Combined Lanreotide Autogel and Temozolomide Treatment of Progressive Pancreatic and Intestinal Neuroendocrine Tumors: The Phase II SONNET Study.

BACKGROUND: In advanced neuroendocrine tumors (NET), antiproliferative treatment options beyond somatostatin analogs remain limited. Temozolomide (TMZ) has shown efficacy in NET alone or combined with other drugs. MATERIALS AND METHODS: SONNET (NCT02231762) was an open, multicenter, prospective, phase II study to evaluate lanreotide autogel 120 mg (LAN) plus TMZ in patients with progressive advanced/metastatic grade 1/2 gastroenteropancreatic (GEP) NET or of unknown primary. Patients could be enrolled at first-line or higher therapy line. The primary endpoint was disease control rate ([DCR], rate of stable disease [SD], partial [PR], and complete response [CR]) at 6 months of LAN and TMZ. Patients with nonfunctioning (NF) NET without progression at 6 months were randomized to 6-month LAN maintenance or watch and wait, patients with functioning (F)-NET with clinical benefit (PR, SD) continued on LAN. RESULTS: Fifty-seven patients were recruited. The majority of patients received the study drug at second or higher treatment line and had an NET G2. DCR at 6 months LAN and TMZ was 73.5%. After 6 months of further LAN maintenance, 54.5% of patients with F-NET and 71.4% with NF-NET had SD or PR vs 41.7% with NF-NET on observation only. LAN and TMZ were effective in all subgroups analyzed. At 12 months of follow-up, median progression-free survival was 11.1 months. Median serum chromogranin A decreased except in NF-NET on observation. O6-methylguanine DNA methyltransferase promoter methylation appeared to better reflect TMZ response than loss of gene expression. During combination therapy, the most frequent treatment-emergent adverse events grade 3/4 reported were nausea (14%), thrombocytopenia (12.3%), and neutropenia (8.8%). Four deaths were reported resulting from severe adverse events not considered related to study medication. CONCLUSIONS: LAN plus TMZ is a treatment option for patients with progressive GEP-NET with more aggressive biological profile showing a manageable safety profile.

PITX2 as a Sensitive and Specific Marker of Midgut Neuroendocrine Tumors: Results from a Cohort of 1157 Primary Neuroendocrine Neoplasms.

As neuroendocrine tumors (NETs) often present as metastatic lesions, immunohistochemical assignment to a site of origin is one of the most important tasks in their pathologic assessment. Because a fraction of NETs eludes the typical expression profiles of their primary localization, additional sensitive and specific markers are required to improve diagnostic certainty. We investigated the expression of the transcription factor Pituitary Homeobox 2 (PITX2) in a large-scale cohort of 909 NET and 248 neuroendocrine carcinomas (NEC) according to the immunoreactive score (IRS) and correlated PITX2 expression groups with general tumor groups and primary localization. PITX2 expression (all expression groups) was highly sensitive (98.1%) for midgut-derived NET, but not perfectly specific, as non-midgut NET (especially pulmonary/duodenal) were quite frequently weak or moderately positive. The specificity rose to 99.5% for a midgut origin of NET if only a strong PITX2 expression was considered, which was found in only 0.5% (one pancreatic/one pulmonary) of non-midgut NET. In metastases of midgut-derived NET, PITX2 was expressed in all cases (87.5% strong, 12.5% moderate), whereas CDX2 was negative or only weakly expressed in 31.3% of the metastases. In NEC, a fraction of cases (14%) showed a weak or moderate PITX2 expression, which was not associated with a specific tumor localization. Our study independently validates PITX2 as a very sensitive and specific immunohistochemical marker of midgut-derived NET in a very large collective of neuroendocrine neoplasms. Therefore, our data argue toward implementation into diagnostic panels applied for NET as a firstline midgut marker.

Clinical Features and Prognosis of Patients with Carcinoid Syndrome and Carcinoid Heart Disease: A Retrospective Multicentric Study of 276 Patients.

INTRODUCTION: Carcinoid syndrome is the most frequent functional syndrome of neuroendocrine neoplasia. It is characterized by flushing, diarrhea, wheezing, hypotension, and exanthema and may cause carcinoid heart disease. METHODS: We assessed clinical characteristics and prognosis of patients with carcinoid syndrome and carcinoid heart disease in 276 patients from 3 referral centers. RESULTS: Carcinoid syndrome patients had a mean age of 57 years (range 21-84) and a normal BMI of 24.9 (SD 4.5; range 13.8-39.6). Most primaries were of small bowel or unknown primaries with distant metastasis in 94.6%. Flushing was the most frequent symptom in 74.3% of patients, followed by diarrhea in 68.8%, and wheezing in 40.9%. Pain was described by 45.3%, weakness by 23.5%, and weight loss of >10% in 6 months by 30.1% of patients. Carcinoid heart disease was diagnosed in 37.3% of patients (n = 104) by echocardiography and involved predominantly in the tricuspid valve. Combinations with other valve defects were common. Somatostatin analogs were taken by 80.4% of patients and 17% needed additional loperamide/opium tincture. Surgery and peptide receptor radiotherapy were most frequent treatments. The median survival of patients with carcinoid syndrome after diagnosis was 9 years. Prognosis was significantly impaired by male sex and diagnosis of carcinoid heart disease but surprisingly significantly increased by the presence of symptoms flushing and weakness. DISCUSSION/CONCLUSION: Carcinoid syndrome is associated with extensive disease and primaries in small bowels or of unknown primary. Weight loss, weakness, and pain are frequent, and carcinoid heart disease is diagnosed in more than one-third of patients.

Localization Defines Streptozotocin/5-FU Response in Primary Pancreatic Neuroendocrine Tumours.

INTRODUCTION: Incidence of pancreatic neuroendocrine tumours (pNETs) is on the rise. The only curative treatment is surgical resection in localized or oligo-metastatic disease. However, patients may present with locally advanced or unresectable primary tumours. So far, no conversion therapy to achieve resectability has been established, which is partly due to lack of data on primary tumour response to therapies. Here, we specifically evaluate the primary tumour response to streptozocin/5-FU in a large cohort of metastatic pNET patients. METHODS: Five ENETS centres in Germany contributed 84 patients to the study cohort for retrospective analysis. RESULTS: Overall response rate (ORR) in primary tumours was 34% and disease control rate (DCR) 88%. ORR was different in metastases at 44% and DCR at 70%. Partial remission in primary tumours was more frequent among those located in pancreatic tail than that in pancreatic head (49% vs. 14%, p = 0.03). Correspondingly, metastases from tumours originating from pancreatic tail responded more frequently than metastases originating from pancreatic head (88.5% vs. 41.7%, p = 0.005). The median PFS of the primary tumours was longer than that in metastases (31 months vs. 16 months; p = 0.04). Considerable downsizing of the primary tumour was rare and occurred primarily in tumours located in the pancreatic tail. CONCLUSION: STZ/5-FU can achieve disease stabilization in a high proportion of metastatic pNET patients. In the majority of cases however it does not induce substantial downsizing of the primary tumour, thus possibly limiting its potential as conversion chemotherapy. Furthermore, the difference in response rate observed between different primary tumour locations warrants further exploration.

Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine?

Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. 'Targeted' treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in the poor prognosis NEN G3 group, though associated with acceptable response rates, only leads to short-term tumour control and their molecular biology requires delineation to provide new and more specific treatment options.The future requires an exploration of the NEN tumour genome, its microenvironment and an identification of critical oncologic checkpoints for precise drug targeting. In the advance to personalised medical treatment of patients with GEPNEN, clinical trials need to be based on mechanistic and multidimensional characterisation of each tumour in order to identify the therapeutic agent effective for the individual tumour.This review surveys advances in NEN research and delineates the current status of translation with a view to laying the basis for a genome-based personalised medicine management of advanced GEPNEN.

Ramucirumab in combination with dacarbazine in patients with progressive well-differentiated metastatic pancreatic neuroendocrine tumors (RamuNET): study protocol for a multicenter single-arm trial.

BACKGROUND: Cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs). However, response rates, side effects and outcome data strongly vary among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing and secondary resistances frequently occur. The RamuNET trial aims to identify the effectiveness of dual treatment with DTIC and ramucirumab in progressive advanced PNET patients. METHODS: The RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months. Patients with progressive well-differentiated and metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 months. Secondary endpoints include progression-free survival, biochemical response, overall survival, quality of life and toxicity. Based on the hypothesis that 80% of the patients can achieve a disease control after 6 months, the sample size calculation follows an exact binomial single-stage design. H0: p < =p0 = 60% versus H1: p > =p1 = 80%, alpha = 0.05, beta = 0.1. DISCUSSION: This study investigates a new therapeutic approach using the combination of cytotoxic and targeted antiangiogenic therapy in advanced PNET. If positive, this trial will be the basis for a randomized two-arm study to investigate the combination of ramucirumab and DTIC against other established therapies in PNET. TRIAL REGISTRATION: EudraCT: 2017-001207-68 . Date of registration: 2018.01.03.

Prognostic Factors in Curative Resected Locoregional Small Intestine Neuroendocrine Neoplasms.

BACKGROUND: Small intestinal neuroendocrine neoplasms (SI-NEN) are rare, and only about 40% of patients are diagnosed without distant metastases. Aim of the study was to identify prognostic factors in patients with potentially curative resected locoregional SI-NEN. METHODS: Patients with curative resected locoregional SI-NEN (ENETS stages I-III) were retrieved from a prospective data base. Demographic, surgical and pathological data of patients with and without disease recurrence were retrospectively analyzed using univariate and multivariate analysis. RESULTS: In a 20-year period, 65 of 203 (32%) patients with SI-NEN were operated for stages I-III disease. Thirty-eight (58.5%) patients were men, and the median age at surgery was 59 (range 37-87) years. After median follow-up of 65 months, 14 patients experienced disease relapse median 28.5 (range 6-122) months after initial surgery, of which 2 died due to their disease. Multivariate analysis revealed age ≥ 60 years (HR = 6.41, 95% CI 1.38-29.67, p = 0.017), tumor size ≥ 2 cm (HR = 26.54, 95% CI 4.46-157.62, p < 0.001), lymph node ratio > 0.5 (HR 7.18, 95% CI 1.74-29.74, p = 0.007) and multifocal tumor growth (HR = 6.98, 95% CI 1.66-29.39, p = 0.008) as independent negative prognostic factors and right hemicolectomy compared to segmental small bowel resection (HR = 0.04, 95% CI 0.01-0.24, p < 0.001) as independent protector against recurrence. CONCLUSION: Patients with locoregional SI-NEN with an age ≥ 60 years, tumor size ≥ 2 cm, lymph node ratio > 0.5 and multiple small bowel tumor foci have an increased risk for recurrence and might benefit from adjuvant treatment. In contrast, right hemicolectomy of ileal SI-NEN seems to reduce the risk of recurrence.

Surgery with Radical Intent: Is There an Indication for G3 Neuroendocrine Neoplasms?

BACKGROUND: While platinum-based chemotherapy represents the standard treatment for advanced grade 3 (G3) neuroendocrine neoplasms (NENs) according to the European Neuroendocrine Tumor Society guidelines, the role of radical-intended surgery in these patients, as well as the use of adjuvant chemotherapy, are still controversial. The aim of the present work is to describe, in a retrospective series of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) G3, the overall survival (OS) rate and risk factors for death after radical surgery. Secondary aims are the description of median recurrence-free survival (RFS) and of the role of adjuvant chemotherapy. PATIENTS AND METHODS: Multicenter analysis of a series of stage I-III GEP-NEN G3 patients receiving radical surgery (R0/R1) with/without adjuvant chemotherapy was performed. RESULTS: Sixty patients from eight neuroendocrine tumor (NET) referral centers, with median follow-up of 23 months (5-187 months) were evaluated. While 28.6% of cases had NET G3, 71.4% had neuroendocrine carcinoma G3 (NEC G3). The 2-year OS rate after radical surgery was 64.5%, with a statistically significant difference in terms of Ki67 threshold (cut-off 55%, P = 0.03) and tumor differentiation (NEC G3 vs. NET G3, P = 0.03). Median RFS after radical surgery was 14 months, and 2-year RFS rate was 44.9%. Use of adjuvant chemotherapy provided no benefit in terms of either OS or RFS in this series. CONCLUSIONS: Surgery with radical intent might represent a valid option for GEP-NEN G3 patients with locoregional disease, especially with Ki67 value ≤ 55%.

Recent Survival Trends in High-Grade Neuroendocrine Neoplasms and Lung Cancer.

BACKGROUND: Poorly differentiated neuroendocrine neoplasms (pdNEN) are a rare cancer entity, treatment of which is to a great part informed by studies on the much more common small-cell lung cancer (SCLC). OBJECTIVE: To reveal and compare recent survival trends for pdNEN and SCLC in an authorative, population-based database. METHODS: Using the Surveillance, Epidemiology, and End Results 18 database, 3,482 digestive tract pdNEN and 30,383 SCLC diagnosed from 2000 through 2015 were analyzed in detail. RESULTS: Whereas changes in one- and 2-year relative survival in pdNEN were small, improvements in median survival appeared consistent and relevant. For example, median survival (95% CI) for distant disease pdNEN diagnosed in 2000-2004, 2005-2009, and 2010-2015 was 4.6 (3.8-5.4), 5.6 (4.5-6.7), and 6.4 (5.4-7.5) months. Changes in SCLC survival during the study period overall were even more limited, which - in the case of distant disease - meant that survival disadvantages of patients with pdNEN as compared to SCLC disappeared during the study period. Unfortunately, relevant improvements in year-wise conditional survival after the first year since diagnosis essentially were restricted to localized pdNEN and localized SCLC. CONCLUSIONS: Our results should stipulate further research, in particular, of the pdNEN-SCLC relationship. They will also be helpful in patient care and communication, providing the first conditional survival details in this context, a highly patient-relevant outcome.

Placenta-Specific 8 Is Overexpressed and Regulates Cell Proliferation in Low-Grade Human Pancreatic Neuroendocrine Tumors.

BACKGROUND/AIMS: Many aspects of the biology of pancreatic neuroendocrine tumors (PanNETs), including determinants of proliferative, invasive, and metastatic potential, remain poorly understood. Placenta-specific 8 (PLAC8), a gene with unknown molecular function, has been reported to have tumor-promoting roles in different human malignancies, including exocrine pancreatic cancer. Since preliminary data suggested deregulation of PLAC8 expression in PanNET, we have performed detailed analyses of PLAC8 expression and function in human PanNET. METHODS: Primary tissue from PanNET patients was immunohistochemically stained for PLAC8, and expression was correlated with clinicopathological data. In vitro, PLAC8 expression was inhibited by siRNA transfection in PanNET cell lines and effects were analyzed by qRT-PCR, Western blot, and proliferation assays. RESULTS: We report that PLAC8 is expressed in the majority of well-differentiated human PanNETs, predominantly in early-stage and low-grade tumors. SiRNA-mediated knockdown of PLAC8 in PanNET cells resulted in decreased proliferation and viability, while apoptosis was not induced. Mechanistically, these effects were mediated by attenuation of cell cycle progression, as Western blot analyses demonstrated upregulation of the tumor suppressor p21/CDKN2A and downregulation of the cell cycle regulator Cyclin D1 as well as reduced levels of phosphorylated ribosomal protein s6 and retinoblastoma protein. CONCLUSION: Our findings establish PLAC8 as a central mediator of cell growth in a subset of human PanNET, providing evidence for the existence of distinct molecular subtypes within this class of tumors.

Long-term outcome of surgical resection in patients with gastroenteropancreatic neuroendocrine neoplasia: results from a German nation-wide multi-centric registry.

BACKGROUND: Neuroendocrine neoplasia (NEN) are rare and heterogenous tumours. Few data exist on the impact of surgical therapy. MATERIALS AND METHODS: This is a retrospective analysis of prospectively collected data of gastroenteropancreatic NEN in the German NET-Registry (1999-2012). It focuses on patients without distant metastases (limited disease, LD, stage I-IIIB). RESULTS: Data of 2239 patients with NEN were recorded. Median age was 59 years, the gender ratio was 1:1.3 (f:m). A total of 986 patients (44%) had LD, and the 5-year survival rate (5 years) was 77% for all and 90% for patients with LD. A total of 1635 patients (73%) received a surgical therapy (1st to 6th line); the 5 and 10 ysr were 83/65% after and 59/35% without surgery for all patients (p < .001). The resection margins in the LD patients were 76%, 16%, and 3% for R0, R1 and R2, respectively. The 10 ysr was 84%, 59% and 42% for R0, R1 and R2 resections, respectively (p = .021 R0/R1, p < .001 R0/R2). The R0 resection rate was 75% for G1/G2 NET and 67% for G3 NEC. CONCLUSION: The rate of complete tumour resection (R0) in LD is independent of tumour grading, and R0 resection is the key determinant of long-term survival, as demonstrated by the 10 ysr. of 84%. All NEN patients with limited disease should be considered for operation, if possible, as the best 10-year survival is shown after an R0 resection.

Brain metastases in patients with neuroendocrine neoplasms: risk factors and outcome.

BACKGROUND: Brain metastases (BM) are rarely reported in patients with neuroendocrine carcinoma (NEC) of non-lung origin and neuroendocrine tumors (NET) of the gastroenteropancreatic (GEP) or bronchopulmonary system. However, symptomatic brain metastases are associated with dismal prognosis, so early detection and treatment could be advisable. METHODS: We retrospectively analyzed 51 patients with GEP-NEN and bronchopulmonary NEN excluding small cell lung cancer. All patients were treated at the University Hospital Marburg and Halle (Saale) between 2000 and 2017. The median overall survival (mOS) and mOS after diagnosis of brain metastases (BM) were calculated using Kaplan-Meier analysis. Risk factors for poor prognosis were evaluated using univariate and multivariate Cox regression method. RESULTS: Overall, 51 patients with a median age of 58 years presented BM. Lung (n = 23, 45.1%) was the most frequent primary localization. Most patients had NEC (n = 31, 60.8%), including 26 carcinomas (51%) with Ki-67 indices > 55%. Singular BM were present in 16 patients (31.4%), but 21 patients (41.2%) had multiple lesions. Overall, the median period from first diagnosis of the tumor disease up to diagnosis of brain metastasis was 5.0 months. Palliative radiation was the most common therapy (n = 31, 60.8%). Median OS after initial diagnosis and diagnosis of BM was 23.0 and 11.0 months, respectively. Univariate and multivariate analysis for prognostic indicators depicted differentiation (NEC HR 4.2, 95% CI 1.1-16.1) and age (≥60 HR 3.0, 95% CI 1.2-7.5) as markers for poor outcome. CONCLUSIONS: Overall, the risk for symptomatic brain metastases is low in GEP-NEN and bronchopulmonary NEN patients. Age above 60 and poor tumor differentiation may deteriorate the overall survival. Therefore, screening for brain metastases could be advisable in NEC patients.

Health-Related Quality of Life for Long-Acting Octreotide versus Placebo in Patients with Metastatic Midgut Neuroendocrine Tumors in the Phase 3 PROMID Trial.

BACKGROUND: In the phase IIIb PROMID study, octreotide long-acting significantly extended time to tumor progression compared with placebo in treatment-naïve patients with well-differentiated metastatic midgut neuroendocrine tumors. We report post hoc analyses for health-related quality of life (HRQoL). METHODS: HRQoL was measured with EORTC QLQ-C30, a 30-item self-report questionnaire (5 functional, 1 global, 9 symptom scales). Assessments were completed at baseline and every 12 weeks until tumor progression. Time to definitive deterioration (TDD; worsening of ≥10 points without further improvement) was analyzed with the Kaplan-Meier method. Linear mixed models were fit to assess change from baseline in QLQ-C30 scores by treatment arm over time. RESULTS: Among 85 patients, 82 (96%) completed the QLQ-C30 at baseline. There were few events of definitive deterioration for many scales. Significantly longer TDD was reported for long-acting octreotide versus placebo for fatigue (median 18.5 months vs. 6.8; p = 0.0006), pain (not reached [NR] vs. 18.2; p = 0.0435) and insomnia (NR vs. 16.4; p = 0.0046). Change from baseline to week 24 fatigue scores were stable for long-acting octreotide (mean 0.78; 95% CI -6.3 to 7.8) but worsened for placebo (mean 9.1; 95% CI 1.9-16.4), and for diarrhea there were improvements for long-acting octreotide (mean -8.0; 95% CI -19.6 to 3.5) and worsening for placebo (mean 11.2; 95% CI -0.7 to 23.1). CONCLUSIONS: HRQoL was maintained with few deteriorations in long-acting octreotide patients, whereas there was earlier and/or more deterioration in placebo patients. In long-acting octreotide patients, HRQoL was maintained or improved for the clinically important neuroendocrine tumor symptoms such as fatigue, insomnia, diarrhea and pain, whereas placebo patients experienced a deterioration of HRQoL scores for these symptoms.

Unmet Needs in Appendiceal Neuroendocrine Neoplasms.

Appendiceal neuroendocrine neoplasms (ANEN) are mostly discovered coincidentally during appendicectomy and usually have a benign clinical course; thus, appendicectomy alone is considered curative. However, in some cases, a malignant potential is suspected, and therefore additional operations such as completion right hemicolectomy are considered. The existing European Neuroendocrine Tumour Society (ENETS) guidelines provide useful data about epidemiology and prognosis, as well as practical recommendations with regards to the risk factors for a more aggressive disease course and the indications for a secondary operation. However, these guidelines are based on heterogeneous and retrospective studies. Therefore, the evidence does not seem to be robust, and there are still unmet needs in terms of accurate epidemiology and overall prognosis, optimal diagnostic and follow-up strategy, as well as identified risk factors that would indicate a more aggressive surgical approach at the beginning and a more intense follow-up. In this review, we are adopting a critical approach of the ENETS guidelines and published series for ANEN, focusing on the above-noted "grey areas".

Unmet Needs in Functional and Nonfunctional Pancreatic Neuroendocrine Neoplasms.

Recently, the European Neuroendocrine Tumor Society (ENETS) held working sessions composed of members of the advisory board and other neuroendocrine neoplasm (NEN) experts to attempt to identify unmet needs in NENs in different locations or with advanced/poorly differentiated NENs. This report briefly summarizes the main proposed areas of unmet needs in patients with functional and nonfunctional pancreatic NENs.

Therapeutic targeting of tumor-associated macrophages in pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PNETs) represent a heterogeneous group of neuroendocrine neoplasms with varying biological behavior and response to treatment. Although targeted therapies have been shown to improve the survival for patients at advanced stage, resistance to current therapies frequently occurs during the course of therapy. Previous reports indicate that the infiltration of tumor-associated macrophages (TAMs) in PNETs might correlate with tumor progression and metastasis formation. We aimed to evaluate the prognostic and functional impact of TAMs in human PNETs in vitro and in vivo and to investigate the effect of therapeutic targeting TAMs in a genetic PNET mouse model. TAM expression pattern was assessed immunohistochemically in human PNET tissue sections and a tissue-micro-array of PNET tumors with different functionality, stage, and grading. The effect of liposomal clodronate on TAM cell viability was analyzed in myeloid cell lines and isolated murine bone macrophages (mBMM). In vivo, RIP1Tag2 mice developing insulinomas were treated with liposomal clodronate or PBS-Liposomes. Tumor progression, angiogenesis and immune cell infiltration were assessed by immunohistochemistry. In human, insulinomas TAM density was correlated with invasiveness and malignant behavior. Moreover, TAM infiltration in liver metastases was significantly increased compared to primary tumors. In vitro, Liposomal clodronate selectively inhibited the viability of myeloid cells and murine bone macrophages, leaving PNET tumor cell lines largely unaffected. In vivo, repeated application of liposomal clodronate to RIP1Tag2 mice significantly diminished the malignant transformation of insulinomas, which was accompanied by a reduced infiltration of F4/80-positive TAM cells and simultaneously by a decreased microvessel density, suggesting a pronounced effect of clodronate-induced myeloid depletion on tumor angiogenesis. Concomitant treatment with the antiangiogenic TKI sunitinib, however, did not show any synergistic effects with liposomal clodronate. TAMs are crucial for malignant transformation in human PNET and correlate with metastatic behavior. Pharmacological targeting of TAMs via liposomal clodronate disrupts tumor progression in the RIP1Tag2 neuroendocrine tumor model and was associated with reduced tumor angiogenesis. Based on these results, using liposomal clodronate to target proangiogenic myeloid cells could be employed as novel therapeutic avenue in highly angiogenic tumors such as PNET.

Bone Metastases in Patients with Neuroendocrine Neoplasm: Frequency and Clinical, Therapeutic, and Prognostic Relevance.

BACKGROUND: The incidence and prevalence of neuroendocrine neoplasms (NEN) are rising. In view of continuously improving imaging techniques, more than half of the patients present with distant metastases at initial diagnosis. An advanced disease stage negatively correlates with the 5-year survival rate. In stage IV disease, bone metastases (BM) are frequent, yet knowledge concerning their clinical or prognostic relevance is rare. This study presents a single-center experience on the frequency and management of BM in patients with gastroenteropancreatic NEN and lung carcinoids. METHODS: Between 2000 and June 2015, 327 of 677 patients treated in the European Neuroendocrine Tumor Society (ENETS) center in Marburg (Germany) presented with distant metastases (48.3%), including 85 patients (12.6%) with BM. Data of both groups were analyzed using descriptive statistics. Overall survival was assessed by Kaplan-Meier curves and compared by log-rank test. RESULTS: Median age in the BM group was 54.9 years, the small intestine and the pancreas being the most common primaries. 83.5% of the tumors were well and moderately differentiated (G1/G2). Nearly half of the patients with BM were symptomatic and suffered either from pain (42.4%) or had fractures (11.7%). Bisphosphonates were employed in almost two-thirds of the patients, radiation therapy in 25.9%. Overall survival was significantly inferior in patients with BM than in those with other distant metastases (p = 0.01; 49.0 vs. 100.8 months). CONCLUSION: BM appear to have a significant clinical and prognostic impact. Further studies are needed to evaluate therapeutic approaches directed to the treatment of BM in particular for asymptomatic patients.

Stage IV Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: A Risk Score to Predict Clinical Outcome.

BACKGROUND: Several risk factors predict clinical outcome in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs); however, the impact of their combination has not been investigated so far. PATIENTS AND METHODS: A retrospective analysis of stage IV GEP-NENs was performed. Multivariate analysis for progression of disease (PD) was performed by Cox proportional hazards method to obtain a risk score. Area under the curve obtained by receiver operating characteristic analysis was used to assess the score performance. Progression-free survival analysis was performed by Kaplan-Meier method. RESULTS: Two hundred eighty-three stage IV GEP-NENs were evaluated, including 93 grade 1 neuroendocrine tumors (32.9%), 153 grade 2 neuroendocrine tumors (54%), and 37 grade 3 neuroendocrine carcinomas (13.1%). Independent risk factors for PD were Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The risk score was calculated as follows: (0.025 × Ki67) + [(0 if no liver metastases or liver involvement <25%) OR (0.405 if liver involvement 25%-50%) OR (0.462 if liver involvement >50%)] + [(0 if no extra-abdominal metastases) OR (0.528 if extra-abdominal metastases present)]. The risk score accuracy to predict PD was superior compared with the G grading system (area under the curve: 0.705 and 0.622, respectively). Three subgroups of patients with low, intermediate, and high risk of PD according to risk score were identified, median progression-free survival being 26 months, 19 months, and 12 months, respectively. CONCLUSION: In stage IV GEP-NENs, a risk score able to predict PD was obtained by combining Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The score may help to discriminate patients with different progression risk level to plan tailored therapeutic approaches and follow-up programs. The Oncologist 2017;22:409-415Implications for Practice: Clinical outcome of patients with advanced gastro-entero-pancreatic neuroendocrine neoplasms is affected by several risk factors, including the proliferative index Ki67, extension of liver metastases, and the presence of distant extra-abdominal lesions. A risk score that combines these variables may help physicians dealing with these diseases to plan the optimal therapeutic approach and follow-up program.

Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival.

BACKGROUND: Somatostatin analogs have been shown to control the growth of well-differentiated metastatic neuroendocrine tumors. Their effect on overall survival is a matter of debate. We analyzed the prognostic significance of early treatment with octreotide LAR and of hepatic tumor load in the PROMID trial cohort. PATIENTS AND METHODS: Between 2001 and 2008, 85 treatment-naïve patients were randomly assigned to monthly octreotide LAR 30 mg or placebo until tumor progression or death. Post-study treatment was at the discretion of the investigator. Upon disease progression, 38 out of 43 placebo patients (88.4%) received octreotide LAR. For survival, patients were followed until May 2014. RESULTS: Forty-eight out of 85 patients (56.5%) died. In 38 patients (79.2%), death was tumor related. The median overall survival (84.7 and 83.7 months) was only slightly different in patients assigned to octreotide and placebo [HR = 0.83 (95% CI: 0.47-1.46); p = 0.51]. The median overall survival was 84.7 months for all 85 patients, 107.6 months in the low-tumor-load (n = 64) and 57.5 months in the high-tumor-load (n = 21) subgroups [HR = 2.49 (95% CI: 1.36-4.55); p = 0.002]. There was a trend towards improved overall survival in patients with a low hepatic tumor load receiving octreotide compared to placebo ['median not reached' and 87.2 months; HR = 0.59 (95% CI: 0.29-1.2); p = 0.142]. CONCLUSION: The extent of tumor burden is a predictor for shorter survival. Overall survival was similar in patients receiving octreotide LAR or placebo treatment at randomization. Crossover of the majority of placebo patients to octreotide LAR may have confounded the data on overall survival.

Neuroendocrine Cancer, Therapeutic Strategies in G3 Cancers.

BACKGROUND: According to the latest WHO classification, neuroendocrine neoplasm (NEN) G3 of the gastrointestinal tract is defined by a proliferation index Ki67 above 20%. Gastrointestinal neuroendocrine carcinoma (NEC) is a rare and highly aggressive malignancy and despite responsiveness to chemotherapy, overall survival is poor. In the last 3-4 years, the heterogeneity of the NEN G3 group has become evident. SUMMARY: In addition to the proliferative activity, the tumour differentiation seems to play a major role, further dividing the NEN G3 group into neuroendocrine tumour (NET) G3 and NEC. NET G3 often arise in the pancreas, and their median proliferation rate is lower and prognosis is better as compared to NEC. However, NET G3 show a limited response to platinum-based chemotherapy. Lack of specific data for NET G3 hampers clear therapeutic recommendations. Cisplatin combined with etoposide is the established standard regimen for advanced gastrointestinal NEC. Substituting carboplatin for cisplatin or irinotecan for etoposide is considered alternative first-line regimen. There is no standard second-line treatment; options are discussed within this review. KEY POINTS: (1) In NEN G3, the distinction between NET G3 and NEC G3 is clinically and prognostically meaningful. (2) Platinum-based chemotherapy remains the recommended first-line treatment in metastasized NEC patients. (3) There is no established standard for NET G3; treatments established for NET G2 such as temozolomide-based chemotherapy or peptide receptor radiotherapy may be considered. (4) Specific trials for NET G3 are necessary. (5) New therapies for NEC are urgently needed. Checkpoint inhibitors should be evaluated.