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Objective: Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways., Design and Methods: Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA)., Results: Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs., Conclusions: We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients., Competing Interests: Conflict of interest: J.C. has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA, Advanz Pharma, Amgen, Bayer, Esteve, Hutchmed, Ipsen, Merck, Novartis, Roche, Sanofi, Lilly, Eisai, Bayer, and ITM, and has received research support from Pfizer, Novartis, Astrazeneca, Eisai, AAA, Amgen, Bayer, Roche, Gilead, and ITM. M.B. reports Advisory from Novartis, Ipsen, and Pfizer. P.J.-F. has received speaker honoraria or consultant honoraria from Adacap, Astellas, BMS, Lilly, and MSD. D.C. has provided scientific advice and/or received honoraria or funding for continuous medical education from Janssen Oncology, Roche/Genetech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ipsen, BMS, MSD, Bayer, Lilly, Sanofi, Pierre Fabre, and Boerhinger. F.S. has received honoraria for medical education and research activity from Ipsen, Novartis, Pfizer, Advanced Accelerator Applications, MSD/Merck, and Hutchmed. A.T. has provided scientific advice and/or received honoraria from ADACAP, Ipsen, Novartis, and Pfizer. R.G.-C. has provided scientific advice and/or received honoraria or funding for continuous medical education from ADACAP, Advanz Pharma, Amgen, Bayer, BMS, Boerhinger, Esteve, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pierre Fabre, Roche, Servier, and Sanofi, and has received research support from Pfizer, BMS, and MSD. The remaining authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Purpose: There is an increasing interest in the role of sex and gender in cancer patients. The impact of sex differences in oncological systemic therapies is still unknown, and there is a lack of evidence specially in uncommon neoplasms like neuroendocrine tumours (NET). In the present study, we combine the differential toxicities by sex in five published clinical trials with multikinase inhibitors (MKI) in gastroenteropancreatic (GEP) NET., Methods: We performed a pooled univariate analysis of reported toxicity in patients treated in five phase 2 and phase 3 clinical trials with MKI in the GEP NET setting: sunitinib (SU11248, SUN1111), Pazopanib (PAZONET), sorafenib-bevacizumab (GETNE0801) and Lenvatinib (TALENT). Differential toxicities between male and female patients were evaluated considering relationship with study drug and different weights of each trial by random effect adjustment., Results: We found nine toxicities which were more frequent in female patients (leukopenia, alopecia, vomiting, headache, bleeding, nausea, dysgeusia, neutrophil count decreased and dry mouth) and two toxicities being more frequent in male patients (Anal Symptoms and Insomnia). Asthenia and diarrhoea were the only severe (Grade 3-4) toxicities more frequent in female patients., Conclusions: Sex-related differences in toxicity with the MKI treatment require targeted information and individualised management of patients with NET. Differential reporting of toxicity should be promoted when clinical trials are published., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jorge Hernando: Speakers Bureau: Angelini, Leo, Eisai, Adacap, Novartis, Pfizer, Advanz, Ipsen. Alejandro García-Alvarez: Speakers Bureau: Angelini. Travel/Accommodation, Expenses: Pfizer, Ipsen, EISAI, Advanz, AAA. Toni Ibrahim: Advisory board (Amgen, Galxosmithkline and Pharmamar). Cover Participation at scientific meeting (Istituto gentili and Pharmamar). Enrique Grande: EG has received honoraria for speaker engagements, advisory roles or funding of continuous medical education from Adacap, AMGEN, Angelini, Astellas, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi Genzyme, Servier, Taiho, and Thermo Fisher Scientific. EG has received research grants from Pfizer, AstraZeneca, Astellas, and Lexicon Pharmaceuticals. Eric Raymond: Consulting and Share holder for Genoscience Pharma, StromaCare, SCOR life science. Share Holder at Neuronax. Scientific and steering committee at Onward Therapeutics and BeiGen. Received travel grant for data presentation from BeiGen. Rocio Garcia-Carbonero: RGC has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA-Novartis, Advanz Pharma, Amgen, Bayer, BMS, Boerhinger, Esteve, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, PharmaMar, Pierre Fabre, Roche, Servier and Sanofi, and has received research support from Pfizer, BMS and MSD. Ramon Salazar: Invited speaker: Advanced Accelerator Applications, Amgen, Astellas, Bayer, BMS, Eisai, GSK, Janssen Oncology, Lilly, Pierre Fabre, Roche, Sanofi Genzyme. Expert testimony: AstraZeneca, Celgene, Merck, MSD, Novartis, Pfizer. Advisory Board: Agendia, Amgen, Ferrer, Guardant Health, Ipsen, Lilly, Merck, MSD, Novartis, Pfizer, Roche Diagnostic, Roche Farma, Tayhoo, VCN-BCN. Alex Teule: Speakers Bureau: AAA, Pfizer, Ipsen, Novartis, AstraZeneca. Travel, Accommodation, Expenses: AAA, Pfizer, Ipsen, Novartis, AstraZeneca. Salvatore Tafuto: S.Tafuto has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA-Novartis, Boerhinger, Ipsen, Merck, PharmaMar and has received research support from NOVARTIS, IPSEN. Vicente Alonso: VA has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA-Novartis, Amgen, Ipsen, Merck, Pierre Fabre, Roche, Servier and Sanofi. Daniel Castellano: Advisory role Lilly, Pierre Fabre, Boehringer Ingelheim, Roche/Genentech, AstraZeneca, Ipsen, Bayer, Sanofi, Janssen Oncology, Pfizer, Bristol Myers Squibb, Astellas Pharma, Novartis, MSD Oncology, Sanofi. The rest of the authors declare no conflict of interest for this publication., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with neuroendocrine tumours (NETs) need alternative therapies after failure of first-line therapy., Patients and Methods: This phase II trial evaluated lurbinectedin, a selective inhibitor of oncogenic transcription, at 3.2 mg/m 2 as a 1-h intravenous infusion every 3 weeks in 32 NETs patients treated in the second- or third-line setting. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1 assessed by the investigators. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety., Results: Two of 31 evaluable patients had confirmed partial responses (ORR = 6.5%; 95%CI, 0.8-21.4%). Median DoR was 4.7 months (95% CI, 4.0-5.4 months), median PFS was 1.4 months (95% CI, 1.2-3.0 months) and median OS was 7.4 months (95% CI, 3.4-16.2 months). Lurbinectedin showed an acceptable, predictable and manageable safety profile. The most common grade 3/4 toxicity was neutropenia (40.6%; grade 4, 12.4%; febrile neutropenia, 3.1%)., Conclusions: Considering the exploratory aim of this trial that evaluated a heterogeneous population of NETs patients, and the signs of antitumour activity observed (two confirmed partial responses and seven long disease stabilisations), further development of lurbinectedin is warranted in a more selected NETs population., Trial Registration Number: Sponsor Study Code: PM1183-B-005-14. EudraCT number: 2014-003773-42., Clinicaltrials: gov reference: NCT02454972., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cristian Fernández, Carmen Kahatt, Vicente Alfaro, Mariano Siguero and Ali Zeaiter are permanent employees of PharmaMar. Victor Moreno reports consulting fees from Roche, Bayer, BMS, Janssen and Basilea. Vivek Subbiah reports grants from Pharmamar, Eli Lilly/LOXO Oncology, Blueprint Medicines Corporation, Turning Point Therapeutics, Boston Pharmaceuticals; and grants from Helsinn Pharmaceuticals during the conduct of the study; in addition, Vivek Subbiah reports a grant and advisory board/consultant position with Eli Lilly/Loxo Oncology during the conduct of the study; research grants from Roche/Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, Pharmamar, Medimmune; an advisory board/consultant position with Helsinn, Incyte, QED Pharma, Daiichi-Sankyo, Signant Health, Novartis, Janssen, Relay Therapeutics, Roche, Medimmune; travel funds from Pharmamar, Incyte, ASCO, ESMO; other support from Medscape; all outside the submitted work. No disclosures were reported by the other authors., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Antitumor activity of the combination of somatostatin analogues (SSAs) and the mammalian target of rapamycin (mTOR) inhibitor everolimus in patients with neuroendocrine tumors (NETs) has been reported but not confirmed in prospective trials., Materials and Methods: This prospective, multicenter, single-arm phase II EVERLAR study evaluated everolimus 10 mg/day and the SSA octreotide 30 mg every 28 days in patients with advanced nonfunctioning well-differentiated gastrointestinal NETs (GI-NETs) that progressed in the last 12 months (ClinicalTrials.gov NCT01567488). Prior treatment with SSAs and any systemic or locoregional therapy was allowed except for mTOR inhibitors. Patients continued treatment until disease progression or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS) at 12 months; secondary endpoints included early biochemical response, objective response rate (ORR) by RECIST v1.0, overall survival (OS), AEs, activation of mTOR pathway (insulin-like growth factor 1 receptor [IGF1R] and phosphoS6 [pS6] expression)., Results: Forty-three patients were included in the intent-to-treat analyses. After 12 months of treatment, 62.3% (95% confidence interval [CI] 48%-77%) of patients had not progressed or died. The 24-month PFS rate was 43.6% (95% CI 29%-58%). The confirmed ORR was 2.3%, and stable disease was 58.1%. Median OS was not reached after 24 months of median follow-up. Dose reductions and temporary interruptions due to AEs were required in 14 (33%) and 33 (77%) patients, respectively. The most frequent AEs were diarrhea, asthenia, mucositis, rash, and hyperglycemia. No correlation was observed between IGFR1 and pS6 expression and PFS/OS., Conclusion: The everolimus-octreotide combination provided clinically relevant efficacy in nonfunctioning GI-NETs, similar to the results of RADIANT-2 in functioning setting., Implications for Practice: The EVERLAR study reports prospective data of somatostatin analogue in combination with everolimus in nonfunctioning gastrointestinal neuroendocrine tumors suggesting meaningful activity and favorable toxicity profile that supports drug combination in this setting., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Background: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a complex family of tumors of widely variable clinical behavior. The World Health Organization (WHO) 2010 classification provided a valuable tool to stratify neuroendocrine neoplasms (NENs) in three prognostic subgroups based on the proliferation index. However, substantial heterogeneity remains within these subgroups, and simplicity sometimes entails an ambiguous and imprecise prognostic stratification. The purpose of our study was to evaluate the prognostic impact of histological differentiation within the WHO 2010 grade (G) 1/G2/G3 categories, and explore additional Ki-67 cutoff values in GEP-NENs., Subjects, Materials, and Methods: A total of 2,813 patients from the Spanish National Tumor Registry (RGETNE) were analyzed. Cases were classified by histological differentiation as NETs (neuroendocrine tumors [well differentiated]) or NECs (neuroendocrine carcinomas [poorly differentiated]), and by Ki-67 index as G1 (Ki-67 <2%), G2 (Ki-67 3%-20%), or G3 (Ki-67 >20%). Patients were stratified into five cohorts: NET-G1, NET-G2, NET-G3, NEC-G2, and NEC-G3., Results: Five-year survival was 72%. Age, gender, tumor site, grade, differentiation, and stage were all independent prognostic factors for survival. Further subdivision of the WHO 2010 grading improved prognostic stratification, both within G2 (5-year survival: 81% [Ki-67 3%-5%], 72% [Ki-67 6%-10%], 52% [Ki-67 11%-20%]) and G3 NENs (5-year survival: 35% [Ki-67 21%-50%], 22% [Ki-67 51%-100%]). Five-year survival was significantly greater for NET-G2 versus NEC-G2 (75.5% vs. 58.2%) and NET-G3 versus NEC-G3 (43.7% vs. 25.4%)., Conclusion: Substantial clinical heterogeneity is observed within G2 and G3 GEP-NENs. The WHO 2010 classification can be improved by including the additive effect of histological differentiation and the proliferation index., Implications for Practice: Gastroenteropancreatic neuroendocrine neoplasms are tumors of widely variable clinical behavior, roughly stratified by the World Health Organization (WHO) 2010 classification into three subgroups based on proliferation index. Real-world data from 2,813 patients of the Spanish Registry RGETNE demonstrated substantial clinical heterogeneity within grade (G) 2 and G3 neuroendocrine neoplasms. Tumor morphology and further subdivision of grading substantially improves prognostic stratification of these patients and may help individualize therapy. This combined, additive effect shall be considered in future classifications of neuroendocrine tumors and incorporated for stratification purposes in clinical trials., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Interest in research on neuroendocrine tumors (NETs) has grown in the past 10 years, coinciding with improvements in our understanding of the molecular pathogenesis of NETs. In addition, NETs have become one of the most exciting settings for drug development. Two targeted agents for the management of advanced pancreatic NETs have been approved, but the development of targeted agents for NETs is limited by problems with both patient selection and demonstration of activity. In this review, we analyze these limitations and discuss ways to increase the predictive value of preclinical models for target discovery and drug development. The role of translational research and 'omics' methodologies is emphasized, with the final aim of developing personalized medicine. Because NETs usually grow slowly and metastatic tumors are found at easily accessible locations, and owing to improvements in techniques for liquid biopsies, NETs provide a unique opportunity to obtain tumor samples at all stages of the evolution of the disease and to adapt treatment to changes in tumor biology. Combining clinical and translational research is essential to achieve progress in the NET field. Slow growth and genetic stability limit and challenge both the availability and further development of preclinical models of NETs, one of the most crucial unmet research needs in the field. Finally, we suggest some useful approaches for improving clinical drug development for NETs: moving from classical RECIST-based response end points to survival parameters; searching for different criteria to define response rates (for example, antiangiogenic effects and metabolic responses); implementing randomized phase II studies to avoid single-arm phase II studies that produce limited data on drug efficacy; and using predictive biomarkers for patient selection.

Background: In a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib., Patients and Methods: In this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan-Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses., Results: Of 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1-20.6) months for sunitinib and 5.8 (3.8-7.2) months for placebo (HR, 0.32; 95% CI 0.18-0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6-56.4) months for sunitinib and 29.1 (16.4-36.8) months for placebo (HR, 0.73; 95% CI 0.50-1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib., Conclusions: BICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib., Trial Registration Number: NCT00428597., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs., Methods: This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated., Results: A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8-14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09-139.2; P = 0.042 and HR: 6.9; 95% CI 0.96-49.9; P = 0.055, respectively]., Conclusions: Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201)., Clinical Trial Number: NCT01280201., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors or antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine tumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice., Methods: This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted therapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical practice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected., Results: Of the 133 patients, with a median age of 59.4 (16-83) years, 70 (52.6%) patients were male, 64 (48.1%) had pancreatic NET, 23 (17.3%) had ECOG PS ≥ 2, 41 (30.8%) had functioning tumours, 63 (47.7%) underwent surgery of the primary tumour, 45 (33.8%) had received prior chemotherapy, and 115 (86.5%) had received prior SSAs. 115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations. Lanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations). The probability of being progression-free was 78.5% (6 months), 68.6% (12 months) and 57.0% (18 months) for patients who only received everolimus plus lanreotide (n = 57) and 89.3% (6 months), 73.0% (12 months), and 67.4% (18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus plus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was 25.8 months (95% CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving sunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted agent alone., Conclusions: The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities and suggests efficacy that should be explored in randomized prospective clinical trials.

Neuroendocrine tumors (NETs) are rare tumors that have been increasing in incidence over the last 30 years with no significant changes in survival. As survival of patients with these tumors depends greatly on stage and histology, early diagnosis, classification and staging of tumors in patients in whom NETs are suspected are of great importance. Surgery, either with curative or palliative intent, is the mainstay of treatment for localized NETs. Therapeutic options for this disease almost invariably include somatostatin analogs to alleviate the symptoms of excessive hormone secretion. Other approaches for advanced disease may include hepatic artery embolization or ablation, peptide receptor radionuclide therapy and systemic chemotherapy. Recent advances regarding the signaling pathways involved in tumor development have allowed the development of novel targeted therapies. However, due to the lack of prognostic molecular markers to identify high-risk patients and the absence of a common pathogenesis in all patients, treatment selection is often empirical. There is therefore a need to establish a consensus for the treatment of this disease and to provide evidence-based clinical recommendations and algorithms to optimize and individualize the treatment and follow-up for these patients.

The systemic management of patients with pancreatic neuroendocrine tumors includes chemotherapy and targeted agents such as everolimus and sunitinib. Which treatment to favor in a particular patient is not known. The most commonly used chemotherapy agents are streptozocin and temozolamide, often prescribed in combination with fluoropyrimidines. A potential biomarker for selection of temozolomide-based chemotherapy is O-6-methylguanine-DNA-methyltrasferase expression. Chemotherapy yields higher response rates and may be preferable in patients with higher-grade tumors and those who are symptomatic. The mammalian target of rapamycin inhibitor everolimus has shown improvement in progression-free survival (PFS) in a robust, well-conducted phase III study. Everolimus, however, can induce limiting toxicities that may result in treatment discontinuation and does not improve survival. However, the objective response rate is very low. Sunitinib, likewise, increases PFS but the data comes from a smaller trial which was terminated early. Sunitinib displays a different toxicity profile and is associated with a trend towards improved overall survival. It is clear that biomarkers to properly select the most effective agents in an individual patient are needed.

Background: Sorafenib and bevacizumab as single agents have shown efficacy and acceptable toxicity in NETs phase II trials. Sorafenib and bevacizumab combination has shown manageable toxicity in phase I trials in solid tumours. The purpose of this study was to evaluate the safety and efficacy of the combination of sorafenib and bevacizumab in patients with advanced neuroendocrine tumours., Methods: Open-label, uncontrolled, multicenter, phase II clinical trial., Eligibility Criteria: age ≥18 years, histologically confirmed measurable advanced NETs; 1 prior chemotherapy allowed; ECOG-PS 0-2. Patients were treated during 6 months and followed up for an additional 6 months., Treatment: sorafenib 200mg bid (days 1-5 of each week) and bevacizumab 5mg/kg once every 2 weeks (day 1, week 1). Tumour response was performed according to RECIST (v1.0) every 2 months during the treatment period. Adverse events were graded according to CTCAE (v3.0)., Findings: 44 Patients enrolled, 59.1% men, median age 60 years (range 32-76). 70.5% carcinoid tumours, 29.5% pancreatic tumour. Baseline target lesions mainly in the liver (86.4%). Global PFSR was 90.9% (91.7% carcinoid tumours and 88.9% pancreatic tumours). Median PFS was 12.4 months, median TTP was 14.5 months, ORR was 9.4% and DCR was 95.1%. Most common grade 3-4 toxicities: asthenia (11.4%) and hand-foot skin reaction (15.9%)., Interpretation: Sorafenib and bevacizumab combination showed clinical benefit but unfavourable safety results compared with drugs in monotherapy. Further development of this combination is not warranted and a sequential approach is recommended instead., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The molecular events of tumorigenesis in neuroendocrine tumors are poorly understood. Understanding of the molecular alterations will lead to the identification of molecular markers, providing new targets for therapeutics. The purpose of this review was to critically analyze the genetic abnormalities in neuroendocrine tumors, with the aim of identifying biomarkers that indicate a response to agents developed against these targets and to serve as an understanding for the combinations of different active compounds. Human epidermal growth factor receptor 1/2 (EGFR and HER2), vascular endothelial growth factor receptors, hepatocyte growth factor receptor (c-Met), platelet-derived growth factor receptor, insulin-like growth factor, phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway, and heat shock proteins are all interesting candidate biomarkers with involvement in carcinogenesis and tumor evolution of several neoplasms, including neuroendocrine tumors. Some of them have already been evaluated both as targets and also as biomarkers in clinical trials conducted in advanced neuroendocrine tumor settings, and others should encourage further investigations into innovative therapeutic opportunities.

Background: Somatostatin analogues (SSAs) are indicated to relieve carcinoid syndrome but seem to have antiproliferative effects on neuroendocrine tumours (NETs). This is the first prospective study investigating tumour stabilisation with the long-acting SSA lanreotide Autogel in patients with progressive NETs., Methods: This was a multicentre, open-label, phase II trial conducted in 17 Spanish specialist centres. Patients with well-differentiated NETs and radiologically confirmed progression within the previous 6 months received lanreotide Autogel, 120 mg every 28 days over ≤92 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, tumour biomarkers, symptom control, quality of life (QoL), and safety. Radiographic imaging was assessed by a blinded central radiologist., Results: Of 30 patients included in the efficacy and safety analyses, 40% had midgut tumours and 27% pancreatic tumours; 63% of tumours were functioning. Median PFS time was 12.9 (95% CI: 7.9, 16.5) months, and most patients achieved disease stabilisation (89%) or partial response (4%). No deterioration in QoL was observed. Nineteen patients (63%) experienced treatment-related adverse events, most frequently diarrhoea and asthenia; only one treatment-related adverse event (aerophagia) was severe., Conclusion: Lanreotide Autogel provided effective tumour stabilisation and PFS >12 months in patients with progressive NETs ineligible for surgery or chemotherapy, with a safety profile consistent with the pharmacology of the class., Trial Registration: ClinicalTrials.gov Identifier NCT00326469; EU Clinical Trial Register EudraCT no 2004-002871-18.

Introduction: Pancreatic neuroendocrine neoplasms (PNENs) are uncommon neoplasms with a wide spectrum of clinical behavior. The objective of this study was to assess in a large cohort of patients the relative impact of prognostic factors on survival., Methods: From June 2001 through October 2010, 1,271 patients were prospectively registered online (www.getne.org) at the Spanish National Cancer Registry for Gastroenteropancreatic Neuroendocrine Tumors (RGETNE) by participating centers. Clinical and histopathological features were assessed as potential prognostic factors by uni- and multivariate analyses., Results: Of 483 PNENs, 171 (35%) were functional (F) and 312 (65%) non-functional (NF). NF-PNENs were associated with a higher incidence of histological features denoting more aggressive disease, such as poor tumor differentiation, Ki-67 >20%, or vascular invasion (NF- vs. F-PNENs, respectively, p < 0.05). Nevertheless, functionality was not a significant predictor of survival (p = 0.19). Stage at diagnosis, Ki-67 index, tumor differentiation and surgical resection of the primary tumor were all significant prognostic factors in univariate analysis. However, Ki-67 (>20 vs. ≤2%) (hazard ratio (HR) 2.21, p = 0.01) and surgical resection (yes vs. no) (HR 0.92, p = 0.001) were the only independent predictors of survival in multivariate analysis. Among patients who underwent surgery, high Ki-67 index (HR 10.37, p = 0.02) and poor differentiation (HR 8.16, p = 0.03) were the only independent predictors of clinical outcome., Conclusion: Ki-67 index and tumor differentiation are key prognostic factors influencing survival of patients with PNENs and, in contrast to what it is observed for other solid malignancies, they seem to have a greater impact on survival than the extent of disease. This should be borne in mind by physicians in order to appropriately tailor therapeutic strategies and surveillance of these patients., (Copyright © 2013 S. Karger AG, Basel.)

Introduction: The incidence of colorectal neuroendocrine tumors (NETs) is increasing, and patients with this disease have particularly poor prognoses. Treatment options are limited, and survival times have not improved in the past decade., Methods: A post hoc analysis of the efficacy and tolerability of everolimus plus octreotide long-acting repeatable (LAR) was conducted in patients with colorectal NETs enrolled in the phase III RAD001 in Advanced Neuroendocrine Tumors, Second Trial (RADIANT-2) study. The primary endpoint (progression-free survival [PFS]), secondary endpoints (including objective response rate), and safety were assessed., Results: Patients with colorectal NETs receiving everolimus plus octreotide LAR had a significantly longer median PFS (29.9 months; n = 19) than did those receiving placebo plus octreotide LAR (6.6 months; n = 20). Everolimus plus octreotide LAR treatment also significantly reduced the risk for disease progression (hazard ratio: 0.34; 95% confidence interval: 0.13-0.89; p = .011). Although no objective responses were observed, tumor shrinkage was more frequently noted in the everolimus plus octreotide LAR arm than in the placebo plus octreotide LAR arm (67% vs. 37%, respectively). The combination of everolimus plus octreotide LAR was generally well tolerated by patients with colorectal NETs; rash and stomatitis were the most commonly reported adverse events., Conclusions: Everolimus plus octreotide LAR treatment had significant benefits and improved outcomes for patients with advanced colorectal NETs compared with placebo plus octreotide LAR treatment. Results of this exploratory analysis are consistent with those reported from the RADIANT-2 primary analysis. These findings support additional investigations of everolimus plus octreotide LAR in patients with colorectal NETs.

Neuroendocrine tumors (NETs) comprise a broad range of neoplasms that share biological and embryological origin. A deeper knowledge in the underlying molecular biology that results in the development and spread of NETs has allowed the use of novel-targeted therapies against angiogenesis and intracellular pathways, key checkpoints that govern growth, and proliferation of these tumors. Unfortunately, the possibility of cure is still far for patients with advanced stages. Cancer stem cells (CSCs) are present in most solid tumors. Nevertheless, there is limited evidence for the presence of CSCs in NETs. In this review, we will discuss the embryonic origin and possible existence of a gastroenteropancreatic neuroendocrine cancer stem cell. Here, we summarize the body of evidence supporting the presence of active embryological pathways like Notch, Wnt-β-catenin, Hedgehog, or transforming growth factor-β in NETs. New therapeutic approaches in the field of CSCs seem to have a clear role in the treatment of medulloblastomas and basal cell carcinomas, but their future value in other solid tumor types including NETs remains unclear.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) show limited sensitivity to cytotoxic agents, requiring the search for novel therapies. Recently, data from a phase III trial demonstrated that sunitinib produces a clinically significant improvement in progression-free survival in patients with unresectable, advanced, or metastatic GEP-NETs. Based on this finding, sunitinib became the first targeted drug approved for the treatment of GEP-NETs, paving the way for the approval of other anticancer agents in this drug-orphan disease. To date, results of trials involving other multitargeted tyrosine kinase inhibitors, such as sorafenib, the monoclonal antibody bevacizumab, and insulin-like growth factor 1 receptor inhibitors, have also shown promising results, and some are already being studied in phase III trials. This review updates the results of ongoing trials using inhibitors of growth factors and tyrosine kinase receptors involved in the carcinogenesis of GEP-NETs.

Neuroendocrine tumors (NETs) consist of a heterogeneous group of malignancies with various clinical presentations and growth rates. The incidence has been estimated to 2.5-5 per 100,000 people per year and prevalence of 35 per 100,000. The largest group is the gastroenteropancreatic NETs. Small intestinal NETs are the most common followed by pancreatic NETs in the gastrointestinal tract. A classification system (World Health Organization) was established in year 2000 and recently updated in 2010, taking into consideration the histopathology and tumor biology of the tumors. To further refine the classification a "tumor node metastasis" staging has been suggested by the European Neuroendocrine Tumor Society. The same organization has also proposed a grading system (G1, G2, and G3). The diagnosis of a NET is based on histopathology on tumor specimens, circulating biomarkers as well as imaging. Traditional radiology, such as computerized tomography and magnetic resonance imaging, is still the basis but is complemented with somatostatin receptor scintigraphy and positron emission tomography with specific isotopes such (68)Ga-DOTA-octreotate, F18-dopamine, or C11-5 hydroxytryptamine. Molecular imaging will increase in importance in the near future. There is still an unmet need for more sensitive biomarkers for diagnosis and follow-up.

In the last 30 years the incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has increased substantially. This could be partly due to improvements in diagnostic imaging, which lead to the incidental diagnosis of asymptomatic cases. However, despite these improvements, patients typically experience long delays before they are diagnosed. In this review, we discuss both the limitations and advances in our understanding of the pathogenesis, molecular and cellular biology, diagnosis, classification, staging, and treatment of GEP-NETs in order to identify which factors could be contributing to the delay in diagnosis and timely treatment of these patients. Within this context, the results from the most relevant clinical trials the available targeted therapies for the treatment of GEP-NETs, such as the "RAD001 in Advanced Neuroendocrine Tumors," will be discussed.

Background: Neuroendocrine tumors (NETs) are an unusual family of neoplasms with a wide and complex spectrum of clinical behavior. Here, we present the first report of a National Cancer Registry of gastroenteropancreatic neuroendocrine tumors from a Southern European country., Patients and Methods: Data was provided online at www.retegep.net by participating centers and assessed for internal consistency by external independent reviewers., Results: The study cohort comprised 907 tumors. The most common tumor types were carcinoids (55%), pancreatic nonfunctional tumors (20%), metastatic NETs of unknown primary (9%), insulinomas (8%) and gastrinomas (4%). Forty-four percent presented with distant disease at diagnosis, most often those from small intestine (65%), colon (48%), rectum (40%) and pancreas (38%), being most unusual in appendix primaries (1.3%). Stage at diagnosis varied significantly according to sex, localization of primary tumor, tumor type and grade. Overall 5-year survival was 75.4% (95% confidence interval 71.3% to 79.5%) and was significantly greater in women, younger patients and patients with hormonal syndrome and early stage or lower grade tumors. Prognosis also differed according to tumor type and primary tumor site. However, stage and Ki-67 index were the only independent predictors for survival., Conclusion: This national database reveals relevant information regarding epidemiology, current clinical practices and prognosis of NETs in Spain, providing valuable insights that may contribute to understand regional disparities in the incidence, patterns of care and survival of this heterogeneous disease across different continents and countries.