunct to radiopeptide receptor therapy for progressive NET.

Peptide receptor radionuclide therapy (PRRT) has been primarily studied in low and intermediate‐grade digestive neuroendocrine tumors (NET G1‐G2). The documentation of a similar benefit for high‐grade digestive neuroendocrine neoplasms (NEN) has been limited. This review evaluates the use of PRRT for high‐grade digestive NEN (well‐differentiated NET G3 and poorly differentiated neuroendocrine carcinomas [NEC]). We identified one phase III trial and seven retrospective studies reporting specifically on PRRT outcome of >10 digestive high‐grade NEN patients. The retrospective single‐arm studies indicate a benefit for PRRT in NET G3. The randomized phase III NETTER‐2 trial demonstrates major PFS superiority of PRRT versus somatostatin analog therapy as the first‐line treatment for the NET G3 subgroup. PRRT can now be considered a potential first‐line treatment for somatostatin receptor‐positive NET G3 patients, but whether it should be the first‐line standard of care for all NET G3 patients is still not clarified. For NEC, scarce data are available, and pathologic distinction between NEC and NET G3 can be difficult when Ki‐67 is below 55%. PRRT could be considered as a treatment for refractory NEC in very selected cases when there is a high uptake on somatostatin receptor imaging, Ki‐67 is below 55%, and there is no rapid tumor progression. [ABSTRACT FROM AUTHOR]

Introduction Patient Reported Outcome Measures (PROMs) are frequently recommended as a clinical strategy, tracking health-related quality of life (HRQOL) indicating symptom burden and treatment tolerance. The PLANET QOL App was launched in 2018 to sit alongside the national PLANET NET Registry. This App tracks PROMs including BMI, ECOG, Bowel symptoms and HRQOL (EORTC QLQ30, GINET21). Peter MacCallum Cancer Centre recently implemented a Nurse Led Clinic (NLC) for patients with NETs (Neuroendocrine Tumours), utilising the PLANET QOL App. Aim To pilot the utilisation of an electronic PROM in the NET NLC. Methodology A NLC model was piloted over three phases: planning, implementation, and evaluation. Eligible patients included those with low/intermediate grade NETs. NLC frequency was determined with supervising Medical Oncologist with medical review at least annually and escalation policies and pathways were established (e.g., symptom escalation, other clinical concerns). New NLC participants were encouraged to download the App, with PROMs to be reported monthly. These data formed the basis of the NLC assessment, with subsequent interventions as appropriate. For patients unable to use the app, a similarly structured assessment was conducted verbally. Results 71 NLC consultations were conducted over six months (18 in person and 53 via telehealth). Of these, five individuals utilised the PLANET QOL App, which was a useful tool in assessing symptoms and overall wellbeing. The main factor in App non-usage was technological (e.g., elderly), those not wanting to be reminded of their disease, and language limitations. Use of the PROM was also hampered by the lack of integration between the PLANET database (designed primarily as a research tool) and patient hospital electronic medical records. Conclusion The use of electronic PROMS in the NET NLC has enabled meaningful inclusion of this data in clinical care. Next steps will include addressing technical challenges, optimising data visualisation, and integration of viewing systems. [ABSTRACT FROM AUTHOR]

Purpose: Bulky disease is an adverse prognostic factor for Lu-DOTA-octreotate (Lu-DOTATATE) peptide receptor radionuclide therapy (PRRT). Y-DOTA-octreotate (Y-DOTATATE) has theoretical advantages in this setting but may less effectively treat co-existent smaller deposits and have higher toxicity than Lu-DOTATATE. The aim of this study was to assess the efficacy and safety of using these agents sequentially. Methods: We reviewed patients (pts) with at least one lesion of a transaxial diameter >4 cm who completed 1-2 cycles of Y-DOTATATE followed by 2-3 cycles of Lu-DOTATATE, with treatment empirically adapted to disease size and burden in individual patients. Data collected included morphological and molecular imaging response, toxicity, and progression-free and overall survival. Results: Twenty-six pts (17 men; aged 27-74 years) received a median cumulative activity of 6.5 GBq Y-DOTATATE, and 21 GBq Lu-DOTATATE. All but one received radiosensitising chemotherapy. Adverse prognostic factors included ENETS grade 2 or 3 in 58 %, and FDG-avid disease in 73 %. Nineteen pts treated for progressive disease had stabilisation (37 %) or regression on CT (42 % partial response, 21 % minor response), with a mean 59 % (8-99 %) reduction in disease burden. All seven pts treated for uncontrolled symptoms reported improvement during PRRT with 4/7 having complete symptom resolution at 3 months. Eight patients had grade 3/4 lymphopaenia, and two patients grade 3/4 thrombocytopaenia without significant hepatic or renal toxicity. Median survival was not reached after a median follow-up of 35 months. Median progression-free survival was 33 months. Conclusion: PRCRT with Y -DOTATATE followed by Lu-DOTATATE in individualised regimens achieved high clinical and morphological response in patients with bulky tumours. Despite lack of a control arm, the efficacy of this treatment approach appears higher than reported results with either agent used alone or other approved treatments, particularly given the adverse prognostic features of this cohort. [ABSTRACT FROM AUTHOR]

Purpose: Tumour sequestration of radiotracer may lead to decreased bioavailability in healthy tissue resulting in lower absorbed radiation dose to critical organs. This study aims to assess the impact of disease burden, body habitus and urinary excretion on the biodistribution of Ga-DOTA-octreotate. Methods: Ten patients with highly varied burden of somatostatin receptor-positive neuroendocrine tumour on Ga-DOTA-octreotate positron emission tomography (PET)/CT were selected. Volumes of interest were drawn to derive the average uptake of renal parenchyma, spleen and body background, as well as to compute the fraction of injected activity sequestered in tumour and excreted in urine. Uptake values were assessed for correlation with tumour sequestration, weight, lean body weight, body surface area and urinary excretion. Results: There was a trend for tumour sequestration, body habitus and urinary excretion to inversely influence all healthy tissue uptake values. In particular, renal uptake, splenic intensity and background soft tissue activity were all significantly correlated to composite factors combining tumour sequestration with body habitus and renal excretion. When combined with body habitus index or a body habitus index and renal excretion, tumour sequestration was strongly and significantly correlated inversely with renal uptake. Conclusion: Our results suggest that tumour sequestration of Ga-DOTA-octreotate is a major factor leading to a sink effect that decreases activity concentration in healthy organs such as the kidney. However, body habitus and renal function also influence tissue biodistribution, in a synergistic fashion. Compared with a fixed-dose peptide receptor radionuclide therapy protocol, an adjusted-dose regimen tailored to tumour burden, body habitus and renal function may allow greater radiation dose to individual lesions without substantially adding to toxicity in normal tissues. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this retrospective study was to determine whether patients with previous peptide receptor radionuclide therapy using high-activity In-pentetreotide can be safely treated with Lu-octreotate and whether addition of radiosensitising chemotherapy increases the toxicity of this agent. Methods: Records of 27 patients (aged 17–75) who received 69 (median 3 per patient) Lu-octreotate administrations, including 29 in conjunction with radiosensitising infusional 5-fluorouracil (5-FU) ( n = 27), or capecitabine ( n = 2), between October 2005 and July 2007 subsequent to 1–8 prior cycles of In-pentetreotide therapy were analysed. Toxicity was assessed during and at 8–12 weeks post-treatment, with further long-term assessments including survival status reviewed till death or study close-out date of 1 November 2009. Results: Reduction in blood counts was most marked following the first dose of Lu-octreotate but at early follow-up the only major haematological toxicity was a single case of grade 4 lymphopaenia. Both the presence of bone metastases and the administration of chemotherapy tended to result in greater reduction in blood counts, but these differences did not reach statistical significance. On long-term follow-up, 16 patients (59%) are alive with median overall survival of 36 months (32–44 months from first Lu-octreotate therapy). None of the recorded deaths was directly related to treatment toxicity. One patient had late grade 4 anaemia and thrombocytopaenia secondary to bone marrow failure from progressive infiltration by tumour. No other significant long-term haematological toxicities were recorded and no leukaemia was observed. No renal toxicity was observed on serial serum creatinine or radionuclide glomerular filtration rate (GFR) determination on initial or long-term follow-up. Conclusion: Lu-octreotate is a safe and well-tolerated therapy for patients who have previously been treated with In-pentetreotide and can be safely combined with radiosensitising chemotherapy. However, caution is recommended in patients with bone metastases. Significant late toxicities including bone marrow or renal failure, or leukaemia directly related to radionuclide therapy, did not occur in our series. [ABSTRACT FROM AUTHOR]

Background: Online information resources and support have been demonstrated to positively influence the well-being of people diagnosed with cancer. This has been explored in past literature for more common cancers; however, for rare cancers, such as neuroendocrine tumors (NETs), there are little to no support or resources available. Despite relatively good prognoses, the quality of life (QoL) of patients with NETs is significantly lower compared with samples of mixed cancer patients and the general population. Patients with NETs also typically report unclear and difficult pathways of disease management and treatment, given the heterogeneity of the diagnosis. There is a vital need to improve the availability of disease-specific information for this patient group and provide supportive care that is tailored to the unique needs of the NET patient population. Objective: This study described the protocol of a study aimed to better understand the outcomes and experiences of patients diagnosed with NETs and to develop and pilot test a nurse-led online and phone-based intervention that will provide tailored supportive care targeted to NET subgroups (functioning vs nonfunctioning). Methods: This is a multisite cohort with 3 phases, incorporating both quantitative and qualitative data collection. Phase 1 is a mixed methods prospective cohort study of NET patients identifying differences in patient experiences and priority of needs between NET subgroups. Phase 2 utilizes results from phase 1 to develop an online and nurse-led phone-based intervention. Phase 3 is to pilot test and evaluate the intervention's acceptability, appropriateness, and feasibility. Results: Currently, the project is progressing through phase 1 and has completed recruitment. A total of 138 participants have been recruited to the study. To date, patient-reported outcome data from 123 participants at baseline and 87 participants at 6-month follow-up have been collected. Of these, qualitative data from semistructured interviews from 35 participants have also been obtained. Phase 2 and phase 3 of the project are yet to be completed. Conclusions: Limited research for patients with NETs suggests that QoL and patient experiences are significantly impaired compared with the general population. Furthermore, past research has failed to delineate how the clinical variability between those with functioning and nonfunctioning NETs impacts patient supportive care needs. This study will improve on the availability of disease-specific information as well as informing the design of a nurse-led online and phone-based supportive care intervention tailored for the unique needs of the NET patient population. International Registered Report Identifier (IRRID): DERR1-10.2196/14361 We help JMIR researchers to raise funds to pursue their research and development aimed at tackling important health and technology challenges. If you would like to show your support for this author, please donate using the button below. The funds raised will directly benefit the corresponding author of this article (minus 8% admin fees). Your donations will help this author to continue publishing open access papers in JMIR journals. Donations of over $100 may also be acknowledged in future publications. Suggested contribution levels: $20/$50/$100 [ABSTRACT FROM AUTHOR]

Peptide receptor radionuclide therapy (PRRT) is an established therapy for metastatic neuroendocrine neoplasms (NEN). The role of PRRT as a neoadjuvant treatment prior to surgery or other local therapies is uncertain. This scoping review aimed to define the landscape of evidence available detailing the utility of PRRT in the neo‐adjuvant setting, including the clinical contexts, efficacy, and levels of evidence. A comprehensive literature search of PUBMED, SCOPUS, and EMBASE through to December 2022 was performed to identify reports of PRRT use as neoadjuvant therapy prior to local therapies. Observational studies and clinical trials were included. A total of 369 records were identified by the initial search, and 17 were included in the final analysis, comprising 179 patients treated with neoadjuvant PRRT. Publications included case reports, retrospective cohort series and a phase 2 trial. Definitions of unresectable disease were variable. Radioisotopes used included 177Lu (n = 142) and 90Y (n = 36), used separately (n = 178) or in combination (n = 1). A combination of PRRT with chemotherapy was also explored (n = 2). Toxicity data was reported in 11/17 studies. Survival analysis was reported in 3/17 studies. Surgical resection following PRRT was reported for both the primary tumor (n = 71) and metastases (n = 12). Resection rates could not be calculated as not all publications reported whether resection was completed. Published literature exploring the use of PRRT in the neoadjuvant setting is mostly limited to case reports and retrospective cohort studies. From these limited data there is reported to be a role of PRRT in neoadjuvant setting in the literature. However, the low quality of evidence precludes any definite conclusion on the grade of disease, site of primary, isotope used or use of concomitant chemotherapy that can benefit from this application. Further prospective studies will require collaboration between multiple centers to gain sufficient high‐quality evidence. [ABSTRACT FROM AUTHOR]

On page 4 of the original version of this article, the text 'Eight (29%) of the patients had significant FDG-avid disease (i.e. with intensity above liver parenchyma) prior to treatment' needs to be corrected. [ABSTRACT FROM AUTHOR]

This document provides a comprehensive overview of recent advancements in nuclear medicine for the diagnosis and treatment of neuroendocrine tumors (NETs). It discusses the use of radioligands and nuclear medicine practices, such as somatostatin receptor imaging and peptide receptor radionuclide therapy, in managing NETs. The document also explores the potential of combination therapies and the use of new agents, such as FAPI, in NET imaging and therapy. Ongoing clinical trials are investigating these advancements and their potential value in the clinical management of NETs. The document is a valuable resource for researchers and healthcare professionals in the field of neuroendocrine tumor management. [Extracted from the article]