The global leadership into malnutrition criteria reveals a high percentage of malnutrition which influences overall survival in patients with gastroenteropancreatic neuroendocrine tumours.

Patients with neuroendocrine tumours located in the gastroenteropancreatic tract (GEP-NETs) and treatment with somatostatin analogues (SSA's) are at risk of malnutrition which has been reported previously evaluating weight loss or body mass index (BMI) only. The global leadership into malnutrition (GLIM) criteria include weight loss, BMI, and sarcopenia, for diagnosing malnutrition. These GLIM criteria have not been assessed in patients with GEP-NETs on SSA. The effect of malnutrition on overall survival has not been explored before. The aim of this study is to describe the presence of malnutrition in patients with GEP-NET on SSA based on the GLIM criteria and associate this with overall survival. Cross-sectional study screening all patients with GEP-NETs on SSA's for malnutrition using the GLIM criteria. Body composition analysis for sarcopenia diagnosis were performed. Bloods including vitamins, minerals, and lipid profile were collected. Overall survival since the date of nutrition screening was calculated. Uni- and multivariate Cox regression analysis were performed to identify malnutrition as risk factor for overall survival. A total of 118 patients, 47% male, with median age 67 years (IQR 56.8-75.0) were included. Overall, malnutrition was present in 88 patients (75%); based on low BMI in 26 (22%) patients, based on weight loss in 35 (30%) patients, and based on sarcopenia in 83 (70%) patients. Vitamin deficiencies were present for vitamin D in 64 patients (54%), and vitamin A in 29 patients (25%). The presence of malnutrition demonstrated a significantly worse overall survival (p-value = .01). In multivariate analysis meeting 2 or 3 GLIM criteria was significantly associated with worse overall survival (HR 2.16 95% CI 1.34-3.48, p-value = .002). Weight loss was the most important risk factor out of the 3 GLIM criteria (HR 3.5 95% CI 1.14-10.85, p-value = .03) for worse overall survival. A high percentage (75%) of patients with GEP-NETs using a SSA meet the GLIM criteria for malnutrition. Meeting more than 1 GLIM criterium, especially if there is weight loss these are risk factors for worse overall survival.

Feasibility of Home Parenteral Nutrition in Patients with Intestinal Failure Due to Neuroendocrine Tumours: A Systematic Review.

INTRODUCTION: Maintaining adequate nutritional status can be a challenge for patients with small bowel neuroendocrine tumours (NETs). Surgical resection could result in short bowel syndrome (SBS), whilst without surgical resection there is a considerable risk of ischemia or developing an inoperable malignant bowel obstruction (IMBO). SBS or IMBO are forms of intestinal failure (IF) which might require treatment with home parenteral nutrition (HPN). Limited data exist regarding the use of HPN in patients with small bowel neuroendocrine tumours, and it is not frequently considered as a possible treatment. METHODS: A systematic review was performed regarding patients with small bowel NETs and IF to report on overall survival and HPN-related complications and create awareness for this treatment. RESULTS: Five articles regarding patients with small bowel NETs or a subgroup of patients with NETs could be identified, mainly case series with major concerns regarding bias. The studies included 60 patients (range 1-41). The overall survival time varied between 0.5 and 154 months on HPN. However, 58% of patients were alive 1 year after commencing HPN. The reported catheter-related bloodstream infection rate was 0.64-2 per 1000 catheter days. CONCLUSION: This systematic review demonstrates the feasibility of the use of HPN in patients with NETs and IF in expert centres with a reasonable 1-year survival rate and low complication rate. Further research is necessary to compare patients with NETs and IF with and without HPN and the effect of HPN on their quality of life.

Improving outcomes in carcinoid heart disease - learning from a single centre.

INTRODUCTION: A significant proportion of patients with carcinoid syndrome develop carcinoid heart disease (CHD). Valve degeneration can lead to right heart failure, and worsening prognosis. Replacement of affected valves is an effective therapy. We reviewed patients treated with valve replacement to assess prognostic factors. METHODS: CHD patients records who underwent valve replacement from 2003-2019 were reviewed. RESULTS: Twenty-six patients underwent valve replacement. Mean (SD) age was 61 (11) years, 54% female. Eleven tumours were grade G1, with the remaining G2. NYHA pre-surgery mean (SD) 2.0 (0.7); post-surgery mean 1.2; follow-up mean (SD) 1.6 (0.8). Mean NYHA score difference from pre- to post-surgery -0.71 ( P  = 0.002). 88.5% two (PR & TR), 3.9% one, 3.9% three and 3.9% four valves replaced. 13 patients received Lu177 oxodotreotide; 27% completed four cycles. Mortality at 1 and 5 years follow up was 42% and 50% respectively. Cox proportional hazards model of survival from surgery, adjusting for age [hazard ratio (HR) 0.96 (0.89-1.03) ( P  = 0.25)], four cycles of Lu177 oxodotreotide demonstrated HR 0.087 (0.0079-0.95) ( P  = 0.045) indicating improved survival. DISCUSSION: Surgical patients were often NYHA grade II, and symptoms improved post-surgery. Four cycles of Lu177 oxodotreotide improved survival, although the confidence interval was wide. Further studies should be performed to assess Lu177 oxodotreotide in CHD.

Optimising Outcomes and Surveillance Strategies of Rectal Neuroendocrine Neoplasms.

Rectal neuroendocrine neoplasms are increasing in incidence, in part due to increased endoscopic procedures being performed for bowel cancer screening. Whilst most of these lesions are low-grade well-differentiated neuroendocrine tumours, they can have a varied clinical behaviour. Frequently, these lesions are incorrectly characterised at endoscopy and, therefore, incompletely excised using standard polypectomy techniques. Furthermore, some cases are not fully staged prior to or post resection. In this article we discuss the endoscopic and surgical options available to improve the likelihood of achieving an R0 resection and the staging procedures that should be used in these NETs. We also review factors that may suggest a higher risk of nodal involvement or recurrence. This information may help determine whether endoscopic or surgical resection techniques should be considered. In cases of R1 resection we discuss the management options available and the long-term surveillance options and when these should be offered to patients.

Second Primary Malignancies in Patients with a Neuroendocrine Neoplasm in England.

INTRODUCTION: Patients with neuroendocrine neoplasms (NENs) may often develop other malignancies. This study aimed to identify the frequency at which these second malignancies occurred in England. METHODS: Data were extracted from the National Cancer Registration and Analysis Service (NCRAS) on all patients diagnosed with a NEN at one of eight NEN site groups between 2012 and 2018: appendix, caecum, colon, lung, pancreas, rectum, small intestine, and stomach. WHO International Classification of Disease Edition-10 (ICD-10) codes were used to identify patients who had been diagnosed with an additional non-NEN cancer. Standardized incidence ratios (SIRs) for tumours diagnosed after the index NEN were produced for each non-NEN cancer type by sex and site. RESULTS: A total of 20,579 patients were included in the study. The most commonly occurring non-NEN cancers after NEN diagnosis were the prostate (20%), lung (20%), and breast (15%). Statistically significant SIRs were observed for non-NEN cancer of the lung (SIR = 1.85, 95% CI: 1.55-2.22), colon (SIR = 1.78, 95% CI: 1.40-2.27), prostate (SIR = 1.56, 95% CI: 1.31-1.86), kidney (SIR = 3.53, 95% CI: 2.72-4.59), and thyroid (SIR = 6.31, 95% CI: 4.26-9.33). When stratified by sex, statistically significant SIRs remained for the lung, renal, colon, and thyroid tumours. Additionally, females had a statistically significant SIR for stomach cancer (2.65, 95% CI: 1.26-5.57) and bladder cancer (SIR = 2.61, 95% CI: 1.36-5.02). CONCLUSION: This study found that patients with a NEN experienced a metachronous tumour of the lung, prostate, kidney, colon, and thyroid at a higher rate than the general population of England. Surveillance and engagement in existing screening programmes are required to enable earlier diagnosis of second non-NEN tumours in these patients.

Sex Differences in Survival from Neuroendocrine Neoplasia in England 2012-2018: A Retrospective, Population-Based Study.

Pre-clinical studies have suggested sex hormone signalling pathways may influence tumorigenesis in neuroendocrine neoplasia (NEN). We conducted a retrospective, population-based study to compare overall survival (OS) between males and females with NEN. A total of 14,834 cases of NEN diagnosed between 2012 and 2018, recorded in England's National Cancer Registry and Analysis Service (NCRAS), were analysed. The primary outcome was OS with 5 years maximum follow-up. Multivariable analysis, restricted mean survival time and mediation analysis were performed. Appendiceal, pulmonary and early-stage NEN were most commonly diagnosed in females; stomach, pancreatic, small intestinal, colonic, rectal and later-stage NEN were more often diagnosed in males. Females displayed increased survival irrespective of the stage, morphology or level of deprivation. On average, they survived 3.62 (95% CI 1.73-5.90) to 10.26 (6.6-14.45) months longer than males; this was statistically significant in NEN of the lung, pancreas, rectum and stomach (p < 0.001). The stage mediated improved survival in stomach, lung, and pancreatic NEN but not in rectal NEN. The reasons underlying these differences are not yet understood. Overall, females diagnosed with NEN tend to survive longer than males, and the stage at presentation only partially explains this. Future research, as well as prognostication and treatment, should consider sex as an important factor.

Outcomes and survival in patients with advanced intestinal neuroendocrine tumours on home parenteral nutrition, an international multicentre retrospective cohort study.

BACKGROUND AND AIMS: Only limited information is available on the use of home parenteral nutrition (HPN) in patients with advanced neuroendocrine tumours (NETs) causing intestinal failure (IF). This study aims to report the outcomes of the explore the use of HPN in this patient cohort, in the largest case series to date. METHODS: A retrospective study in the United Kingdom and the Netherlands was performed, using the UK National British Artificial Nutrition Survey (BANS) and local databases in the Netherlands. Data regarding age, sex, NET grading, staging, treatment, HPN characteristics and survival outcomes were collected. RESULTS: Data were collected on 41 patients (n = 18 males, 44%) with a median age of 65. Most primary tumours were in the small bowel (n = 35, 85%). The NETs were Grade 1 (n = 16, 39%), Grade 2 (n = 7, 17%), Grade 3 (n = 1, 2%). In 28 patients (n = 68%) there was stage IV disease with metastases located in the peritoneum, mesentery and or liver. There were two indications for HPN; short bowel syndrome (n = 27, 66%) and inoperable malignant bowel obstruction (n = 14, 34%). The median period on HPN was 11 months (interquartile range 4-25 months). 11 patients were still alive and receiving HPN treatment after 2 years, and 6 patients after 3 years. Six patients (22%) with short bowel syndrome (SBS) could be weaned from HPN. There was a statistically significant improved survival for patients with short bowel syndrome (median 24 months) compared to inoperable malignant bowel obstruction (median 7 months). The catheter-related bloodstream infection rate was comparable to other HPN patient cohorts at 1.0 per 1000 catheter days. CONCLUSION: This study shows that HPN can be used safely in patients with NET and IF to increase survival beyond that reasonably expected in the context of either short bowel syndrome or inoperable malignant bowel obstruction. Patients with short bowel syndrome are most likely to benefit. Further prospective studies are necessary to validate survival benefits and to demonstrate the effect of HPN on quality of life.

Prevalence of Sarcopenia and Impact on Survival in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumours.

Sarcopenia in patients with cancer is associated with adverse outcomes such as shorter survival. However, there exists little evidence regarding the prevalence of sarcopenia in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Patients with a histologically confirmed newly diagnosed metastatic GEP-NET between 2006 and 2018, CT scan, and anthropometric data at diagnosis were included in this study. CT scans were analysed for the presence of sarcopenia and correlated with overall survival (OS). In total, 183 patients, 87 male (48%), with a median age of 62 years (IQR 52-68 years), were included. In 44 patients (24%), there was a pancreas NET, and in 136 patients, there was a small bowel NET (74%). Sarcopenia was present in 128 patients (69%) and unrelated to BMI (median 25.1). There were significant survival differences between patients with pancreatic and small bowel NETs at 86 vs. 141 months, respectively (p = 0.04). For patients with pancreatic NETs, the presence of sarcopenia was independently associated with shorter OS (HR 3.79 95% CI 1.1-13.03, p-value 0.035). A high prevalence of sarcopenia at the time of diagnosis of a metastatic GEP-NET was seen and associated with worse OS in patients with pancreatic NETs. Further research should focus on how to reverse sarcopenia and its impact on OS and/or quality of life.

Primary renal neuroendocrine neoplasms: A systematic literature review, report of four local cases, and original survival analysis of 63 patients from a national registry 2012-2018.

Primary renal neuroendocrine neoplasms (NEN) are rare. We aimed to conduct a systematic review, present local cases, and analyse data from the England's National Cancer Registration and Analysis Service (NCRAS) to provide comprehensive evidence on clinical experience, incidence, and survival to better characterize these tumours. First, a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method; second, a synthesis of local cases; and, finally, a retrospective population-based cohort analysis of renal NEN recorded between 2012 and 2018 on NCRAS were performed. Kaplan-Meier estimator was used to calculate overall survival and Cox proportional hazard regression to identify prognostic factors. Systematic review identified 48 articles and the evidence was summarized and presented. We reported data from four local cases presenting with abdominal and back pain but without carcinoid syndrome. In population-based analysis, we identified 63 cases of renal NEN between 2012 and 2018 from the registry. Age-standardized incidence was 0.09-0.32 per million with a median age of 64 years (interquartile range = 48-72 years). Survival was worse in males and those aged 64 years and over. Five-year survival for renal neuroendocrine tumours (NET) was 69.8% (95% confidence interval = 66.6-72.7) and neuroendocrine carcinomas (NEC) was 38.4% (95% confidence interval = 34.6-42.0). No independent predictive factor was identified in the multivariable analyses. We have given a systematic review of evidence, published local experience, and reported incidence and survival of renal NEN in England for the first time. We have provided clinicians with evidence on diagnosis and proposed a treatment algorithm of theses rare tumours. The incidence and median age of presentation in England is similar to other published series. Renal NET has better survival than renal NEC as expected. A uniform classification system would reduce inconsistencies in reporting and standardize treatment decisions for this neoplasia.

Incidence and survival of neuroendocrine neoplasia in England 1995-2018: A retrospective, population-based study.

Background: Neuroendocrine neoplasia (NEN) incidence is rising internationally. We aimed to evaluate the epidemiology of NEN in England and examine changes in survival over time. Methods: A retrospective, population-based study using nationally representative data between 1995 and 2018 from the National Cancer Registry and Analysis Service (NCRAS) in England was conducted on 63,949 tumours. Age-standardized incidence was calculated using Office for National Statistics (ONS) data. Overall survival (OS) was calculated using the Kaplan-Meier estimator. Multivariable analysis was performed using an accelerated failure time model. Findings: Of 63,949 cases, 50.5% (32,309) were female. Age-adjusted incidence increased 3.7-fold between 1995 and 2018 from 2.35 to 8.61 per 100,000. In 2018, highest incidence occurred in lung (1.47 per 100,000), small intestine (1.46 per 100,000), pancreas (1.00 per 100,000) and appendix (0.95 per 100,000). In multivariable analysis, age, sex, morphology, stage, site and deprivation were independent predictors of survival (p < 0.001). Survival of the entire cohort, and by primary site, is improving over time. Interpretation: NEN incidence continues to rise in England with survival improving over time. Relatively high survival compared to other cancers is an issue for long-term outcomes and funding of care. Funding: Data were extracted and transferred using a grant from Neuroendocrine cancer UK.

Goblet Cell Adenocarcinoma of the Appendix: A Systematic Review and Incidence and Survival of 1,225 Cases From an English Cancer Registry.

Background: Goblet cell adenocarcinoma (GCA) of the appendix is a rare and aggressive tumour with varying nomenclature and classification systems. This has led to heterogeneity in published data, and there is a lack of consensus on incidence, survival, and management. Methods: We provide an overview of GCA with a comprehensive systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology and a retrospective analysis of all cases recorded in the English National Cancer Registration and Analysis Service database between 1995 and 2018. The Kaplan-Meier estimator was used to calculate overall survival, and Cox proportional hazards regression was used to identify prognostic factors. Results: The systematic review demonstrated an incidence of 0.05-0.3 per 100,000 per year among North American registry studies. The 1-, 3-, and 5-year survival rate was 95.5%, 85.9%-87.6%, and 76.0%-80.6%, respectively. Age, stage, and grade were identified as prognostic factors for survival. Our analysis included 1,225 cases. Age-standardised incidence was 0.0335 per year in 1995 and gradually rose to 0.158 per year in 2018. The 1-, 3-, and 5-year survival rate was 90.0% [95% confidence interval (95% CI): 85.4-94.0], 76.0% (95% CI: 73.8-80.9), and 68.6% (95% CI: 65.9-72.2), respectively. On univariate Cox regression analyses, female sex, stage, and grade were associated with worse overall survival. On multivariate analysis, only stage remained a statistically significant prognostic factor. Conclusions: GCA of the appendix is rare, but incidence is increasing. We report a lower incidence and survival than North American registry studies. Higher stage was associated with decreased survival. Further prospective studies are required to establish optimal management.

Circulating tumour cells and tumour biomarkers in functional midgut neuroendocrine tumours.

CALM-NET was a phase IV exploratory study in the UK that aimed to evaluate if the presence of circulating tumour cells (CTCs) at baseline predicted symptomatic response in patients with midgut neuroendocrine tumours (NETs) treated with lanreotide autogel (LAN). Adults with functional, well/moderately differentiated (Ki-67 <20%) midgut NETs received LAN 120 mg/28 days for 1 year. CTCs were present in blood if enumeration was >0. Primary endpoint was the clinical value of baseline CTCs to predict symptomatic response (decrease in diarrhoea or flushing of ≥50% frequency, or ≥1 severity level). Other endpoints included progression-free survival (PFS) and correlations between plasma and urinary biomarkers (including 5-hydroxyindoleacetic acid [5-HIAA]). Fifty patients were enrolled; 40 completed the study. Baseline CTCs were present in 22 (45.8%) patients (missing baseline CTC status n = 2). Overall, 87.5% (95% confidence interval [CI]: 73.9; 94.5) of patients had a symptomatic response; a 5.9-fold higher odds of symptomatic response in patients without CTC versus patients with CTC at baseline was observed, although this was not statistically significant (odds ratio: 0.17 [95% CI: 0.02; 1.65], p = .126). One-year PFS rate was 66.4% (95% CI: 48.8; 79.2). Biomarker concentrations did not correlate to baseline CTC status. However, there was a strong correlation between plasma and urinary 5-HIAA (Spearman correlation coefficients ≥0.87 [p < .001], all time points). In conclusion, patients without CTC at baseline may be more likely to achieve a symptomatic response following LAN treatment than patients with CTC. Plasma 5-HIAA correlated with urinary 5-HIAA during LAN treatment. ClinicalTrials.gov identifier: NCT02075606.

Development of a quality of life questionnaire for patients with pancreatic neuroendocrine tumours (the PANNET module).

Pancreatic neuroendocrine tumours (panNET) are heterogeneous neoplasms usually characterised by slow growth and secretion of hormones, which often cause symptoms. The effect of these symptoms on quality of life (QoL) has not previously been examined in detail. EORTC (European Organisation for Research and Treatment of Cancer) guidelines were followed in phases 1-3 to produce a potential module of questions usable for trials in panNET, focusing on three common types of panNET. For two less common types, a list of symptoms was constructed. Following an extensive literature search and phase 1a interviews with patients and healthcare workers, a long list of potential issues (169) was obtained. This list was shown to 12 patients from three countries in phase 1b interviews to check that no items were missed. The list was reduced to 57 issues. The list of issues was converted to questions, mainly from existing validated questions within the EORTC item library. The list of questions was then used in a phase 3 international study in eight countries using seven languages. A provisional module of 24 items is presented for use in nonfunctioning panNET, gastrinoma and insulinoma. This module increases knowledge concerning QoL in this condition and may be a useful adjunct in clinical trials. A phase 4 trial is being considered for validation of this questionnaire.

Nodal metastases in small rectal neuroendocrine tumours.

AIM: Rectal neuroendocrine tumours (NETs) are the most common type of gastrointestinal NET. European Neuroendocrine Tumour Society guidelines suggest that rectal NETs measuring ≤10 mm are indolent with low risk of spread. In practice, many patients with lesions ≤1 cm do not undergo complete tumour staging. However, the size of the lesion may not be the only risk factor for nodal involvement/metastases. The aim of this study was to determine if MRI ± nuclear medicine imaging alters tumour stage in patients with rectal NETs ≤10 mm. METHODS: Patients referred to a tertiary NET centre between 2005 and 2020 who met the inclusion criteria of a rectal NET ≤10 mm, full cross-sectional imaging, primarily an MRI scan and, if abnormal findings were identified, a subsequent 68 Ga-DOTATATE positron emission tomography scan were included. All patients were followed up at our institution. RESULTS: In all, 32 patients with rectal NETs 10 mm or less were included in the study: 16 women; median age 58 years (range 33-71); 47% (n = 15) were referred from bowel cancer screening procedures. The median size of the lesions was 5 mm (range 2-10 mm). 81% (n = 26) were World Health Organization Grade 1 tumours with Ki67 <3%. Radiological staging confirmed nodal involvement in 25% (8/32); two cases had distant metastatic disease. Lymphovascular invasion was present in 3% (1/32) of patients but none demonstrated peri-neural invasion. CONCLUSION: This study demonstrates that small rectal NETs can develop nodal metastases; therefore it is important to stage these tumours accurately with MRI at baseline and, if there are concerns regarding potential lymph node metastases, to consider 68 Ga-DOTATATE positron emission tomography imaging.

Calcitonin-secreting neuroendocrine neoplasms of the lung: a systematic review and narrative synthesis.

Calcitonin-secreting neuroendocrine neoplasms of the lung are rare, with few cases reported in the literature. Differentiating between medullary thyroid carcinoma and an ectopic source of calcitonin secretion can represent a complex diagnostic conundrum for managing physicians, with cases of unnecessary thyroidectomy reported in the literature. This manuscript reports a case of ectopic hypercalcitonaemia from a metastatic neuroendocrine neoplasm of the lung with concurrent thyroid pathology and summarises the results of a systematic review of the literature. Medical Literature Analysis and Retrieval System Online, Excerpta Medica, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and SCOPUS databases were systematically and critically appraised for all peer reviewed manuscripts that suitably fulfilled the inclusion criteria established a priori. The protocol for this systematic review was developed according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols, and followed methods outlined in The Cochrane Handbook for Systematic Reviews of Interventions. This systematic review is registered with PROSPERO. It is vital to consider diagnoses other than medullary thyroid carcinoma when presented with a patient with raised calcitonin, as it is not pathognomonic of medullary thyroid carcinoma. Lung neuroendocrine neoplasms can appear similar to medullary thyroid carcinoma histologically, they can secrete calcitonin and metastasize to the thyroid. Patients with medullary thyroid carcinoma may show stimulated calcitonin values over two or more times above the basal values, whereas calcitonin-secreting neuroendocrine neoplasms may or may not show response to stimulation tests. The present review summarises existing evidence from cases of ectopic hypercalcitonaemia to lung neuroendocrine neoplasms.

Quality of life in patients with gastroenteropancreatic tumours: A systematic literature review.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are slow-growing cancers that arise from diffuse endocrine cells in the gastrointestinal tract (GI-NETs) or the pancreas (P-NETs). They are relatively uncommon, accounting for 2% of all gastrointestinal malignancies. The usual treatment options in advanced GEP-NET patients with metastatic disease include chemotherapy, biological therapies, and peptide receptor radionuclide therapy. Understanding the impact of treatment on GEP-NET patients is paramount given the nature of the disease. Health-related quality of life (HRQoL) is increasingly important as a concept reflecting the patients' perspective in conjunction with the disease presentation, severity and treatment. AIM: To conduct a systematic literature review to identify literature reporting HRQoL data in patients with GEP-NETs between January 1985 and November 2019. METHODS: The PRISMA guiding principles were applied. MEDLINE, Embase and the Cochrane library were searched. Data extracted from the publications included type of study, patient population data (mid-gut/hind-gut/GI-NET/P-NET), sample size, intervention/comparators, HRQoL instruments, average and data spread of overall and sub-scores, and follow-up time for data collection. RESULTS: Forty-three publications met the inclusion criteria. The heterogeneous nature of the different study populations was evident; the percentage of female participants ranged between 30%-60%, whilst average age ranged from 53.8 to 67.0 years. Eight studies investigated GI-NET patients only, six studies focused exclusively on P-NET patients and the remaining studies involved both patient populations or did not report the location of the primary tumour. The most commonly used instrument was the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (n = 28) with consistent results across studies; the GI-NET-specific module Quality of Life Questionnaire-GINET21 was used in six of these studies. A number of randomised trials demonstrated no HRQoL changes between active treatment and placebo arms. The Phase III NETTER-1 study provides the best data available for advanced GEP-NET patients; it shows that peptide receptor radionuclide therapy can significantly improve GEP-NET patients' HRQoL. CONCLUSION: HRQoL instruments offer a means to monitor patients' general disease condition, disease progression and their physical and mental well-being. Instruments including the commonly used European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and GINET21 lack, however, validation and a defined minimal clinical important difference specifically for GI-NET and P-NET patients.

Health-related quality of life in neuroendocrine neoplasia: a critical review.

Incidence of neuroendocrine neoplasia (NEN) is increasing, as is use of health-related quality of life (HRQoL) measurement in clinical trials. Following development of validated questionnaires, HRQoL is widely used to assess outcomes. This review is intended for healthcare professionals and is based on a selection of data published in the last decade. HRQoL is on par with other clinical endpoints such as performance status. Assessments in clinical trials have been particularly useful for monitoring the symptom burden of NEN, for the effects of treatments on patients' lives, and have provided new data allied to the usual clinical endpoints. QoL expressed as quality-adjusted life years (QALYs) have become the most important primary outcome to establish cost-effectiveness in health economic evaluation. From looking at clinical trials over the last 10 years, we see that the quality of HRQoL evidence reported in published studies has improved and, in general, recent studies are likely to be more methodologically robust. Assessment of HRQoL in clinical trials is likely to become a standard part of clinical practice in NEN, as in other cancers. However, clear methods for calculating the clinical meaningfulness of changes in scores are needed. Other limitations of HRQoL measurement include lack of specificity to certain symptom sets and ease of completion and administration. An international group taking a lead on developing HRQoL research specifically in NEN patients is needed to address limitations of the evidence base. In order for greater weight to be placed on HRQoL data, agreement on optimal, validated scoring systems is needed.

International validation of the EORTC CAT Core: a new adaptive instrument for measuring core quality of life domains in cancer.

BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group (QLG) has developed computerised adaptive tests (CATs) for the 14 functional and symptom domains of the EORTC QLQ-C30 quality of life questionnaire. This is expected to optimise measurement precision, relevance to patients and flexibility. Here, we present the first international validation of the EORTC CAT Core. METHODS: A heterogeneous sample of 699 cancer patients scheduled for chemotherapy and/or radiotherapy was recruited across seven European countries. The EORTC CAT Core and all QLQ-C30 items were administered to participants before and after initiating treatment. Correlations between CAT and QLQ-C30 scores and floor/ceiling effects were calculated. Using several grouping variables, relative validity (cross-sectional known groups difference), responsiveness (changes over time) and relative sample size requirements of the CAT compared to the QLQ-C30 were estimated. RESULTS: Correlations of the CAT and QLQ-C30 ranged from 0.81 to 0.93 across domains. The mean relative reduction in floor and ceiling effects using the CAT was 42% (range 3-99%). Analyses of known groups validity and responsiveness indicated that, across domains, mean sample size requirements for the CAT were 72% and 70%, respectively, of those using the QLQ-C30. CONCLUSIONS: The EORTC CAT Core measures the same domains as the QLQ-C30 with reduced floor/ceiling effects. The CAT generally facilitated the use of smaller samples (about 30% smaller on average) without loss of power compared to the QLQ-C30. Based on this study, the EORTC QLG will release the EORTC CAT Core for general use.

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study.

Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN <2 cm of diameter. Several retrospective series demonstrated that a non-operative management is safe and feasible, but no prospective studies are available. Aim of the ASPEN study is to evaluate the optimal management of asymptomatic NF-PanNEN ≤2 cm comparing active surveillance and surgery. Methods: ASPEN is a prospective international observational multicentric cohort study supported by ENETS. The study is registered in ClinicalTrials.gov with the identification code NCT03084770. Based on the incidence of NF-PanNEN the number of expected patients to be enrolled in the ASPEN study is 1,000 during the study period (2017-2022). Primary endpoint is disease/progression-free survival, defined as the time from study enrolment to the first evidence of progression (active surveillance group) or recurrence of disease (surgery group) or death from disease. Inclusion criteria are: age >18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at 68Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach.

Nutritional and vitamin status in patients with neuroendocrine neoplasms.

Symptoms of gastroenteropancreatic located neuroendocrine neoplasms (GEP-NENs) are often related to food intake and manifest as abdominal pain or diarrhoea which can influence patients nutritional status. Malnutrition is common in cancer patients and influences quality of life, treatment options and survival but is also present in up to 40% of patients with GEP-NENs. As part of malnutrition there are often deficiencies in fat-soluble vitamins, mainly vitamin D. Little knowledge exists on trace elements. Several factors influence the development of malnutrition such as size and localisation of the primary tumour as well as metastases, side effects from treatment but also hormone production of the tumour itself. One of the main influencing factors leading to malnutrition is diarrhoea which leads to dehydration and electrolyte disturbances. Treatment of diarrhoea should be guided by its cause. Screening for malnutrition should be part of routine care in every GEP-NEN patient. Multidisciplinary treatment including dietician support is necessary for all malnourished patients with GEP-NENs.