Gastroenteropancreatic Neuroendocrine Tumors Patients Research Articles

Development and validation of a nomogram for predicting the overall survival of patients with gastroenteropancreatic neuroendocrine neoplasms.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasing in incidence. Clinicians urgently need a method that can effectively predict the prognosis of GEP-NENs.A total of 14770 GEP-NENs patients with pathologically confirmed between 1975 and 2016 were obtained from the surveillance, epidemiology, and end results database. All the patients were divided into primary (n = 10377) and validation (n = 4393) cohorts based on the principle of random grouping. Multivariate Cox proportional hazards proportional hazards regression analysis was performed to evaluate predictors associated with overall survival, and a nomogram was constructed based on the primary cohort. An independent external validation cohort and comparison with the eighth edition American Joint Committee on Cancer TNM staging system were subsequently used to assess the predictive performance of the nomogram.The multivariate Cox model indicated that age, tumour differentiation, and distant metastases were independent predictors associated with overall survival. With respect to the primary cohort, the nomogram exhibited better discriminatory power than the TNM classification (C-index: 0.821 vs 0.738). Discrimination was also superior to that of TNM classification for the validation cohort (C-index: 0.823 vs 0.738). The calibrated nomogram predicted 3- and 5-years survival rate that closely corresponded to the actual survival rate.This study developed and validated a prognostic nomogram applied to patients with GEP-NENs, which may help clinicians make reasonable prognostic judgments and treatment plans to a certain extent.

Cardiovascular Mortality Risk among Patients with Gastroenteropancreatic Neuroendocrine Neoplasms: A Registry-Based Analysis.

Background This research is aimed to explore mortality patterns and quantitatively assess the risks of cardiovascular mortality (CVM) in patients with primary gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Methods We extracted data from the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with GEP-NENs between 2000 and 2015. The standardized mortality ratio (SMR) and the absolute excess risk were obtained based on the reference of the general US population. The cumulative incidence function curves were constructed for all causes of death. Predictors for CVM were identified using a multivariate competing risk model. Results Overall, 42027 patients were enrolled from the SEER database, of whom 1598 (3.8%) died from cardiovascular disease (CVD). The SMR for CVM was 1.20 (95% CI: 1.14-1.26) among GEP-NEN patients. The cumulative mortality of CVD was the lowest among all causes of death, including primary cancer, other cancer, and other noncancer diseases. Furthermore, age at diagnosis, race, Hispanic origin, sex, marital status, year of diagnosis, grade, education level, region, SEER stage, primary site, surgery, and chemotherapy were identified as independent predictors of CVM in GEP-NEN patients. Conclusions GEP-NEN patients have a significantly increased risk of CVM relative to the general population. Cardioprotective interventions might be considered a preferred method for these patients.

Thrombotic risk in gastroenteropancreatic neuroendocrine tumor patients: a single-center experience.

BackgroundOnly scanty specific studies are available on venous thromboembolism (VTE) in neuroendocrine neoplasms (NEN). We retrospectively assessed the incidence of VTE in gastroenteropancreatic (GEP) NEN patients.MethodsBetween 2000 and 2016, GEP-NEN patients were retrospectively evaluated for VTE. Major thrombotic events included deep venous thrombosis (DVT) and pulmonary embolism (PE). 160 patients were included. The primary tumor site was: the gut in 99, pancreas in 54, and unknown in 7. A total of 93 patients had grade (G) 1 tumor, 36 G2, 4 G3; G was not available in 27 patients. TNM stage was I in 76 patients, II in 17, III in 23, and IV in 44.ResultsTwelve patients developed VTE: 9 had DVT and 3 PE. The primary site of the tumor was located in the pancreas in 9 patients, in the gut in 2, and it was unknown in one patient. Two patients had a functioning tumor. Grading was G1 in 3 patients, G2 in 6, G3 in 2 cases, and not available in one. The TNM stage was IV in 5 patients, III in 2, II in 3, and I in 2. Two patients died during the study period, one of whom died from PE.ConclusionGEP-NEN patients harbor a considerable risk of VTE, particularly high for pancreatic NEN patients, for patients with moderate-poorly differentiated neoplasms, and at an advanced tumor stage.

Chronic Use of Long-Acting Somatostatin Analogues (SSAs) and Exocrine Pancreatic Insufficiency (EPI) in Patients with Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): An Under-recognized Adverse Effect

Somatostatin Analogues (SSAs) are used to treat Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and acromegaly. Side effects of SAAs usually include biliary disorders, gastrointestinal disorders, injection-site pain and hyperglycemia. Exocrine Pancreatic Insufficiency (EPI) is often misdiagnosed as disease progression or failure to SAAs or diagnosed after a delay in patients receiving SAAs. We present our experience with EPI developing in patients following use of SAAs. We reviewed chart and pharmacy records of 110 GEP-NETs patients who received SSAs. Data was collected including demographics, pathology, stage, dose/duration of long and short-acting SA, use of antidiarrheal, pancreatic enzyme replacement (PER), proton pump inhibitors (PPI) or H2 blockers). Laboratory data include chromogranin-A (CgA), urine 5-HIAA and quantitative fecal fat test (QFFT) or fecal elastase test (FE). EPI was defined by a FE below normal level OR by a reduction of ≥ 21.2% or steatorrhea on QFFT. Patients who were identified to develop EPI were treated with pancreatic exocrine replacement therapy (PERT). Among, 110 GEP-NETs patients, 104 received LA Octreotide and 6 Somatuline Depot Injection. Of these, 23 received short-acting SSA for worsening diarrhea, 96 had intensification of antidiarrheal and 1 got telotristat ethyl. QFFT confirmed EPI in 19, 11 based on clinical symptoms, and 16 had sample error or refusal to collect specimen. CTCAE 4.0 grades of EPI were: grade 2(69%), grade 3(22%) and grade 4(9%). Median time to development of EPI was 12 months (95%CI 3 - 23). Except 1, all patients received PERT either with concomitant PPI (13) or later if no improvement with PERT (6) and 2 on H2 blockers. 37% of the patients had improvement in EPI within 4-8 weeks. Deficiency of vitamins and trace elements was found in 11 of 19 patients, who received supplementation. Our experience constitutes the first and the largest study addressing EPI as a rare but serious complication of chronic use of SAAs. Although SAAs are used to treat diarrhea, paradoxically they can worsen diarrhea secondary to EPI. Early recognition and diagnosis of this under-diagnosed and under-reported side effect of SAAs, such as EPI, can improve not only diarrhea and weight loss in these patients but also can reduce cost of using short-acting SAAs and antidiarrheal.

Systemic Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors in Korea: Literature Review and Expert Opinion.

Neuroendocrine tumors (NETs) are a group of malignancies arising from neuroendocrine cells and frequently originate in the gastrointestinal tract and pancreas. Although curative resection is the main treatment for localized disease, systemic therapy is needed for relapsed or metastatic/unresectable gastroenteropancreatic NETs (GEP-NETs). Although there are several NET treatment guidelines from various countries, the geographical discrepancies between patient clinical characteristics, the regulatory approval status for therapeutic agents, and medical practices necessitate specific guidelines for Korean patients. We here provide a consensus review of the diagnosis, staging and systemic treatment of Korean GEP-NET patients. Systemic therapy options and the current Korean expert consensus on these treatments, including somatostatin analogs, targeted therapies such as everolimus and sunitinib, peptide receptor radionuclide treatments, and cytotoxic chemotherapies are addressed.

Distinct Expression Patterns of VEGFR 1-3 in Gastroenteropancreatic Neuroendocrine Neoplasms: Supporting Clinical Relevance, but not a Prognostic Factor.

Introduction: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are an increasing tumor entity. Since many patients are diagnosed at an advanced stage, treatment is still challenging and dependent on many tumor and patient specific factors. Therefore, the aim of the present study was to elucidate the expression rates and the prognostic value of vascular endothelial growth factor receptor (VEGFR) 1-3 in GEP-NENs. A potential association to immune checkpoint markers was further investigated. Material and Methods: The expression levels of VEGFR 1-3 were analyzed by immunohistochemistry and correlated with the expression of the checkpoint markers PD-1 and PD-L1. Furthermore, the tumor samples of 249 GEP-NEN patients were studied and correlated with overall survival rates and clinicopathological features. Kaplan–Meier analyses and the log rank test were used for survival analyses. Categorical variables were compared by the χ2 test. Results: The most common primary tumor site was the small intestine (50.6%), followed by the pancreas (25.7%). VEGFR 1 was highly expressed in 59%, VEGFR 2 in 6.4%, and VEGFR 3 in 61.8% of the analyzed samples. The expression of VEGFR 1-3 was not significantly associated with survival rates. Pancreatic NENs had the highest expression of VEGFR 1 and 3 in 80% of the cases. VEGFR 1-3 positivity correlated with the expression levels of immune checkpoint markers. Discussion: VEGFR 1-3 show a distinct expression pattern in different subgroups of neuroendocrine neoplasias indicating a conceivable target. Moreover, there was a substantial association between VEGFRs and immune checkpoint markers. Taken together, anti-VEGFR therapy represents a promising therapeutic approach in GEP-NEN patients and should be addressed in future studies.

Myeloid-derived suppressor cells in gastroenteropancreatic neuroendocrine neoplasms.

Expanded myeloid-derived suppressor cells (MDSCs) correlate with disseminated metastases and poor prognosis in various human cancers. However, the role of MDSCs in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is still unknown. We investigated the distribution of MDSCs and their clinical significance in patients with GEP-NENs. Peripheral blood mononuclear cells (PBMCs) and paraffin-embedded tumor tissues were acquired from patients with GEP-NENs. Multicolor flow cytometry was performed to determine the frequency of MDSCs in peripheral blood, and immunohistochemistry was performed to determine the distribution of MDSCs in primary NEN tissues. Compared to healthy donors, patients with GEP-NENs had significantly higher levels of circulating monocytic (M)-MDSCs. Frequency of M-MDSCs in both peripheral blood and primary NEN tissues was significantly higher in GEP-NEN patients with metastases compared to patients without metastases. Tumor-infiltrating M-MDSCs can serve as a valuable prognostic marker of metastasis in patients with GEP-NENs, as indicated by the area under the curve (AUC) = 0.71; 95% confidence interval (CI) = 0.56-0.87, p < 0.01. High M-MDSC levels were associated with significantly increased metastases in patients with GEP-NENs. M-MDSCs appear to be a promising prognostic immunologic biomarker and therapeutic target in GEP-NEN management.

A Consensus-Developed Morphological Re-Evaluation of 196 High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms and Its Clinical Correlations

High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are classified according to morphology as well-differentiated neuroendocrine tumours (NETs) G3 or poorly differentiated neuroendocrine carcinomas (NECs). Little data exist concerning which morphological criteria this subdivision should be based on. Uncertainty exists if the NEC group should be further subdivided according to proliferation rate. Clinical data on NET G3 and NEC with a lower Ki-67 range are limited. A total of 213 patients with high-grade GEP-NEN (Ki-67 >20%) were included from the Nordic NEC Registries. Four experienced NET pathologists re-evaluated the cases to develop the best morphological criteria to separate NET G3 from NEC, assuming longer survival in NET G3. Organoid growth pattern, capillary network in direct contact to tumour cells, and absence of desmoplastic stroma were found to best separate NET G3 from NEC. Of 196 patients with metastatic disease, NET G3 was found in 12.3%, NEC with a Ki-67 <55% (NEC < 55) in 29.6%, and NEC with a Ki-67 ≥55% (NEC ≥ 55) in 56.6%. Only in 1.5%, the morphology was ambiguous. Of 164 patients receiving first-line chemotherapy, 88% received platinum/etoposide treatment. Response rate was higher for NEC ≥ 55 (44%) than that of NEC < 55 (25%) and NET G3 (24%) (p = 0.025 and p = 0.026). Median progression-free survival was 5 months for all groups. Median overall survival was 33 months for NET G3 compared to 11 months for both NEC < 55 and NEC ≥ 55 (p = 0.004 and 0.003). Specific morphological criteria can separate NET G3 from NECs and show prognostic significance. High-grade GEP-NEN patients stratified by morphology and proliferation rate demonstrate significant differences in response to chemotherapy and survival.

Evaluation of a Correction Method for 111In-Pentetreotide SPECT Imaging of Gastroenteropancreatic Neuroendocrine Tumors.

The number of patients with the extremely rare disease gastroenteropancreatic (GEP) neuroendocrine tumor (NET) has increased rapidly in recent years. 111In-pentetreotide SPECT in somatostatin receptor scintigraphy has been used for the assessment of GEP NET patients. To diagnose GEP NET, appropriate selection of image correction parameters is critical. Correction methods may improve the 111In-pentetreotide SPECT image quality, but there is currently no standard technique. The purpose of this study was to determine the optimal correction parameter settings for 111In-pentetreotide SPECT. Methods: A phantom study produced images with a tumor-to-background ratio of as high as 16:1. A triple energy window was used for scatter correction (SC), and attenuation correction (AC) was CT-based. Correlation analysis was performed in 4 groups: no correction (NC), SC, AC, and combined SC with AC (CC). The 111In-pentetreotide SPECT results for 20 randomly selected patients (13 men and 7 women; age range, 37-81 y) with confirmed GEP NET were analyzed using data collected 4 h after injection of 111 MBq of 111In-pentetreotide. Emission data were reconstructed using ordered-subset expectation maximization (OSEM) with different settings. Different combinations of the correction parameters were used to analyze the contrast-to-noise ratios (CNRs) obtained with the phantom. In the clinical study, 20 GEP NET patients were used to evaluate the GEP NET lesion CNR by 4 different image correction methods obtained from 111In-pentetreotide SPECT images: NC, SC, AC, and CC. NC was used as a reference method. Results: The phantom study revealed that the optimal energy window in the photopeak for somatostatin receptor scintigraphy was 171 keV ± 10% and 245 keV ± 7.5%, and the optimal OSEM reconstruction conditions were 8 subsets and 6 iterations. Among the OSEM collection conditions, CC produced a significantly higher CNR than NC or SC (P < 0.05). In the clinical study, CC was found to increase the CNR (P < 0.05). Conclusion: CC improves the correction in 111In-pentetreotide SPECT studies, compared with NC, providing better contrast and sharper outlines of lesions and organs.

Clinicopathological Features of Gastroenteropancreatic Neuroendocrine Neoplasms.

Descriptive study. Bezmialem Vakif University School of Medicine Hospital from April 2012 to September 2018. Sixty-one patients with GEP-NENs were analysed in retrospect for the clinical, pathological and survival characteristics. The Kaplan-Meier method was used for survival analysis and the Log-rank test was performed to analyse the comparisons between the groups. Forty-five of the 61 GEP-NENs patients (73.8%) were neuroendocrine tumor (NET) and 26.2% of patients were neuroendocrine carcinoma (NEC). The mean age of patients was 55.5 ± 11.3 years. The most frequent localisation of tumors was stomach (34.4%), and the most common symptom was abdominal pain (27.9%). The rate of distant metastases was 31.1% at diagnosis and 63.9% of the patients were operated. The median follow-up period was 27 months. The rate of three-years overall survival (OS) was 88.5% and the five-years OS rate was 86.9%. The variables that can significantly influence the OS rate were high grade (grade 3; p= 0.005), Ki-67 proliferation index (Ki-67 >20%; p= 0.002) and distant metastases (p= 0.018). GEP-NENs may develop anywhere in the digestive tract. Approximately one-third of the patients may be metastatic due to delay in diagnosis. Key Words: Gastroenteropancreatic neuroendocrine tumor, Neuroendocrine cancers, Neuroendocrine neoplasms.

PD-12 Clinical, pathological and molecular profiles of G3 neuroendocrine tumors and neuroendocrine carcinomas

In 2019, WHO subclassified grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) into neuroendocrine carcinoma (NEC) or tumors (G3 NET). Yet, few data exist on clinical and molecular profiles for G3 NEN. We aimed to compare the clinicopathological and molecular characteristics of G3 GEP NET and GEP NEC. We retrospectively collected data of all G3 GEP NEN patients (pts) diagnosed and treated at our cancer center from 2000 to 2019. Cases with available tumor tissues were reviewed and reclassified according to the WHO 2019 classification. Formalin-fixed, paraffin-embedded NEN tissues had DNA extracted for genomic profiling through next-generation sequencing (NGS), which evaluated mutations profiles, tumor mutation burden (TMB) and the presence of microsatellite instability. Survival from treatment start was the primary endpoint. Seventy-seven pts were included: median age at the diagnosis was 56 (26-91) years and 62% (48/77) were males. The most common primary sites were gastric (27%, 21/77), pancreas (23%, 18/77) and unknown primary NEN (23%, 18/77). Metastatic disease was present in 69% at diagnosis and 91% developed metastasis. Out of 77, 43 (56%) had pathology revision: 29 cases were NEC (67%) and 14 were reclassified as G3 NET (33%), with a change in diagnosis of 23%. In a median follow-up of 44 months, median OS in non-pancreatic digestive G3 NET, pancreatic G3 NET, and GEP NEC were 23.7, 55.6 and 10.8 months, respectively (non-pancreatic G3 NET vs NEC, p=0.01). Median OS in G3 NET with ki67 > 55%, NEC 55% was 19, 25 and 8 months, respectively. In Cox regression multivariate analysis, only cell differentiation sustained as a risk of death (HR 3.14 NEC vs G3 NET; P = 0.025). NGS was performed in 42% (32/77) cases: 21 NEC and 11 G3 NET. Median tumour mutational burden was 5.67 (0 – 66.82) mutations per megabase among NEC and 4.52 (0 – 8.83) among G3 NET. Tumors were microsatellite unstable in 3 (14.3%) NEC cases but zero among G3 NET pts. The most commonly mutated genes in G3 NET were TP53 (N=3; 27.3%), CDKN2A (N=3; 27.3%) and KRAS (2/11, 18.2%) and TP53 (N=15; 71.4%), Rb1 (N=7; 33.3%), PTEN (N=6; 28.6%) and APC (N=4; 19%) among NEC. Non-pancreatic digestive G3 NET is associated with increased survival compared to NEC. Pathology revision is essential to estimate prognosis and consequently therapeutic plan, as some of G3 NET can be treated as G2 NET. While G3 GEP NEN generally harbours low TMB and fewer actionable mutations, 14% of NEC cases were microsatellite unstable and could benefit from immune checkpoint inhibitors.

Multiple endocrine neoplasia type&amp;nbsp;1 in patients with gastroenteropancreatic neuroendocrine tumors: An opportunity for early diagnosis and appropriate management

Gastroenteropancreatic neuroendocrine tumors (GEPNET) are rare tumors that may be sporadic or develop as part of multiple endocrine neoplasia type 1 syndrome (MEN1). The aim of the present study was to report the experience of a Brazilian multidisciplinary outpatient neuroendocrine tumor clinic regarding the clinical diagnosis of MEN1 in a cohort of GEPNET patients. Patient data, including clinical characteristics and the lag time from the onset of symptoms to diagnosis of the first tumor, and further lag time until the diagnosis of MEN1, were retrospectively reviewed. Among 44 GEPNET patients, 6 had a clinical diagnosis of MEN1. Primary hyperparathyroidism and GEPNET were present in all patients in the cohort, and pituitary neuroendocrine tumors were present in 33.3%. The median time interval from the onset of initial symptoms to the diagnosis of the first tumor was 42 months (range, 0-204 months). The median time interval between the diagnosis of the first tumor and the diagnosis of MEN1 was 22 months (range, 1-109 months). The prolonged lag time between the onset of initial symptoms and MEN1 diagnosis may result in substantial morbidity and loss of opportune interventions for the patients. Therefore, greater efforts should be made to shorten these times and improve the care of patients with MEN1.

SUN-626 Survival of Patients with Gastroenteropancreatic Neuroendocrine Tumors and Diabetes Mellitus in a Seer-Medicare Cohort

Background: The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) is increasing globally and has been associated with diabetes mellitus (DM). In this study we aimed to compare tumor characteristics, disease-specific survival (DSS) and overall survival (OS) of GEP-NET patients (pts) with and without DM. Methods: Using the Surveillance, Epidemiology, and End Results registry (SEER) linked to Medicare claims, we identified pts diagnosed with GEP-NET between January 1995 and December 2010, aged ≥65 years at the time of GEP-NET diagnosis. We included patients who were in exclusive Medicare coverage without healthcare management organizations and had Medicare Parts A and B coverage for ≥1year after GEP-NET diagnosis or until death. Within the pts with GEP-NET diagnosis, we identified those without a diagnosis of DM prior to the GEP-NET diagnosis. We compared baseline sociodemographics, co-morbidities, and GEP-NET location, stage, grade and treatment between pts with and without DM using χ 2 analysis. Kaplan Meier (KM) curves were used to compare OS and DSS up to 10 years between the DM and non-DM groups. We used Cox proportional hazards analysis to compare the DSS between the groups, adjusting for confounding variables. Results: We identified a cohort of 1,969 well-characterized GEP-NET patients with accurate tumor stage, grade, comorbidities, and treatment data. 478 (25.7%) had DM and 1,383 (74.3%) did not have DM. There were no statistically significant differences in gender or age at the time of GEP-NET diagnosis in the DM (mean age 74.7±SD 6.6 yrs) and non-DM (74.9±7.4 yrs) groups. Significant differences in race were found in the DM (80.6% white, 13.6% black, 1.3% hispanic) and non-DM (86.8% white, 8.2% black, 1.8% Hispanic) groups (p=0.002). Patients with DM had more gastric (14.7%), duodenal (10.9%) and pancreatic (21.0%), and less jejunal/ ileal (12.8%) NETs compared with the non-DM group (9.7%, 6.4%, 16.9%, 18.2%, respectively, p<0.0001). Patients with DM had earlier stage disease than those without DM (p=0.0012), but no difference in tumor grade or treatment was found. KM curves revealed no differences in OS and DSS in the GEP-NET patients with and without DM across all stages. Multivariate adjusted Cox proportional-hazards model found no significant difference in DSS between those with and without DM (HR=0.97, 95%CI: 0.76–1.24). Compared with pts with pancreatic NETs, pts with colon (HR=1.39, 95%CI: 1.04–1.86) had worse survival, while those with jejunal/ileal (HR = 0.59, 95%CI: 0.42–0.83) NETs had a better survival. Discussion: This is the first study to investigate the effect of DM on survival of pts GEP-NETs. We found a high prevalence of pre-existing DM in pts with GEP-NETs, but no difference in OS or DSS in pts with and without DM. Interestingly, pts with DM had more foregut GEP-NETs which may suggest mechanistic links between DM and GEP-NETs at these sites.

Histopathological Revision for Gastroenteropancreatic Neuroendocrine Neoplasms in Expert Centers: Does It Make the Difference?

Background: The correct histopathological diagnosis of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is crucial for treatment selection and prognostication. It is also very challenging due to limited experience in nonexpert centers. Revision of pathology is standard of care for most patients who are referred to NEN expert centers. Objectives: To describe the clinical impact of histopathological revision for GEP-NEN patients referred to an expert center. Methods: Retrospective multicenter analysis of all GEP-NENs receiving a histopathological revision in 6 European NEN expert centers (January 2016 to December 2016) to evaluate the impact on patient management. Results: 175 patients were included and 14.7% referred for a second opinion. Histological samples were 69.1% biopsies, 23.4% surgical specimens, and 7.5% endoscopic resections. Histopathological changes due to revision included first assessment of Ki67 in 8.6% of cases, change in grading in 11.4% (3.4% G1 to G2; 5.7% G2 to G1; 0.6% G2 to G3; 1.7% G3 to G2), definition of tumor invasion in 10.8%, additional immunohistochemical staining in 2.3%, diagnosis of mixed adenoneuroendocrine carcinoma in 3.4%, exclusion of NEN in 3.4%, first diagnosis of NEN in 2.3%, and tumor differentiation for G3 in 1.7%. The revision had a clinical impact in 36.0% of patients, leading to a new therapeutic indication in 26.3%. The indication to then perform a new imaging test occurred in 21.1% and recommendation to follow-up with no further treatment in 6.3%. Conclusions: Histopathological revision in expert centers for NENs can change the diagnosis, with a significant clinical impact in about one third of patients.

Inflammation-related cytokines and their roles in gastroenteropancreatic neuroendocrine neoplasms.

Proinflammatory counterworks are important at different stages of tumor development, particularly during invasion and metastasis. Immune cells and their signal molecules can influence all stages of tumor progression, as well as therapeutic intervention. Proinflammatory cytokines are known triggers of growth in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we explored the immunohistochemical expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), IL-2, and IL-6 in tissues from 43 GEP-NEN patients with tumors of gastric, duodenal, ileal, appendiceal, and colonic origin. The immunohistochemical expression of TNF-α was increased in tumor groups with high proliferation rates (Ki-67; p = 0.034), as well as in those with higher tumor grades (p = 0.05). Moreover, the immunohistochemical expression of TNF-α positively correlated with death outcomes (p = 0.016). Expression of IL-6, IL-1β, and IL-2 displayed similar immunohistochemical expression patterns regardless of Ki-67, although the expression between the ILs differed. Most GEP-NENs had high levels of IL-6 and lower levels of IL-1β and IL-2. Although further comprehensive studies are required for a complete understanding of activated mechanisms in proinflammatory protumoral microenvironment of GEP-NENs, TNF-α is a potential marker in the prognosis of those tumors.

177Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors

ABSTRACTIntroduction: 177Lutetium-[DOTA°,Tyr3]octreotate (177Lu-DOTATATE) is a type of peptide receptor radionuclide therapy that garnered FDA approval in January 2018 for the treatment of somatostatin receptor-positive gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients. The therapy approval was based on findings from the randomized international phase III NETTER-1 trial as well as outcome data from a large European registry. The mechanism of the drug stems directly from its structure: a somatostatin analog (octreotate) selectively binding to somatostatin receptor expressing cells and being internalized, along with a chelated beta-emitting isotope 177Lu.Areas Covered: Herein we describe the pharmacology, clinical efficacy and adverse event data from prospective and retrospective studies with 177Lu-DOTATATE. We discuss the role of 177Lu-DOTATATE within the current treatment landscape for GEP NET patients.Expert Opinion: 177Lu-DOTATATE represents a unique addition to the treatment armamentarium for GEP NETs because of its potential to elicit tumor cytoreduction, which is rare among other existing treatment options, and prolonged disease control. Where 177Lu-DOTATATE fits into the treatment sequence for GEP NET patients remains an area of active investigation.

Multimodality management, recurrence patterns, and long-term outcome of gastroenteropancreatic neuroendocrine neoplasms: Progress over 17years.

Many advances in the management of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) happened in the last two decades. This study highlights the progress in its management over 17years, outcomes, recurrence patterns, and follow up protocols. This retrospective analysis of prospectively maintained database at a single tertiary center included GEP-NEN patients from January 2001toAugust 2017. Management protocols were based on European Neuroendocrine Tumor Society guidelines. Recurrences were categorized as follows: localized nodal, regional, distant hepatic, or combined. Patients were divided into cohorts: cohort 1 (2001-2006), cohort 2 (2007-2011), and cohort 3 (2012-2017). Survival patterns were analyzed. One hundred andninety-two patients were included with 98 (51.04%) grade (G) 1, 64 (33.34%) G2, and 30 (15.63%) G3. One hundred andfour (54.16%) underwent curative surgery (58G1, 27 G2, and 19 G3). Overall follow up ranged from 3 to 276months; 39 were lost to follow up. Ninety-six patients had recurrences: 44 regional + distant and 40 liver-limited recurrences. One-, 3-, and 5-year survivals show significant differences among different treatment groups (p < 0.05). Significant increase in curative resections, chemotherapy utilization, and reduced recurrences were noted in cohort 3. Curative (R0) resection offered 1- and 3-year overall survival of 93.3% and 66.7% in cohort 1; 95.8% and 83.1% in cohort 2; and 100% and 92.9% in cohort 3. Curative resection is the most significant factor for improved survival. Debulking surgerical procedure have a role whereas upfront peptide receptor radionuclide therapy is questionable. Chemotherapy improves overall survival in inoperable/metastatic setting. Recurrence patterns indicate that a long-term follow up greater than 10years is necessary.

Resection of the primary tumor improves survival in patients with gastro-entero-pancreatic neuroendocrine neoplasms with liver metastases: A SEER-based analysis.

Patients who suffer from gastro‐entero‐pancreatic neuroendocrine neoplasms (GEP‐NENs) often present with liver metastatic disease. The efficacy of primary tumor resection (PTR) for these patients remains controversial due to the relatively heterogeneous behavior of the primary tumor and the lack of clinical evidence. In this series, GEP‐NEN patients with liver metastases (LM) were selected from the Surveillance, Epidemiology, and End Results database between 2010 and 2015. A logistic regression model was used to analyze variables that were associated with PTR. A Cox proportional hazards model was used to identify independent prognostic risk factors. In total, 1547 patients were enrolled in our study, including 897 patients who underwent PTR. Resection of the primary tumor was associated with prolonged survival in all patients (5‐year overall survival (OS) rates: 57.0% vs 15.4%, P < .001), and improved 5‐year OS rates were observed in patients with gastric, small intestinal, colorectal, and pancreatic subtypes (39.7%, 73.3%, 24.6%, and 59.7%, respectively). On the multivariate analysis, PTR was an independent prognostic factor of prolonged OS (HR = 0.48, 95% CI: 0.39‐0.59, P < .001). Patients with a young age (≤60 years), small intestinal or colorectal NENs, a large primary tumor, lymph node (LN) metastases, and high tumor differentiation were more likely to undergo PTR. However, patients with colorectal NENs or a large primary tumor (≥4 cm) were at an increased risk of death independently in the PTR subgroup. The risk factors for OS also included old age, gastric tumor location, and poor differentiation. In conclusion, although PTR prolonged OS in all GEP‐NEN patients presenting with LM, surgical recipients should be considered carefully. Age, primary tumor site, size, and differentiation might help surgeons identify patients who could benefit from PTR.

Abstract CT067: A Phase I study of Fosbretabulin in combination with everolimus in neuroendocrine tumors (Grades 1-3) that have progressed after at least one prior regimen for metastatic disease

Abstract Background: Based on the SEER database, the incidence of gastroenteropancreatic neuroendocrine tumors (GEPNETs) has risen six-fold in the last four decades. At present, more than 150,000 GEPNET patients exist in the United States. Fosbretabulin, a synthetic, water-soluble, phosphorylated prodrug of the natural product combretastatin A4 (CA4P), initially isolated from the bark of the South African bush willow, Combretum caffrum, is the lead compound in a class of agents termed vascular disrupting agents (VDAs) and has shown activity as a single agent in ovarian cancer and GEPNETs. Everolimus, an mTOR inhibitor, is FDA approved for the management of well-differentiated NETs. A Phase I trial combining fosbretabulin and everolimus to determine the recommended Phase II trial dose (RP2D) and safety data in metastatic GEPNET patients was conducted. Method: An investigator-initiated, single center, open-label, phase I study involving GEPNETs incorporated partial order continual reassessment method (PO-CRM) to define the dose escalation. The primary objective was to establish the maximum tolerated dose (MTD) of the combination of everolimus and fosbretabulin in NETs that have progressed after at least one prior regimen for metastatic disease. Secondary objective included identifying the safety profile of the combination using NCI CTCAE4 reporting criteria. Patients received daily oral everolimus (2.5 mg, 5 mg, 7.5 mg, and 10 mg). Fosbretabulin was administered IV 60 mg/m2 either q3 weekly or q weekly based on PO-CRM. Patients were treated for 12 weeks with all combinations. Results: Of the 17 patients enrolled, 16 completed the 12-week trial. One patient was not evaluable due to noncompliance with the treatment regimen. No DLTs were observed at day 21. The highest dose of 10 mg daily oral everolimus in combination with weekly 60mg/m2 IV fosbretabulin is the RP2D. No grade 4 or 5 toxicities were noted. Grade 3 toxicities were seen in 5 patients that include increased abdominal pain and hyperglycemia (not related to study drug), fatigue (possibly related), decreased lymphocyte count and anemia (related). Several patients had delay in treatment due to grade 2 AE’s (GI symptoms, rash, thrombocytopenia) and one patient was unable to complete treatment due to pneumonitis. Only one patient had radiologic progression at the first q 3 monthly CT scan of chest, abdomen, and pelvis. A detailed table with all grade toxicities will be presented at the meeting. Conclusion: Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. ClinicalTrials.gov Identifier: NCT0301429 Citation Format: Aman Chauhan, Susanne Arnold, John Wu, Stacey Slone, Emily Dressler, Heather Flynn, Val Adams, Heidi Weiss, Lowell Anthony. A Phase I study of Fosbretabulin in combination with everolimus in neuroendocrine tumors (Grades 1-3) that have progressed after at least one prior regimen for metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT067.

Economic impact of post-progression treatment in gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients previously treated with octreotide monotherapy.

e18366 Background: For unresectable, well-differentiated, advanced GEP-NET patients somatostatin analogs octreotide LAR (OCT) and lanreotide depot (LAN) are recommended as first-line systemic therapy. Recent evidence suggests that GEP-NET patients may benefit from LAN after OCT prior to modifying treatment class. The goal of this analysis is to quantify treatment escalation costs among patients who progress on OCT. Methods: A decision-tree model was used to assess the cost of treating GEP-NET patients over a 6-month time horizon after they progress on OCT. Drug acquisition (Wholesale Acquisition Costs), administration, grade 3/4 adverse event (AE) management, and patient monitoring costs were considered. Patients could utilize either OCT escalation (30 mg every 3 weeks or 40 or 60 mg every 4 weeks), OCT + peptide receptor radionuclide therapy (PRRT), OCT + liver directed therapy (e.g. transarterial chemoembolization (TACE)), everolimus, or LAN 120mg every 4 weeks. Administration and monitoring test costs were based on CMS physician and laboratory fee schedules, respectively. AE management costs were determined from the CMS Inpatient prospective payment system based on reimbursements corresponding to the associated DRG codes. Results: LAN ($44,462) was found to be cost-saving versus alternatives when used post-OCT. OCT escalations to 30mg every 3 weeks, 40mg every 4 weeks, and its use with liver directed therapy were 2nd, 3rd, and 4th lowest cost treatment options ($52,873, $53,041, and $72,152, respectively); all three had higher drug acquisition and AE management costs. Drug acquisition costs for everolimus were more than twice those of LAN and for PRRT + OCT nearly 4 times that amount. GA-68 Dotatate PET/CT imaging greatly increased the monitoring costs of PRRT + OCT, which were $3,682 higher than the nearest alternative. Conclusions: LAN was the lowest cost treatment option over a 6-month interval for GEP-NET patients who progressed on OCT, however clinical appropriateness must be considered when transitioning patients. Evidence for the appropriate clinical strategy of sequencing of patients is still needed.