Enteropancreatic Neuroendocrine Tumors Research Articles

Response heterogeneity as a new biomarker of treatment response in patients with neuroendocrine tumors.

Aim: The RAISE project aimed to find a surrogate end point to predict treatment response early in patients with enteropancreatic neuroendocrine tumors (NET). Response heterogeneity, defined as the coexistence of responding and non-responding lesions, has been proposed as a predictive marker for progression-free survival (PFS) in patients with NETs. Patients & methods: Computerized tomography scans were analyzed from patients with multiple lesions in CLARINET (NCT00353496; n=148/204). Cox regression analyses evaluated association between response heterogeneity, estimated using the standard deviation of the longest diameter ratio of target lesions, and NET progression. Results: Greater response heterogeneity at a given visit was associated with earlier progression thereafter: week 12 hazard ratio (HR;95% confidence interval): 1.48 (1.20-1.82);p< 0.001;n=148; week 36: 1.72 (1.32-2.24);p<0.001;n=108. HRs controlled for sum of longest diameter ratio: week 12: 1.28 (1.04-1.59);p=0.020 and week 36: 1.81 (1.20-2.72);p=0.005. Conclusion: Response heterogeneity independently predicts PFS in patients with enteropancreatic NETs. Further validation is required.

Increased Incidence, Prevalence, and Surgical Management of Enteropancreatic Neuroendocrine Tumors Is Associated with Improvements in Survival - A Contemporary Analysis

Increased Incidence, Prevalence, and Surgical Management of Enteropancreatic Neuroendocrine Tumors Is Associated with Improvements in Survival - A Contemporary Analysis

Radical Resection in Entero-Pancreatic Neuroendocrine Tumors: Recurrence-Free Survival Rate and Definition of a Risk Score for Recurrence.

Surgery with radical intent is the only potentially curative option for entero-pancreatic neuroendocrine tumors (EP-NETs) but many patients develop recurrence even after many years. The subset of patients at high risk of disease recurrence has not been clearly defined to date. The aim of this retrospective study was to define, in a series of completely resected EP-NETs, the recurrence-free survival (RFS) rate and a risk score for disease recurrence. This was a multicenter retrospective analysis of sporadic pancreatic NETs (PanNETs) or small intestine NETs (SiNETs) [G1/G2] that underwent R0/R1 surgery (years 2000-2016) with at least a 24-month follow-up. Survival analysis was performed using the Kaplan-Meier method and risk factor analysis was performed using the Cox regression model. Overall, 441 patients (224 PanNETs and 217 SiNETs) were included, with a median Ki67 of 2% in tumor tissue and 8.2% stage IV disease. Median RFS was 101 months (5-year rate 67.9%). The derived prognostic score defined by multivariable analysis included prognostic parameters, such as TNM stage, lymph node ratio, margin status, and grading. The score distinguished three risk categories with a significantly different RFS (p<0.01). Approximately 30% of patients with EP-NETs recurred within 5 years after radical surgery. Risk factors for recurrence were disease stage, lymph node ratio, margin status, and grading. The definition of risk categories may help in selecting patients who might benefit from adjuvant treatments and more intensive follow-up programs.

ASO Author Reflection: Risk of Recurrence After Radical Resection in Entero-Pancreatic Neuroendocrine Tumors.

ASO Author Reflection: Risk of Recurrence After Radical Resection in Entero-Pancreatic Neuroendocrine Tumors.

Association of Upfront Peptide Receptor Radionuclide Therapy With Progression-Free Survival Among Patients With Enteropancreatic Neuroendocrine Tumors

Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking. To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs). This retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias. Upfront PRRT or upfront chemotherapy or targeted therapy. The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors. Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329 (64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8] years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the chemotherapy or targeted therapy group in the unmatched (2.5 years [95% CI, 2.3-3.0 years] vs 0.7 years [95% CI, 0.5-1.0 years]; HR, 0.35 [95% CI, 0.28-0.44; P < .001]) and matched (2.2 years [95% CI, 1.8-2.8 years] vs 0.6 years [95% CI, 0.4-1.0 years]; HR, 0.37 [95% CI, 0.27-0.51; P < .001]) populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95% CI, 10.7-14.1 years] vs 11.6 years [95% CI, 9.1-13.4 years]; HR, 0.81 [95% CI, 0.62-1.06; P = .11]) and matched (12.2 years [95% CI, 9.1-14.2 years] vs 11.5 years [95% CI, 9.2-17.9 years]; HR, 0.83 [95% CI, 0.56-1.24; P = .36]) populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37; 95% CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction, upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning: adjusted HR [aHR], 0.39 [95% CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95% CI, 0.16-0.56]), grade of 1 to 2 (grade 1: aHR, 0.21 [95% CI, 0.12-0.34]; grade 2: aHR, 0.52 [95% CI, 0.29-0.73]), and site of tumor origin (pancreatic: aHR, 0.41 [95% CI, 0.24-0.61]; intestinal: aHR, 0.19 [95% CI, 0.11-0.43]) (P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95% CI, 0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95% CI, 0.29-1.43; P = .31). In this cohort study, treatment with upfront PRRT in patients with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA treatment was associated with significantly improved survival outcomes compared with upfront chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy, timing, and optimal specific sequence of these therapeutic options.

Impact of Diabetes and Metformin Use on Enteropancreatic Neuroendocrine Tumors: Post Hoc Analysis of the CLARINET Study.

Simple SummaryLanreotide was found to be effective for preventing tumors from worsening in patients with neuroendocrine tumors of the intestines and pancreas, regardless of whether or not patients also had diabetes. Metformin, a drug for treating diabetes, also seemed to prevent tumors from worsening.The prognostic role of diabetes mellitus (DM) in advanced enteropancreatic neuroendocrine tumors (NETs) is unclear. Progression free survival (PFS) was assessed in post-hoc analyses of the 96-week, phase III, double-blind, placebo-controlled CLARINET study of lanreotide 120 mg in patients with advanced non-functional enteropancreatic NETs with DM (with/without metformin) and without DM. Of 204 patients, there were 79 with DM (lanreotide, n = 42 {metformin, n = 14}; placebo, n = 37 {metformin, n = 10}) and 125 without DM (lanreotide, n = 59; placebo, n = 66). Median PFS was 96.0 and 98.0 weeks with and without DM, respectively (hazard ratio 1.20 {95% confidence interval 0.79 to 1.82}; p = 0.380). No difference in PFS was observed in lanreotide-treated patients with/without DM (p = 0.8476). In the placebo group, median PFS was numerically shorter with versus without DM (p = 0.052) and was significantly longer in patients with DM and metformin (85.7 weeks) versus without metformin (38.7 weeks; p = 0.009). Multivariable Cox analyses showed that DM at baseline was not associated with PFS (p = 0.079); lanreotide was significantly associated with lower disease progression risk (p = 0.017). Lanreotide efficacy was confirmed in patients with advanced enteropancreatic NETs, regardless of diabetic status; DM was not a negative prognostic factor. A potential antitumor effect of metformin was observed in patients receiving placebo.

Somatostatin-derived amyloidosis: a novel type of amyloidosis associated with well-differentiated somatostatin-producing neuroendocrine tumours

Objective To report the clinicopathologic and proteomic characteristics of a novel form of amyloidosis derived from the precursor protein somatostatin. Materials and methods Cases were identified by searching the Mayo Clinic amyloid liquid chromatography and tandem mass spectrometry (LC-MS/MS) typing database from 1 January 2008 to 1 September 2020 for specimens with the amyloid signature proteins and abundant somatostatin, in the absence of other amyloid precursor proteins. All available medical records and pathologic materials were examined. Results Somatostatin-derived amyloid deposits were found in four patients, two females and two males, with a median age of 61.5 years (range 47–73 years). One patient also had neurofibromatosis-1. The amyloid in each case was associated with a well-differentiated, somatostatin-producing neuroendocrine tumour arising in the small bowel or pancreas. The amyloid deposits were Congo Red-positive and were readily identified by LC- MS/MS analysis. Somatostatin was present exclusively in somatostatin-associated amyloid cases (p < .001), compared to small bowel and pancreas amyloidosis cases of other types. Long-term follow-up is available for one patient who is alive 6 years after initial presentation. Conclusion We propose that somatostatin-related amyloidosis is a novel localised human amyloid type that arises in association with well-differentiated somatostatin-producing enteropancreatic neuroendocrine tumours. Treatment of the associated neuroendocrine tumour may be adequate therapy for these patients.

Efficacy of FOLFOX Chemotherapy in Metastatic Enteropancreatic Neuroendocrine Tumors.

FOLFOX (5-Fluorouracile and oxaliplatin) exhibits promising activity in advanced well-differentiated neuroendocrine tumors (NETs). This retrospective study aimed to analyze the outcome of metastatic enteropancreatic NETs patients treated with FOLFOX. We retrospectively identified patients treated with FOLFOX for NETs of enteropancreatic or unknown origin among those referred to our Regional Multidisciplinary Tumor Board. Among 48 patients, most often pancreatic NETs (n=33, 68.8%), the median Ki67 index was 10%. The median number cycle of FOLFOX was 6 and median follow-up was 34.8 months. Disease control rate (DCR) was 83.3%. Median PFS and OS were 12.6 and 29.4 months respectively. Median chemotherapy break was 14.1 months. No significant difference was observed between PFS and the following criteria: Ki67 index, primary tumor site, alkaline phosphatase levels, primary tumor surgery and 18F-FDG PET positivity. FOLFOX exhibits a high DCR and a short duration of treatment with a relative long chemotherapy break in patients with metastatic enteropancreatic NETs.

MicroRNAs and Treatment with Somatostatin Analogs in Gastro- Entero-Pancreatic Neuroendocrine Neoplasms: Challenges in Personalized Medicine.

Molecular predictive biomarkers represent an essential tool for the future of personalized oncotherapy. Gastro- entero-pancreatic neuroendocrine neoplasms are a heterogeneous group of epithelial tumors with a steady increase in incidence and prevalence. Their effective management depends on early diagnosis, personalized risk stratification, and monitoring response to therapy. A crucial element is identifying accurate biomarkers to predict/monitor therapeutic responses, assess drug resistance, and quantify residual disease in a reproducible and less invasive way. Taking into consideration their role in cell differentiation, cell proliferation, apoptosis and tumor development, microRNAs have gained interest as potential prognostic markers and treatment response predictors in neuroendocrine neoplasms. This review is the first to summarize the available data on the possible role of microRNAs in evaluating the efficacy of somatostatin analogs treatment in gastro- entero-pancreatic neuroendocrine neoplasms. Although the literature is scarce, the let-7 family targeting phosphoinositide 3 kinase - protein kinase B 1 - mammalian target of rapamycin signaling pathway might represent a promising biomarker with potential clinical benefit, but further research is required before their eventual clinical application. Furthermore, the ambiguous molecular mechanisms of neuroendocrine proliferation and the undefined signaling pathway of somatostatin analogs should encourage future research in this field that may lead to a different clinical approach to neuroendocrine disease.

Lanreotide autogel/depot in advanced enteropancreatic neuroendocrine tumours: final results of the CLARINET open-label extension study

PurposeIn the phase III CLARINET study (NCT00353496), lanreotide autogel/depot (lanreotide) significantly improved progression-free survival (PFS) vs placebo in patients with non-functioning intestinal or pancreatic neuroendocrine tumours (NETs). The aim of CLARINET open-label extension (OLE) (NCT00842348) was to evaluate long-term safety and efficacy of lanreotide in these patients.MethodsPatients from the CLARINET study were eligible for the OLE if they had stable disease (irrespective of treatment group) or progressive disease (PD) (placebo-treated patients only). All patients in the OLE received lanreotide 120 mg every 28 days. Computed tomography or magnetic resonance imaging scans were conducted every 6 months and assessed locally for PD (the final scan was also assessed centrally).ResultsOverall, 89 patients took part in the OLE (lanreotide, n = 42; placebo, n = 47). Median (range) exposure to lanreotide in patients who received lanreotide in the core study and OLE (LAN–LAN group) was 59.0 (26.0–102.3) months. In this group, the overall incidences of adverse events (AEs) and treatment-related AEs were lower in the OLE than in the core study. Median [95% CI] PFS in the LAN–LAN group was 38.5 [30.9; 59.4] months. In placebo-treated patients with PD at the end of the core study, time to death or subsequent PD during the OLE was 19 [10.1; 26.7] months.ConclusionsThis study provides new evidence on the long-term safety profile and sustained anti-tumour effects of lanreotide autogel/depot in indolent and progressive metastatic intestinal or pancreatic NETs.

A tool to predict survival in stage IV entero-pancreatic NEN

PurposeWell-differentiated stage IV neuroendocrine neoplasms (NEN) have an extremely heterogeneous, unpredictable clinical behavior. Survival prognostic markers, such as the recently proposed NEP-Score, would be very useful for better defining therapeutic strategies. We aim to verify NEP-Score applicability in an independent cohort of stage IV well-differentiated (WD) gastroentero-pancreatic (GEP) NEN, and identify a derivate prognostic marker taking into account clinical and pathological characteristics at diagnosis.MethodsAge, site of primary tumor, primary tumor surgery, symptoms, Ki67, timing of metastases of 27 patients (10 females; mean age at diagnosis 60.2 ± 2.9 years) with stage IV WD GEP NEN were evaluated to calculate the NEP-Score at the end of follow-up (NEP-T). We calculated the NEP-Score at diagnosis (NEP-D), which does not consider the appearance of new metastases during follow-up. Patients were subdivided according to whether they were alive or not at the end of follow-up (EOF) and an NEP-Score threshold was investigated to predict survival.ResultsMean NEP-T and mean NEP-D were significantly lower in 15 live patients as compared to 12 deceased patients (p < 0.01) at EOF. We identified an NEP-D = 116 as the cutoff that significantly predicts survival. No gender differences were identified.ConclusionsIn our series, we confirmed NEP-Score applicability. In addition, we propose NEP-D as a simple, quick and cheap prognostic score that can help clinicians in decision making. NEP-D threshold can predict NEN aggressiveness and may be used to define the best personalized therapeutic strategy.

Cost-Effectiveness of Initial Versus Delayed Lanreotide for Treatment of Metastatic Enteropancreatic Neuroendocrine Tumors.

The Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors (CLARINET) trial showed prolonged progression-free survival in patients initially treated with lanreotide versus placebo. We evaluated the cost-effectiveness of upfront lanreotide versus active surveillance with lanreotide administered after progression in patients with metastatic enteropancreatic neuroendocrine tumors (NETs), both of which are treatment options recommended in NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine and Adrenal Tumors. We developed a Markov model calibrated to the CLARINET trial and its extension. We based the active surveillance strategy on the CLARINET placebo arm. We calculated incremental cost-effectiveness ratios (ICERs) in dollars per quality-adjusted life-year (QALY). We modeled lanreotide's cost at $7,638 per 120 mg (average sales price plus 6%), used published utilities (stable disease, 0.77; progressed disease, 0.61), adopted a healthcare sector perspective and lifetime time horizon, and discounted costs and benefits at 3% annually. We examined sensitivity to survival extrapolation and modeled octreotide long-acting release (LAR) ($6,183 per 30 mg). We conducted one-way, multiway, and probabilistic sensitivity analyses. Upfront lanreotide led to 5.21 QALYs and a cost of $804,600. Active surveillance followed by lanreotide after progression led to 4.84 QALYs and a cost of $590,200, giving an ICER of $578,500/QALY gained. Reducing lanreotide's price by 95% (to $370) or 85% (to $1,128) per 120 mg would allow upfront lanreotide to reach ICERs of $100,000/QALY or $150,000/QALY. Across a range of survival curve extrapolation scenarios, pricing lanreotide at $370 to $4,000 or $1,130 to $5,600 per 120 mg would reach ICERs of $100,000/QALY or $150,000/QALY, respectively. Our findings were robust to extensive sensitivity analyses. The ICER modeling octreotide LAR is $482,700/QALY gained. At its current price, lanreotide is not cost-effective as initial therapy for patients with metastatic enteropancreatic NETs and should be reserved for postprogression treatment. To be cost-effective as initial therapy, the price of lanreotide would need to be lowered by 48% to 95% or 27% to 86% to reach ICERs of $100,000/QALY or $150,00/QALY, respectively.

True Chromogranin A concentrations in plasma from patients with small intestinal neuroendocrine tumours

Objective: The incidence of enteropancreatic neuroendocrine tumours (NET) is increasing. Chromogranin A (CgA) in plasma is a marker in patients suspected of NET tumours. CgA, however, is a precursor protein subjected to cellular processing that challenges quantitation and hence the use of CgA in diagnostics.Materials and methods: CgA concentrations in plasma sampled from 130 well-characterized patients with small intestinal NETs and from 30 healthy subjects were measured with eight commercial CgA kits, an in-house radioimmunoassay (RIA) and a processing-independent assay (PIA). For the evaluation of diagnostic accuracy, we performed regression analyses and plotted receiver-operating characteristic curves (ROC). The specificity was further assessed by size chromatography.Results: Five commercial assays (Thermo-Fisher, DRG Diagnostics, Eurodiagnostica (RIA and ELISA), and Phoenix), displayed a diagnostic accuracy with area under the curve (AUC) values >0.90, whereas three immunoassays (Yanaihara, CisBio RIA, and CisBio ELISA) discriminated poorly between disease stages (AUC: 0.60–0.78). Compared with the in-house assays, however, even the most accurate commercial immunoassay still missed patients with metastatic disease. Chromatography showed non-uniform patterns of large and small CgA fragments in plasma.Conclusion: Available commercial immunoassays measure CgA in plasma with gross variability. Three commercial CgA immunoassays discriminate so poorly between health and disease that they should not be used. The highest diagnostic accuracy was obtained with processing-independent measurement of total CgA concentrations in plasma.

Prognostic value of the neutrophil/lymphocyte ratio in enteropancreatic neuroendocrine tumors.

Accessible prognostic tools are needed to individualize treatment of neuroendocrine tumors (NETs). Data suggest neutrophil/lymphocyte ratios (NLRs) have prognostic value in some solid tumors, including NETs. In the randomized double-blind CLARINET study (NCT00353496; EudraCT 2005-004904-35), the somatostatin analog lanreotide autogel/depot increased progression-free survival (PFS) compared with placebo in patients with inoperable or metastatic intestinal and pancreatic NETs (grades 1–2, Ki-67 < 10%). The exploratory post-hoc analyses presented here evaluated the prognostic value of NLR in the CLARINET study cohort, in the context of and independently from treatment. Kaplan–Meier PFS plots were generated for patients with available NLR data, in subgroups based on NLR values, and 24-month survival rates were calculated. P values and hazard ratios for prognostic effects were generated using Cox models. 31216222 Baseline characteristics were balanced between lanreotide autogel/depot 120 mg (n = 100) and placebo (n = 101) arms. Irrespective of treatment, raw 24-month PFS rates were comparable across subgroups based on NLR tertiles [37.3% (low), 38.8% (middle), 38.8% (high); n = 67 per group] and NLR cutoff of 4 [38.1% (NLR ≤ 4; n = 176), 40.0% (NLR > 4; n = 25)]. Furthermore, NLRs were not prognostic in Cox models, irrespective of subgroups used. The therapeutic effect of lanreotide autogel/depot 120 mg was independent of NLRs (P > 0.1). These exploratory post-hoc analyses in patients with advanced intestinal and pancreatic NETs contrast with previous data suggesting NLR has prognostic potential in NETs. This may reflect the inclusion of patients with lower-grade tumors or use of higher NLR cutoff values in the current analysis.

1324P - The role of modulation of somatostatin analogues (SSAs) in association to peptide receptor radionuclide therapy (PRRT) after SSAs progression disease (PD) in advanced well-differentiated (WD) entero-pancreatic neuroendocrine tumours (EP-NETs)

Background: The NETTER-1 trial has recently shown the efficacy of 177Lu-DOTATATE in association with Octreotide (OCT) in somatostatin receptor positive midgut NETs, progressing to OCT. The aim of this analysis was to evaluate the role of SSA in association to PRRT beyond PD or after switch to other SSA at PD. Methods: Out of 107 WD EP-NETs, treated with PRRT (90Y-DOTATOC/DOTATATE and/or 177Lu-DOTATOC/DOTATATE) at the Istituto Nazionale Tumori of Milan, from 2008 to 2017, 69 patients (pts) treated with the combination of PRRT and SSA (OCT or Lanreotide, LAN) after SSA treatment failure, were evaluated for present analysis. We identified 2 groups: S1, pts who kept the same SSA treatment beyond first PD; S2, pts who switched the SSA with another SSA after first PD. Median Progression Free Survival (mPFS) (from the start of first SSA) and Overall Survival (OS) have been evaluated using the Kaplan-Maier method. Results: In S1 (n = 47) and S2 (n = 22) groups median age and sex were 58 ys (range 29-78) and 59.5% males vs 52.5 ys (range 35-78) and 45.4% males, respectively. We had a P-NETs percentage of 34% vs 40.9% in the S1 vs S2 groups, respectively. The most of pts (82.9% in S1 and 86.3% in S2) received PRRT with alternate radionuclides (90Y/177Lu). Overall the median number of PRRT cycles was 4.2 in S1 and 4.8 in S2 (p = 0.09). In the S1 (SSA beyond PD) group PRRT was associated with OCT in 74.5% and LAN in 25.5% of pts. In the S2 group (SSA switched with other SSA) PRRT was associated with OCT in 27.3% and LAN in 72.7% of pts. In the overall population the mPFS and OS were 70 (CI95% 52.8-87.1) and 82 (CI95% 66.7-97.2) months (mo), respectively. The difference on mPFS was 53 and 127 mo in S1 and S2, respectively (p = 0.001; HR: 0.31; CI95% 0.15-0.63). In S1 group the OS was 69 mo vs 150 mo in S2 (p = 0.004; HR: 0.32; CI95% 0.14-0.71). Conclusions: Despite the retrospective nature of the analysis and the low number of pts, we found a significant difference on mPFS and OS between S1 and S2 groups. In pts with advanced WD EP-NETs treated with PRRT plus SSA after SSA failure, the “switch” strategy of SSA after PD, might improve PFS and/or OS. Legal entity responsible for the study: Sara Pusceddu. Funding: Has not received any funding. Disclosure: N. Prinzi: Italfarmaco, Novartis: Consultancies. G. Lo Russo: AstraZeneca, BMS, MSD: Consultancies. S. Pusceddu: Novartis, Ipsen, Italfarmaco, Pfizer and advanced accelerator applications (AAA). All other authors have declared no conflicts of interest.

Clinical Usefulness of 18F-Fluorodeoxyglucose Positron Emission Tomography in the Diagnostic Algorithm of Advanced Entero-Pancreatic Neuroendocrine Neoplasms.

The role of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in the diagnostic algorithm of entero-pancreatic neuroendocrine neoplasms (EP NENs) is unclear because most available data derive from heterogeneous populations in terms of tumor biology and disease status at time of examination. The aim of this study was to determine the ability of 18F-FDG PET to identify patients with more aggressive disease among those with advanced EP NENs. Subjects, Materials, and Methods . Patients with advanced EP NENs and known disease status (progressive disease [PD] or stable disease [SD]) according to imaging procedures, who received 18F-FDG PET and computed tomography scans during a time frame of 1 month, were included. A total of 93 patients, including 69 patients with pancreatic NENs and 24 patients with small-intestine NENs, were included. At the time of study entry, 64 patients (68.8%) had PD, and the remaining 29 patients (31.2%) had SD. A total of 62 patients (66.7%) had positive 18F-FDG PET, whereas 18F-FDG PET was negative in the remaining 31 patients (33.3%). Overall, 18F-FDG PET sensitivity and specificity to detect PD were 90.6% and 86.2%, respectively, resulting in a diagnostic accuracy of 89.2%. A positive 18F-FDG PET was significantly associated with PD at the time of study entry (p < .0001 at multivariate analysis). Although a higher proportion of 18F-FDG PET-positive examinations were observed in patients with higher tumor grade (p = .01), 53.8% of patients with grade 1 neuroendocrine tumors (NETs) had positive 18F-FDG PET, and 37.5% of patients with grade 2 NETs had negative 18F-FDG PET. Overall survival was significantly shorter in 18F-FDG PET-positive patients (median: 60 months) in comparison with 18F-FDG PET-negative patients (median not reached; p = .008). 18F-FDG PET has a high diagnostic accuracy to identify progression of disease with unfavorable clinical outcome in patients with advanced EP NENs. Knowledge of disease status and G grading are key factors for physicians to better select patients for whom 18F-FDG PET is clinically useful. The findings of the present study may help physicians dealing with advanced neuroendocrine neoplasms to select patients for whom 18F-fluorodeoxyglucose positron emission tomography is useful to predict poor clinical outcome.

451P - Final analysis of time to subsequent disease progression/death in patients with metastatic enteropancreatic neuroendocrine tumours progressing under placebo and switched to lanreotide autogel/depot 120mg in the CLARINET open-label extension

451P - Final analysis of time to subsequent disease progression/death in patients with metastatic enteropancreatic neuroendocrine tumours progressing under placebo and switched to lanreotide autogel/depot 120mg in the CLARINET open-label extension

Impact of Ki67 re-assessment at time of disease progression in patients with pancreatic neuroendocrine neoplasms.

BackgroundAlthough re-assessment of proliferative activity by K67 evaluation during the course of neuroendocrine neoplasms (NENs) is recommended in selected patients, its impact on patients’ management is not clear due to the lack of data supporting this practice.AimTo investigate Ki67 change at time of progressive disease (PD) in entero-pancreatic NENs (EP-NENs).Patients and methodsRetrospective analysis of sporadic EP-NENs which received histological re-assessment after PD once radiologically documented.ResultsForty-three patients were evaluated, including 24 pancreatic NENs (PNENs), and 19 small intestine NENs (SI-NENs). At time of initial histological evaluation, 19 patients had grade 1 (G1) NETs (44.2%), and 24 grade 2 (G2) NETs (55.8%), overall median Ki67 being 3% (range 1%-20%). At time of PD, 13 patients had G1 NETs (30.2%), 26 G2 NETs (60.5%), and 4 had grade 3 (G3) NECs (9.3%), thus resulting in a significant median Ki67 increase (8%, range 1%-70%; p = 0.0006), and a G upgrading in 12 patients (27.9%). A statistically significant Ki67 increase and G grading change at time of PD was observed in PNENs (p = 0.0005 and p = 0.028, respectively). Conversely, no statistically significant change occurred in non-PNENs.ConclusionsIn PNENs with documented PD, Ki67 increase occurs in a significant proportion of patients, providing useful information necessary to choose appropriate therapeutic options.

Anti-tumoral effects of somatostatin analogs: a lesson from the CLARINET study.

Octreotide and lanreotide, the first-generation somatostatin analogs, successfully control hormone hyperproduction, and related syndromes, in patients with acromegaly and neuroendocrine tumors. However, their anti-tumor effect, rather evident in large number of pituitary adenomas in acromegalic patients, has been hypothesized for a long time in patients with neuroendocrine tumors as well, although a significant tumor shrinkage has rarely been observed. However, the recent publication of the CLARINET study has strengthened the evidence, already emerged with the PROMID trial, that the long-term treatment with the first-generation long-acting somatostatin analogs may exert an anti-tumor activity on G1 and G2 enteropancreatic neuroendocrine tumors, as well. After the publication, majority of international guidelines have updated their algorithms in line with these results and this class of drugs obtained the indication as anti-tumor agents in the majority of patients with neuroendocrine tumors.

Impact of Vitamin D on the Clinical Outcome of Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: Report on a Series from a Single Institute

Background/Aims: Vitamin D deficiency is hypothesized to represent a risk factor in several neoplasms. The aim of this study was to determine whether serum 25-hydroxyvitamin D (25-OHvitD) deficiency represents a risk factor for neuroendocrine neoplasms (NENs) and can be associated with overall survival (OS) and progression-free survival (PFS). Methods: From 2010 to 2015, 138 patients with gastro- entero-pancreatic NENs (61 females; median age, 63 years) were included in the study. Serum 25-OHvitD levels, which were measured at baseline, were defined as deficient if ≤20 ng/mL. In such cases, 25-OHvitD supplementation was administered to the patients. The possible associations between 25-OHvitD levels and disease grading, staging, overall OS, and PFS were considered. Furthermore, the possible association between 25-OHvitD supplementation and PFS or OS was evaluated by Cox proportional hazards regression. Results: Median 25-OHvitD levels were 12.9 ng/mL (range 2-32); in detail, 94 patients (68%) had ≤20 ng/mL, with 46 cases (33%) having ≤10 ng/mL. An inverse correlation was observed between 25-OHvitD levels and OS (p = 0.03, rs = -0.18) and PFS (p = 0.01, rs = -0.22). At Cox proportional hazards regression, mortality was not related to 25-OHvitD levels; however, there was an association between 25-OHvitD supplementation and OS (p < 0.002). Conclusions: Vitamin D deficiency is highly prevalent among NEN patients. 25-OHvitD supplementation potentially plays an important role in the correction of 25-OHvitD values, and has an influence on the clinical outcome. However, further studies are needed to confirm this observation.