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Background: There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [ 177 Lu]Lu-DOTA-TATE ( 177 Lu-Dotatate) treatment., Methods: NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177 Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks ( 177 Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting., Findings: Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177 Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177 Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177 Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period., Interpretation: First-line 177 Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177 Lu-Dotatate should be considered a new standard of care in first-line therapy in this population., Funding: Advanced Accelerator Applications, a Novartis Company., Competing Interests: Declaration of interests SS reports support for the present work from Novartis; grants or contracts from Novartis; consulting fees from Ipsen, Novartis, and Camurus; and meeting attendance support from Ipsen and Novartis. DH reports support for the present work from Novartis; grants or contracts from Novartis, ITM, RayzeBio, Thermo Fisher Scientific, Camurus, and Genentech/Roche; consulting fees from Novartis, TerSera, ITM, Crinetics, Amryt, Camurus, Chimeric Therapeutics, Harpoon Therapeutics, HarbourBioMed, Lantheus, Exelixis, and Ipsen; and participation on a data safety monitoring board for Alphamedix. SM reports advisory board participation for Novartis Oncology and Ipsen. KH reports payment for steering committee participation from Novartis; grants or contracts from Novartis and SOFIE Biosciences; consulting fees from Advanced Accelerator Applications (a Novartis company), Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, ITM, Janssen, Merck, Molecular Partners, NVision, Pfizer, POINT Biopharma, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, SOFIE Biosciences, Telix, Theragnostics, and Y-mAbs; honoraria from PeerVoice; meeting support from Janssen; advisory board participation for Fusion and GE Healthcare; and stock or stock options for SOFIE Biosciences, Pharma15, NVision, Convergent, Aktis Oncology, and AdvanCell. MP reports grants or contracts from Advanced Accelerator Applications (a Novartis company), Novartis, Ipsen, ITM, Camurus, and Boehringer Ingelheim; consulting fees from Advanced Accelerator Applications (a Novartis company), Novartis, Ipsen, Riemser, and HUTCHMED; honoraria from Ipsen, Advanced Accelerator Applications (a Novartis company), Novartis, Boehringer Ingelheim, MSD, Lilly, Recordati, Sanofi, and Serb; advisory board participation for Crinetics and Advanced Accelerator Applications (a Novartis company); and unpaid roles as ENETS committee member and President, on the ESMO education committee, and on the INCA advisory board. PLK reports grants or contracts from RayzeBio and Novartis; honoraria from Natera, ITM, BMS, and Foundation Medicine; steering committee participation (uncompensated) for RayzeBio and Exelixis; and advisory board participation and honoraria from Amgen, Genentech, Crinetics, HUTCHMED, and Ipsen. BC reports advisory board participation and honoraria from Advanced Accelerator Applications (a Novartis company). SL reports advisory board participation for Advanced Accelerator Applications (a Novartis company). JC reports grants or contracts from Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications (a Novartis company), Eisai, Amgen, and Bayer; and consulting fees and honoraria from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications (a Novartis company), Amgen, Sanofi, Lilly, Hutchinson Pharma, ITM, Advanz, Merck, Esteve, and Roche. AG-B reports consulting fees from Advanced Accelerator Applications (a Novartis company), Bayer, and Sanofi; and speaker fees and meeting support from Novartis. D-YO reports grants or contracts from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, and Handok; and advisory board participation for AstraZeneca, Novartis, Genentech/Roche, Merck, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD, LG Chem, Astellas, AbbVie, J-Pharma, Mirati Therapeutics, Eutilex, Moderna, and Idience. CY reports grants or contracts from Bayer, Ipsen, AstraZeneca, Boehringer Ingelheim, Servier, and Eisai; and honoraria from Bayer, Ipsen, MSD, Merck, Celgene, AstraZeneca, GSK, Eisai, Roche, Genentech, and Novartis. TRH reports consulting fees from TerSera; advisory board participation and research support from Camurus, ITM, Advanced Accelerator Applications (a Novartis company), Crinetics, and Perspective Therapeutics; research support from Thermo Fisher Scientific; and an unpaid role as President of NANETS. IF, YZ, and PA report employment by Novartis and stock or stock options for Novartis. WWdH reports consulting fees and honoraria from Ipsen, Novartis, and Advanced Accelerator Applications (a Novartis company); and consulting fees from ITM. DF reports grants or contracts from Camurus and Pfizer; honoraria from Novartis and Recordati Rare Diseases; and advisory board participation for Camurus, Ipsen, Novartis, Recordati Rare Diseases, and Pfizer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: The aim of this study was to assess the yield of somatostatin receptor PET in patients with clinical, imaging, and/or biochemical suspicion of a neuroendocrine tumor (NET)., Patients and Methods: This analysis includes patients referred for the initial diagnosis of an unconfirmed NET, as part of a prospective, single-arm registry study (NCT03873870) assessing the utility of 68 Ga-DOTATATE PET/CT in the management of NETs. Inclusion criteria to this cohort consisted of elevated biomarkers and/or clinical presentation suspicious for a NET, with negative conventional cross-sectional imaging, or presence of a lesion suspicious for a NET on conventional imaging, not amenable for biopsy. Patients with histological confirmation of a NET were excluded., Results: There were 220 patients included between April 2019 and March 2022 with a mean age ± SD of 59.5 ± 16.1 years with biochemical, morphological, and/or clinical suspicion of a NET. Overall, 132/220 patients (60%) had a positive 68 Ga-DOTATATE PET/CT. 68 Ga-DOTATATE PET/CT confirmed a type 2 somatostatin receptor overexpressing tumor in 123/171 (71.9%) of patients with a radiographically suspicious abnormality. The positivity rate for pancreatic, small bowel/mesenteric, adrenal, and other sites was 78/96 (81.2%), 38/57 (66.7%), 7/7 (100%), and 1/11 (9.1%), respectively. 68 Ga-DOTATATE PET/CT was positive in 9/49 (18.4%) of those with a biochemical and/or clinical suspicion of a NET., Conclusions: 68 Ga-DOTATATE PET/CT is positive in nearly 3 of 4 patients with morphological suspicion of a NET, with the highest yield in those with pancreatic and small bowel or mesenteric masses, and in approximately 1 of 6 patients with biochemical and/or clinical suspicion of a NET., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Important progress has been made over the last decade in the classification, imaging, and treatment of neuroendocrine neoplasm (NENs), with several new agents approved for use. Although the treatment options available for patients with well-differentiated neuroendocrine tumors (NETs) have greatly expanded, the rapidly changing landscape has presented several unanswered questions about how best to optimize, sequence, and individualize therapy. Perhaps the most important development over the last decade has been the approval of 177Lu-DOTATATE for treatment of gastroenteropancreatic-NETs, raising questions around optimal sequencing of peptide receptor radionuclide therapy (PRRT) relative to other therapeutic options, the role of re-treatment with PRRT, and whether PRRT can be further optimized through use of dosimetry among other approaches. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trial planning meeting in 2021 with multidisciplinary experts from academia, the federal government, industry, and patient advocates to develop NET clinical trials in the era of PRRT. Key clinical trial recommendations for development included 1) PRRT re-treatment, 2) PRRT and immunotherapy combinations, 3) PRRT and DNA damage repair inhibitor combinations, 4) treatment for liver-dominant disease, 5) treatment for PRRT-resistant disease, and 6) dosimetry-modified PRRT., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

High-grade neuroendocrine neoplasms are a rare disease entity and account for approximately 10% of all neuroendocrine neoplasms. Because of their rarity, there is an overall lack of prospectively collected data available to advise practitioners as to how best to manage these patients. As a result, best practices are largely based on expert opinion. Recently, a distinction was made between well-differentiated high-grade (G3) neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas, and with this, pathologic details, appropriate imaging practices and treatment have become more complex. In an effort to provide practitioners with the best guidance for the management of patients with high-grade neuroendocrine neoplasms of the gastrointestinal tract, pancreas, and gynecologic system, the North American Neuroendocrine Tumor Society convened a panel of experts to develop a set of recommendations and a treatment algorithm that may be used by practitioners for the care of these patients. Here, we provide consensus recommendations from the panel on pathology, imaging practices, management of localized disease, management of metastatic disease and surveillance and draw key distinctions as to the approach that should be utilized in patients with well-differentiated G3 neuroendocrine tumors vs poorly differentiated neuroendocrine carcinomas.

There is an increased risk of second primary cancers (SPCs) after neuroendocrine tumor (NET) diagnosis. The clinical significance of SPCs in this population is unknown. The purpose of this study was to evaluate the association between SPCs after NET diagnosis and survival. We performed a population-based, retrospective cohort study of NET patients (gastrointestinal, pancreatic, or lung primary) from 2000 to 2016 using the Surveillance, Epidemiology, and End Results database. Cox regression models assessed the association between SPCs and NET-specific (NET-SS), cancer-specific (CSS), and overall survival (OS). Of 58,553 NET patients, 7.9% experienced an SPC. SPCs were associated with worse OS (hazard ratio (HR) 2.14, 95% CI 1.94-2.36) and CSS (HR 2.31, 95% CI 2.06-2.59) with no difference in NET-SS (HR 1.04, 95% CI 0.87-1.23). Stratified analyses by histologic grade showed similar results for well and moderately differentiated NETs, but no difference in OS or CSS for poorly differentiated NETs (P > 0.05). In stratified analyses by NET site, SPCs were associated with worse OS (HR 3.41, 95% CI 3.01-3.87) and CSS (HR 4.96, 95% CI 4.28-5.74) in gastrointestinal NETs and worse OS (HR 1.25, 95% CI 1.03-1.52) with no difference in CSS (HR 1.08, 95% CI 0.85-1.36) in lung NETs. SPCs were not associated with a difference in OS or CSS in pancreatic NETs (P > 0.05). In conclusion, SPCs after NETs were associated with inferior OS and CSS compared to no SPC but were not associated with NET-SS. These data highlight the need for long-term follow-up in NETs to include the detection of SPCs to ensure early diagnosis and timely management.

Purpose: Diversion of tryptophan to tumoral hormonal production has been suggested to result in psychiatric illnesses in neuroendocrine tumors (NET). We measured the occurrence of psychiatric illness after NET diagnosis and compare it to colon cancer (CC)., Methods: We conducted a population-based retrospective cohort study. Adults with NET were matched 1:1 to CC (2000-2019). Psychiatric illness was defined by mental health diagnoses and mental health care use after a cancer diagnosis, categorized as severe, other, and none. Cumulative incidence functions accounted for death as a competing risk., Results: A total of 11,223 NETs were matched to CC controls. Five-year cumulative incidences of severe psychiatric illness for NETs vs. CC was 7.7% (95%CI 7.2-8.2%) vs 7.6% (95%CI 7.2-8.2%) (p = 0.50), and that of other psychiatric illness was 32.9% (95%CI 32.0-33.9%) vs 31.6% (95%CI 30.8-32.6%) (p = 0.005). In small bowel and lung NETs, 5-year cumulative incidences of severe (8.1% [95%CI 7.3-8.9%] vs. 7.0% [95%CI 6.3-7.8%]; p = 0.01) and other psychiatric illness (34.7% [95%CI 33.3-36.1%] vs. 31.1% [95%CI 29.7-32.5%]; p < 0.01) were higher than for matched CC. The same was observed for serotonin-producing NETs for both severe (7.9% [95%CI 6.5-9.4%] vs. 6.8% [95%CI 5.5-8.2%]; p = 0.02) and other psychiatric illness (35.4% [95%CI 32.8-38.1%] vs. 31.9% [95%CI 29.3-34.4%]; p = 0.02)., Conclusions: In all NETs, there was no difference observed in the incidence of psychiatric illness compared to CC. For sub-groups of small bowel and lung NETs and of serotonin-producing NETs, the incidence of psychiatric illness was higher than for CC. These data suggest a signal towards a relationship between those sub-groups of NETs and psychiatric illness., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: We examined the impact of upfront small bowel resection (USBR) for metastatic small bowel neuroendocrine (SB-NET) compared to nonoperative management (NOM) on long-term healthcare utilization and survival outcomes., Summary of Background Data: The role of early resection of the primary tumor in metastatic SB-NET remains controversial. Conflicting data exist regarding its clinical and survival benefits., Methods: This is a population-based retrospective matched comparative cohort study of adults diagnosed with synchronous metastatic SB-NET between 2001 and 2017 in Ontario. USBR was defined as resection within 6 months of diagnosis. Primary outcomes were subsequent unplanned acute care admissions and small bowel-related surgery. Secondary outcome was overall survival. USBR and NOM patients were matched 2:1 using a propensity-score. We used time-to-event analyses with cumulative incidencefunctions and univariate Andersen-Gill regression for primary outcomes. E value methods assessed the potential for residual confounding., Results: Of 1000 patients identified, 785 had USBR. The matched cohort included 348 patients with USBR and 174 with NOM. Patients with USBR had lower 3-year risk of subsequent admissions (72.6% vs 86.4%, P < 0.001) than those with NOM, with hazard ratio 0.72 (95% confidence interval 0.570.91). USBR was associated with lower risk of subsequent small bowel-related surgery (15.4% vs 40.3%, P < 0.001), with hazard ratio 0.44 (95% confidence interval 0.29-0.67). E -values indicated it was unlikely that the observed risk estimates could be explained by an unmeasured confounder. Sensitivity analysis excluding emergent resections to define USBR did not alter the results., Conclusions: USBR for SB-NETs in the presence of metastatic disease was associated with better patient-oriented outcomes of decreased subsequent admissions and interventions, compared to NOM. USBR should be considered for metastatic SB-NETs., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Liver metastases are common in patients with neuroendocrine neoplasms. The role of stereotactic ablative radiotherapy (SABR) is not well understood in this population., Objective: The objective of this study was to evaluate the safety and efficacy of SABR in treating well-differentiated neuroendocrine liver metastases (WD-NELM)., Methods: A retrospective review of patients with WD-NELM treated with SABR was conducted between January 2015 and July 2019. Demographic, treatment, and clinical/radiographic follow-up data were abstracted. RECIST 1.1 criteria were applied to each individual target to evaluate the response to treatment. Local control (LC) and progression-free survival (PFS) were determined using the Kaplan-Meier methodology. Toxicity was reported according to the CTCAE v5.0., Results: Twenty-five patients with a total of 53 liver metastases treated with SABR were identified. Most patients (68%) had midgut tumors, were grade 2 (80%), and had high-volume intrahepatic and/or extrahepatic disease (76%). The median number of liver metastases treated was 2, with a median size of 2.5 cm. The median radiation dose delivered was 50 Gy/5 fractions. The median follow-up was 14 months; 24 of the 25 patients were alive at the time of analysis. The objective response rate was 32%, with improvement or stability in 96% of lesions treated. The median time to best response was 9 months. The 1-year LC and PFS were 92 and 44%, respectively. No grade 3/4 acute or late toxicity was identified., Conclusions: Liver SABR is a safe and promising means of providing LC for WD-NELM. This treatment modality should be evaluated in selected patients in concert with strategies to manage systemic disease., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

The aim of this study was to determine whether quantitative PET parameters on baseline 68 Ga-DOTATATE PET/CT and interim PET (iPET) performed before the second cycle of therapy are predictive of the therapy response and progression-free survival (PFS). Methods: Ninety-one patients with well-differentiated neuroendocrine tumors (mean Ki-67 index, 8.3%) underwent 68 Ga-DOTATATE PET/CT to determine suitability for peptide receptor radionuclide therapy as part of a prospective multicenter study. The mean follow-up was 12.2 mo. Of the 91 patients, 36 had iPET. The tumor metrics evaluated were marker lesion-based measures (mean SUV max and ratio of the mean lesion SUV max to the SUV max in the liver or the SUV max in the spleen), segmented 68 Ga-DOTATATE tumor volumes (DTTVs), SUV max and SUV mean obtained with the liver and spleen as thresholds, and heterogeneity parameters (coefficient of variation, kurtosis, and skewness). The Wilcoxon rank sum test was used for the association between continuous variables and the therapy response, as determined by the clinical response. Univariable and multivariable Cox proportional hazards models were used for the association with PFS. Results: There were 71 responders and 20 nonresponders. When marker lesions were used, higher mean SUV max and ratio of the mean lesion SUV max to the SUV max in the liver were predictors of the therapy response ( P  = 0.018 and 0.024, respectively). For DTTV parameters, higher SUV max and SUV mean obtained with the liver as a threshold and lower kurtosis were predictors of a favorable response ( P  = 0.025, 0.0055, and 0.031, respectively). The latter also correlated with a longer PFS. The iPET DTTV SUV mean obtained with the liver as a threshold and the ratio of mean SUV max obtained from target lesions at iPET to baseline PET correlated with the therapy response ( P  = 0.024 and 0.048, respectively) but not PFS. From the multivariable analysis with adjustment for age, primary site, and Ki-67 index, the mean SUV max ( P  = 0.019), ratio of the mean lesion SUV max to the SUV max in the liver ( P  = 0.018), ratio of the mean lesion SUV max to the SUV max in the spleen ( P  = 0.041), DTTV SUV mean obtained with the liver ( P  = 0.0052), and skewness ( P  = 0.048) remained significant predictors of PFS. Conclusion: The degree of somatostatin receptor expression and tumor heterogeneity, as represented by several metrics in our analysis, were predictive of the therapy response or PFS. Changes in these parameters after the first cycle of peptide receptor radionuclide therapy did not correlate with clinical outcomes., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Liver metastases are common in patients with neuroendocrine tumours. For patients, management must balance disease control with consideration of toxicity, given limited treatment options. Everolimus has demonstrated effectiveness in neuroendocrine neoplasms. Given emerging data of a synergistic effect with radiation therapy, we evaluated combined everolimus and radiation for neuroendocrine liver metastases. This single-arm, single-centre prospective pilot study evaluated the safety and efficacy of combined everolimus and radiotherapy for well-differentiated neuroendocrine liver metastases. Patients with unresectable liver metastases received everolimus for 30 days, followed by concurrent everolimus and liver radiotherapy, then a further 14 days of everolimus. Tolerability was evaluated using the CTCAE v.4.03. Individual metastasis response rate and local control were measured by RECIST v1.1. Overall survival, progression-free survival and freedom from a change in systemic therapy were estimated by the Kaplan-Meier method. Forty metastases were treated in 14 patients. No grade 3 or higher toxicities were identified in the concurrent treatment phase; one patient developed grade 3 toxicity in the post-radiation phase. Overall response rate was 38%. One- and 2-year local control were 97% and 71%. Median progression-free survival was 12 months. One- and 2-year overall survival were 100% and 92%. In conclusion, combined everolimus and radiation are well-tolerated for neuroendocrine liver metastases and are associated with excellent local control. The approach of selective local ablation of oligometastatic or oligoprogressive disease warrants further evaluation in this patient population.

Background: Although patients with neuroendocrine tumors (NETs) are known to have prolonged overall survival, the contribution of cancer-specific and noncancer deaths is undefined. This study examined cancer-specific and noncancer death after NET diagnosis., Methods: We conducted a population-based retrospective cohort study of adult patients with NETs from 2001 through 2015. Using competing risks methods, we estimated the cumulative incidence of cancer-specific and noncancer death and stratified by primary NET site and metastatic status. Subdistribution hazard models examined prognostic factors., Results: Among 8,607 included patients, median follow-up was 42 months (interquartile range, 17-82). Risk of cancer-specific death was higher than that of noncancer death, at 27.3% (95% CI, 26.3%-28.4%) and 5.6% (95% CI, 5.1%-6.1%), respectively, at 5 years. Cancer-specific deaths largely exceeded noncancer deaths in synchronous and metachronous metastatic NETs. Patterns varied by primary tumor site, with highest risks of cancer-specific death in bronchopulmonary and pancreatic NETs. For nonmetastatic gastric, small intestine, colonic, and rectal NETs, the risk of noncancer death exceeded that of cancer-specific deaths. Advancing age, higher material deprivation, and metastases were independently associated with higher hazards, and female sex and high comorbidity burden with lower hazards of cancer-specific death., Conclusions: Among all NETs, the risk of dying of cancer was higher than that of dying of other causes. Heterogeneity exists by primary NET site. Some patients with nonmetastatic NETs are more likely to die of noncancer causes than of cancer causes. This information is important for counseling, decision-making, and design of future trials. Cancer-specific mortality should be included in outcomes when assessing treatment strategies.

Lung neuroendocrine tumors (LNETs) are uncommon cancers, and there is a paucity of randomized evidence to guide practice. As a result, current guidelines from different neuroendocrine tumor societies vary considerably. There is a need to update and harmonize global consensus guidelines. This article reports the best practice guidelines produced by a collaboration between the Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society. We performed a formal endorsement and updating process of the 2015 European Neuroendocrine Tumor Society expert consensus article on LNET. A systematic review from January 2013 to October 2017 was conducted to procure the most recent evidence. The stepwise endorsement process involved experts from all major subspecialties, patients, and advocates. Guided by discussion of the most recent evidence, each statement from the European Neuroendocrine Tumor Society was either endorsed, modified, or removed. New consensus statements were added if appropriate. The search yielded 1109 new publications, of which 230 met the inclusion criteria. A total of 12 statements were endorsed, 22 statements were modified or updated, one was removed, and two were added. Critical answered questions for each topic in LNET were identified. Through the consensus process, guidelines for the management of patients with local and metastatic neuroendocrine tumors have been updated to include both recent evidence and practice changes relating to technological and definitional advances. The guidelines provide clear, evidence-based statements aimed at harmonizing the global approach to patients with LNETs, on the basis of the principles of person-centered and LNET-specific care. The importance of LNET-directed research and person-centered care throughout the diagnosis, treatment, and follow-up journey is emphasized along with directions for future collaborative research., (Copyright © 2020. Published by Elsevier Inc.)

Background: How to best support patients with neuroendocrine tumors (NETs) remains unclear. Improving quality of care requires an understanding of symptom trajectories. Objective validated assessments of symptoms burden over the course of disease are lacking. This study examined patterns and risk factors of symptom burden in NETs, using patient-reported outcomes., Subjects, Materials, and Methods: A retrospective, population-based, observational cohort study of patients with NETs diagnosed from 2004 to 2015, who survived at least 1 year, was conducted. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to provincial administrative health data sets. Moderate-to-severe symptom scores were presented graphically for both the 1st year and 5 years following diagnosis. Multivariable Poisson regression identified factors associated with record of moderate-to-severe symptom scores during the 1st year after diagnosis., Results: Among 2,721 included patients, 7,719 symptom assessments were recorded over 5 years following diagnosis. Moderate-to-severe scores were most frequent for tiredness (40%-51%), well-being (37%-49%), and anxiety (30%-40%). The proportion of moderate-to-severe symptoms was stable over time. Proportion of moderate-to-severe anxiety decreased by 10% within 6 months of diagnosis, followed by stability thereafter. Changes were below 5% for other symptoms. Similar patterns were observed for the 1st year after diagnosis. Primary tumor site, metastatic disease, younger age, higher comorbidity burden, lower socioeconomic status, and receipt of therapy within 30 days of assessment were independently associated with higher risk of elevated symptom burden., Conclusion: Patients with NETs have a high prevalence of moderate-to-severe patient-reported symptoms, with little change over time. Patients remain at risk of prolonged symptom burden following diagnosis, highlighting potential unmet needs. Combined with identified patient and disease factors associated with moderate-to-severe symptom scores, this information is important to support symptom management strategies to improve patient-centered care., Implications for Practice: This study used population-level, prospectively collected, validated, patient-reported outcome measures to appraise the symptoms burden and trajectory of patients with neuroendocrine tumors (NETs) after diagnosis. It is the largest and most detailed analysis of patient-reported symptoms for NETs. Patients with NETs present a high burden of symptoms at diagnosis that persists up to 5 years later, highlighting unmet needs. Early and comprehensive symptom screening and management programs are needed. This information should serve to devise pathways and policies to better support patients, evaluate supportive interventions, and assess the effectiveness of symptom management at the provider, institutional, and system levels., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Background: Given a slow course of disease, end-of-life issues are understudied in neuroendocrine tumors (NETs). To date, there are no data regarding symptoms at the end of life. This study examined symptom trajectories and factors associated with high symptom burden in NETs at the end of life., Methods: We conducted a retrospective cohort study of NET patients diagnosed from 2004 to 2015 and who died between 2007 and 2016, in Ontario, Canada. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to administrative healthcare datasets. Moderate-to-severe symptom scores (≥ 4 out of 10) in the 6 months before death were analyzed, with multivariable modified Poisson regression identifying factors associated with moderate-to-severe symptoms scores., Results: Among 677 NET decedents, 2579 symptom assessments were recorded. Overall, moderate-to-severe scores were most common for tiredness (86%), wellbeing (81%), lack of appetite (75%), and drowsiness (68%), with these proportions increasing as death approached. For symptoms of lack of appetite, drowsiness, and shortness of breath, the increase was steepest in the 8 weeks before death. On multivariable analyses, the risk of moderate-to-severe symptoms was significantly higher in the last 2 months before death and for patients with shorter survival (< 6 months). Women had higher risks of anxiety, nausea, and pain., Conclusion: A high prevalence of moderate-to-severe symptoms was observed for NETs at the end of life, not previously described. The proportion of moderate-to-severe symptoms increases steeply as death nears, highlighting an opportunity for improved management. Combined with identified factors associated with moderate-to-severe symptoms, this information is important to improve patient-centred and personalized supportive care for NETs at the end of life.

Background: Neuroendocrine tumors (NETs) have a uniquely indolent biology. Management focuses on tumor and hormonal burden reduction. Data on cytoreduction with extrahepatic disease remain limited., Objective: We sought to define the outcomes of cytoreduction for metastatic NETs with extrahepatic metastases., Methods: Patients undergoing cytoreductive surgery for grade 1 or 2 NETs with extrahepatic metastases (with or without intrahepatic disease) were identified from an institutional database (2003-2014). Primary outcomes included postoperative hormonal response (> 50% urinary 5HIAA decrease), progression-free survival (PFS) and overall survival (OS), while secondary outcomes were 30-day postoperative major morbidity (Clavien grade III-V), mortality, and length of stay., Results: Fifty-five patients were identified (median age 59.3 years, 80% small bowel primaries, 56.4% grade 1); 87% of patients presented with combined intra- and extrahepatic metastases. Resection most commonly included the liver (87%), small bowel (22%), mesenteric (25%) and retroperitoneal (11%) lymph nodes, and peritoneum (7%). Thirty-day major morbidity (Clavien III-V) was 18%, with 3.6% mortality, and median length of stay was 7 days [interquartile range (IQR) 5-9]. Liver embolization was performed in 31% of patients after surgery, at a median of 23 months following surgery. Overall, postoperative hormonal response occurred in 70% of patients. At median follow-up of 37 months (IQR range 22-93), 42 (76%) patients were alive and 23 (41.8%) had progressed. Five-year OS was 77% and 5-year PFS was 51%., Conclusion: Patients undergoing cytoreduction of metastatic well-differentiated NET in the setting of extrahepatic metastatic disease experience good tumoral control with favorable PFS and OS. Cytoreductive surgery can be safely included in the therapeutic armamentarium for NET with extrahepatic metastases.

Important progress has been made over the last decade in the classification, imaging, and treatment of neuroendocrine neoplasm (NENs), with several new agents approved for use. Although the treatment options available for patients with well-differentiated neuroendocrine tumors (NETs) have greatly expanded, the rapidly changing landscape has presented several unanswered questions about how best to optimize, sequence, and individualize therapy. Perhaps the most important development over the last decade has been the approval of 177Lu-DOTATATE for treatment of gastroenteropancreatic-NETs, raising questions around optimal sequencing of peptide receptor radionuclide therapy (PRRT) relative to other therapeutic options, the role of re-treatment with PRRT, and whether PRRT can be further optimized through use of dosimetry among other approaches. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trial planning meeting in 2021 with multidisciplinary experts from academia, the federal government, industry, and patient advocates to develop NET clinical trials in the era of PRRT. Key clinical trial recommendations for development included 1) PRRT re-treatment, 2) PRRT and immunotherapy combinations, 3) PRRT and DNA damage repair inhibitor combinations, 4) treatment for liver-dominant disease, 5) treatment for PRRT-resistant disease, and 6) dosimetry-modified PRRT. [ABSTRACT FROM AUTHOR]

Dysregulated hormonal production remains a challenge in the management of neuroendocrine neoplasms (NEN). We report 4 cases of patients with functional NEN treated with stereotactic body radiation therapy (SBRT) to either the primary/dominant metastatic site of disease or the end organ of hormonal release. No significant toxicities were observed during or after treatment. Each patient has had biochemical, clinical and radiographic response to therapy, providing proof of concept that SBRT is an effective therapeutic strategy for functional neuroendocrine neoplasms. [ABSTRACT FROM AUTHOR]