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Pancreatic Neoplasms: HELP
Articles by Nicola Fazio
Based on 41 articles published since 2009
(Why 41 articles?)
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Between 2009 and 2019, N. Fazio wrote the following 41 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline None 2018

Grimaldi, Franco / Fazio, Nicola / Attanasio, Roberto / Frasoldati, Andrea / Papini, Enrico / Cremonini, Nadia / Davi, Maria V / Funicelli, Luigi / Massironi, Sara / Spada, Francesca / Toscano, Vincenzo / Versari, Annibale / Zini, Michele / Falconi, Massimo / Oberg, Kjell. ·Endocrinology and Metabolic Disease Unit, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumor, European Institute of Oncology, Milan, Italy. · Endocrinology Service, Galeazzi Institute IRCCS, Milan, Italy. · Endocrinology Unit, Azienda Ospedaliera S. Maria Nuova IRCCS, Reggio Emilia, Italy. · Department of Endocrinology and Metabolic Diseases, Regina Apostolorum Hospital, Albano Laziale (Rome), Italy. · Endocrinology Clinics, Clinica Villalba, Bologna, Italy. · Section of Endocrinology, Medicina Generale e Malattie Aterotrombotiche e Degenerative, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · Division of Radiology, European Institute of Oncology, Milan, Italy. · Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. · Endocrinology, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy. · Nuclear Medicine Unit, Azienda Ospedaliera S. Maria Nuova IRCCS, Reggio Emilia, Italy. · Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Vita e Salute University, Milan, Italy. · Department of Endocrine Oncology, University Hospital, Uppsala, Sweden. ·Endocr Metab Immune Disord Drug Targets · Pubmed #29237387.

ABSTRACT: Well-established criteria for evaluating the response to treatment and the appropriate followup of individual patients are critical in clinical oncology. The current evidence-based data on these issues in terms of the management of gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are unfortunately limited. This document by the Italian Association of Clinical Endocrinologists (AME) on the criteria for the follow-up of GEP-NEN patients is aimed at providing comprehensive recommendations for everyday clinical practice based on both the best available evidence and the combined opinion of an interdisciplinary panel of experts. The initial risk stratification of patients with NENs should be performed according to the grading, staging and functional status of the neoplasm and the presence of an inherited syndrome. The evaluation of response to the initial treatment, and to the subsequent therapies for disease progression or recurrence, should be based on a cost-effective, risk-effective and timely use of the appropriate diagnostic resources. A multidisciplinary evaluation of the response to the treatment is strongly recommended and, at every step in the follow-up, it is mandatory to assess the disease state and the patient performance status, comorbidities, and recent clinical evolution. Local expertise, available technical resources and the patient preferences should always be evaluated while planning the individual clinical management of GEP-NENs.

2 Review Systemic therapies in patients with advanced well-differentiated pancreatic neuroendocrine tumors (PanNETs): When cytoreduction is the aim. A critical review with meta-analysis. 2018

Pozzari, Marta / Maisonneuve, Patrick / Spada, Francesca / Berruti, Alfredo / Amoroso, Vito / Cella, Chiara Alessandra / Laffi, Alice / Pellicori, Stefania / Bertani, Emilio / Fazio, Nicola. ·Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy. · Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Milan, Italy. · Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia at ASST Spedali Civili, Brescia, Italy. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. · Division of Gastrointestinal Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy. Electronic address: nicola.fazio@ieo.it. ·Cancer Treat Rev · Pubmed #30352319.

ABSTRACT: INTRODUCTION: Cytoreduction is sometimes an important aim of systemic anti-tumor therapies in well-differentiated pancreatic neuroendocrine tumors (PanNETs). As there is not a gold standard treatment for these tumors in this field, we conducted a literature review in order to identify objective criteria for treatment choice. MATERIALS AND METHODS: We critically reviewed and performed a meta-analysis of all published clinical studies of systemic therapies in patients with well-differentiated unresectable PanNETs, selecting only those articles which reported tumor shrinkage (TS) with a waterfall plot (WP). Tumor downsizing of ≥10% was considered as objective response. RESULTS: We selected 17 out of 2758 studies, comprising 1118 patients with tumor response reported as WP. Proliferation index, tumor burden and anti-tumor therapies were heterogeneous. Chemotherapy alone (mainly, capecitabine/temozolomide) or in combination showed the best results, with ≥10% TS ranging from 65% to 93%. Peptide receptor radionuclide therapy combined with chemotherapy (Chemo-PRRT) and sunitinib appeared promising by inducing objective response in a significant proportion of patients (93% and 60%, respectively). Time to tumor response was reported in only two trials. No clear clinical and/or biological predictive factors emerged. CONCLUSION: Based on response criteria used in our retrospective analysis, systemic chemotherapy alone or in combination appeared to have the main cytoreductive impact. However no conclusions regarding either a specific regimen or combination can be drawn. Furthermore, tumor population selection and/or choice of regimen may have a significant influence. Further analysis should be also conducted to identify potential predictive biomarkers of responses, in order to design future prospective interventional clinical trials enrolling more homogenous populations of advanced well-differentiated PanNETs.

3 Review Biology and Systemic Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors. 2018

Raj, Nitya / Fazio, Nicola / Strosberg, Jonathan. ·From the Division of Solid Tumor Oncology, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY; Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy; Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL. ·Am Soc Clin Oncol Educ Book · Pubmed #30231344.

ABSTRACT: In recent years, there have been important scientific advances in the biologic characterization of neuroendocrine neoplasms and in their treatment. This review will describe these scientific advances, the evolving systemic treatment approaches, and important topics to be addressed in future research.

4 Review Predictive Markers of Response to Everolimus and Sunitinib in Neuroendocrine Tumors. 2017

Martins, Diana / Spada, Francesca / Lambrescu, Ioana / Rubino, Manila / Cella, Chiara / Gibelli, Bianca / Grana, Chiara / Ribero, Dario / Bertani, Emilio / Ravizza, Davide / Bonomo, Guido / Funicelli, Luigi / Pisa, Eleonora / Zerini, Dario / Fazio, Nicola / Anonymous5180910. ·Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, 20141 via Ripamonti, 435, Milan, Italy. · Division of Otolaryngology-Head and Neck Surgery, European Institute of Oncology, IEO, Milan, Italy. · Division of Nuclear Medicine, European Institute of Oncology, IEO, Milan, Italy. · Division of Hepatobiliopancreatic Surgery, European Institute of Oncology, IEO, Milan, Italy. · Division of Endoscopy, European Institute of Oncology, IEO, Milan, Italy. · Division of Interventional Radiology, European Institute of Oncology, IEO, Milan, Italy. · Division of Radiology, European Institute of Oncology, IEO, Milan, Italy. · Division of Pathology, European Institute of Oncology, IEO, Milan, Italy. · Division of Radiotherapy, European Institute of Oncology, IEO, Milan, Italy. · Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, 20141 via Ripamonti, 435, Milan, Italy. nicola.fazio@ieo.it. ·Target Oncol · Pubmed #28634872.

ABSTRACT: Neuroendocrine tumors (NETs) represent a large and heterogeneous group of malignancies with various biological and clinical characteristics, depending on the site of origin and the grade of tumor proliferation. In NETs, as in other cancer types, molecularly targeted therapies have radically changed the therapeutic landscape. Recently two targeted agents, the mammalian target of rapamycin inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have both demonstrated significantly prolonged progression free survival in patients with advanced pancreatic NETs. Despite these important therapeutic developments, there are still significant limitations to the use of these agents due to the lack of accurate biomarkers for predicting tumor response and efficacy of therapy. In this review, we provide an overview of the current clinical data for the evaluation of predictive factors of response to/efficacy of everolimus and sunitinib in advanced pancreatic NETs. Surrogate indicators discussed include circulating and tissue markers, as well as non-invasive imaging techniques.

5 Review Critical focus on mechanisms of resistance and toxicity of m-TOR inhibitors in pancreatic neuroendocrine tumors. 2017

Antonuzzo, L / Del Re, M / Barucca, V / Spada, F / Meoni, G / Restante, G / Danesi, R / Di Costanzo, F / Fazio, N. ·S.C. Oncologia Medica 1, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; Medical Genetics, University of Siena, Siena, Italy. Electronic address: lorenzo.antonuzzo@gmail.com. · Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. · Division of Medical Oncology, Misericordia General Hospital, Grosseto, Italy. · Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy. · S.C. Oncologia Medica 1, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy. ·Cancer Treat Rev · Pubmed #28535439.

ABSTRACT: Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms representing less than 2% of all pancreatic malignancies. The PI3K-AKT-mTOR pathway is often deregulated in pNETs and seems to play a key role in tumorigenesis. Everolimus, an inhibitor of the mTOR pathway, has demonstrated efficacy in the treatment of pNETs. Nevertheless de novo or acquired drug resistance is responsible for disease progression and represents a major obstacle to overcome by clinicians. Blocking the PI3K/AKT/mTOR pathway may cover the supposed main mechanisms of resistance to everolimus. Therefore, BEZ-235, a potent oral dual PI3K/mTOR inhibitor was investigated in clinical trials. Globally more than 250 patients with different types of solid tumors were treated. Two studies were conducted in pNETs with BEZ-235 as single agent. The former was a phase 2 trial conducted in pNETs resistant to everolimus while the latter a randomized trial comparing everolimus and BEZ-235. Unfortunately, both the studies disappointed the expectations and were prematurely halted mainly due to severe toxicity. On this basis we reviewed m-TOR inhibitors in pNETs, focusing on their mechanisms of resistance and toxicity.

6 Review Heterogeneity of grade 3 gastroenteropancreatic neuroendocrine carcinomas: New insights and treatment implications. 2016

Fazio, Nicola / Milione, Massimo. ·Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy. Electronic address: nicola.fazio@ieo.it. · 1(st) Division of Pathology, Department of Pathology and Laboratory Medicine, IRCCS Foundation National Cancer Institute, Milan, Italy. Electronic address: massimo.milione@istitutotumori.mi.it. ·Cancer Treat Rev · Pubmed #27636009.

ABSTRACT: Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are currently classified as grade (G) 1, G2 and G3, in accordance with the 2010 WHO classification. G1 and G2 are named neuroendocrine tumors (NETs) whereas G3 neuroendocrine carcinomas (NECs). While advanced G1 and G2 are usually treated with several different therapies, including somatostatin analogs, chemotherapy, interferon, molecular targeted agents, peptide receptor radionuclide therapy (PRRT) and liver-directed treatments, advanced G3 NECs are usually treated with a platinum-etoposide chemotherapy, trusting their clinical homogeneity is similar to that of small cell lung cancer. However, over the last years a number of reports suggested that 2010 WHO G3 GEP NECs are more heterogeneous than expected. Therefore, we critically reviewed the literature about this topic and reported pathological and clinical considerations on 2010 WHO G3 GEP NEC category proposing new sub-categories. Over the last five years, six studies specifically investigating large series of G3 GEP NECs have been published, including around 800 patients. Tumor morphology and Ki-67 Labeling Index (that will be mentioned as Ki-67 in this manuscript) combination has been reported as a tool to define two or even three subgroups of this category with different prognosis and potentially different therapeutic approach. Prospective trials are warranted to investigate if several types of therapy other than the platinum/etoposide chemotherapy can be effective in well differentiated GEP NEN with 21-55% Ki-67 and alkylating-based chemotherapy in poorly differentiated GEP NEN with 21-55% Ki-67.

7 Review Temozolomide in Advanced Neuroendocrine Neoplasms: Pharmacological and Clinical Aspects. 2015

Koumarianou, Anna / Kaltsas, Gregory / Kulke, Matthew H / Oberg, Kjell / Strosberg, Jonathan R / Spada, Francesca / Galdy, Salvatore / Barberis, Massimo / Fumagalli, Caterina / Berruti, Alfredo / Fazio, Nicola. ·Hematology-Oncology Unit, Fourth Department of Internal Medicine, Attikon University Hospital, Athens, Greece. ·Neuroendocrinology · Pubmed #25924937.

ABSTRACT: Alkylating agents, such as streptozocin and dacarbazine, have been reported as active in neuroendocrine neoplasms (NENs). Temozolomide (TMZ) is an oral, potentially less toxic derivative of dacarbazine, which has shown activity both as a single agent and in combination with other drugs. Nevertheless, its role in NENs has not been well defined. Several retrospective and prospective phase I-II studies have been published describing its use in a variety of NENs. In a retrospective series, the combination of capecitabine and TMZ was reported to be associated with a particularly high tumour response in pancreatic NENs as a first-line treatment. Although in NENs, determination of the O6-methylguanine-DNA methyltransferase (MGMT) status has been suggested as a predictive biomarker of response, its role still remains investigational, awaiting validation along with the establishment of the optimal detection method. Metronomic schedules have been reported to potentially overcome MGMT-related drug resistance. Toxicity is manageable if well monitored. We reviewed the literature regarding pharmacological and clinical aspects of TMZ, focusing on specific settings of NENs, different schedules, toxicity and safety profiles, and potential predictive biomarkers of response.

8 Review Molecular targeted therapy in enteropancreatic neuroendocrine tumors: from biology to clinical practice. 2014

Fazio, N / Scarpa, A / Falconi, M. ·Unit of Gastrointestinal and Neuroendocrine Tumor, European Institute of Oncology, Via Ripamonti 435 20141 Milan, Italy. nicola.fazio@ieo.it. ·Curr Med Chem · Pubmed #23992320.

ABSTRACT: Advanced enteropancreatic (EP) neuroendocrine tumors (NETs) can be treated with several different therapies, including chemotherapy, biotherapy, and locoregional treatments. Over the last few decades, impressive progress has been made in the biotherapy field. Three main druggable molecular targets have been studied and developed in terms of therapy: somatostatin receptor (sstr), mammalian target of rapamycin (mTOR), and angiogenic factors. In particular, research has moved from the old somatostatin analogs (SSAs), such as octreotide (OCT) and lanreotide (LAN), specifically binding to the sstr-2, to the newer pasireotide (PAS), which presents a wider sstr spectrum. Over the last ten years, several molecular targeted agents (MTAs) have been studied in phase II trials, and very few of them have reached phase III. The mTOR inhibitor everolimus and the multitargeted inhibitor sunitinib have been approved for clinical use by the FDA and EMA in advanced well/moderately-differentiated (WD, MD) progressive pancreatic neuroendocrine tumors (PNETs), on the basis of the positive results of two international large randomized phase III trials vs. placebo. Bevacizumab has been studied in a large US phase III trial vs. interferon (IFN)-alfa2b, and results are pending. In this review, the biological and clinical aspects of MTAs introduced into clinical practice or which are currently in an advanced phase of clinical investigation are addressed.

9 Review Chemotherapy in gastroenteropancreatic (GEP) neuroendocrine carcinomas (NEC): a critical view. 2013

Fazio, Nicola / Spada, Francesca / Giovannini, Monica. ·Unit of Upper Gastrointestinal and Neuroendocrine Tumors, Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. nicola.fazio@ieo.it ·Cancer Treat Rev · Pubmed #22819619.

ABSTRACT: Neuroendocrine tumors (NET) are classified according to the Ki67 in low-intermediate grade (Ki67<20%) and high grade (Ki67>20%). The NET of the latter group are also known as neuroendocrine carcinoma (NEC), and their prognosis is dismail. While in the former group biotherapy and radionuclide therapy can be proposed, chemotherapy represents the only treatment usually proposed for NEC. Cisplatin/etoposide combination is usually chosen based on the rationale that NEC are clinically similar to small cell lung cancer. However, evidence for cisplatin/etoposide in NEC is poor and controversial, and different schedules and response rate have been published so far. These aspects, combined with the heterogeneous characteristics of NEC, prompt us to have some doubt in considering cisplatin/etoposide as the gold standard. Some evidence exists that carboplatin can be used instead of cisplatin and irinotecan instead of etoposide without reducing efficacy. Furthermore other drugs, as gemcitabine, oxaliplatin or temozolomide can be evaluated in NEC with non-neuroendocrine component or in mixed adenoneuroendocrine carcinomas. NEC are a category of NET that should be deeply studied to verify if the response to cisplatin/etoposide is homogeneous related to the different Ki67, different morphology and/or different primary site.

10 Review Biological targeted therapies in patients with advanced enteropancreatic neuroendocrine carcinomas. 2010

Fazio, Nicola / Cinieri, Saverio / Lorizzo, Katia / Squadroni, Michela / Orlando, Laura / Spada, Francesca / Maiello, Evaristo / Bodei, Lisa / Paganelli, Giovanni / Delle Fave, Gianfranco / de Braud, Filippo. ·European Institute of Oncology, IEO NET Study Group, Via Ripamonti 435, Milan, Italy. nicola.fazio@ieo.it ·Cancer Treat Rev · Pubmed #21129617.

ABSTRACT: Enteropancreatic (EP) neuroendocrine carcinomas (NECs) represent relatively rare and heterogeneous malignancies. They are the most common group among neuroendocrine tumors (NETs). In most cases they are advanced at diagnosis and slow-growing, therefore conditioning a better prognosis compared with non neuroendocrine carcinomas from the same sites. No standard medical therapy exists, except for somatostatin analogs in functioning tumors, and octreotide LAR in functioning or non functioning well differentiated NECs from small bowel. Several systemic therapeutic options exist, including chemotherapy, somatostatin analog, interferon, peptide receptor radionuclide therapy (PRRT), and molecular targeted drugs. Among them some therapies have specific biological tumor targets and can be defined as "biological targeted therapies". This review focuses on the status of EP NECs targeted therapies in the light of recent advances. Somatostatin receptors (SSTRs) are the first therapeutic target detected in EP NECs. Through them SS analogs and PRRT act, producing symptomatic, biochemical, and, to a lesser extent, antiproliferative effects. New SS analogs, covering a higher number of SSTR subtypes, were developed, including pasireotide (SOM230), which controls 25% of carcinoid syndromes resistant to full dose octreotide LAR. Chimeric analogs, which bind SSTR2/SSTR5 and dopamine-2 receptor subtype (D2), are in preclinical phase of development. Among the numerous molecular targeted agents investigated in NETs, mTOR inhibitors and VEGF/VEGFR/PDGFR inhibitors are in most advanced clinical phase of investigation. In particular, everolimus, sunitinib, and bevacizumab are all studied in phase III trials. Both everolimus and sunitinib produced significant survival benefit versus placebo in advanced progressing well-differentiated pancreatic NECs. Sunitinib data have been presented at the last ASCO in June 2010, and everolimus data will be presented at next ESMO in September 2010.

11 Review Chemotherapy in pancreatic adenocarcinoma. 2010

Squadroni, M / Fazio, N. ·Medical Division, European Institute of Oncology, Milan, Italy. ·Eur Rev Med Pharmacol Sci · Pubmed #20496553.

ABSTRACT: Pancreatic cancer is a malignancy with a very poor prognosis, even when radically resected. In advanced disease chemotherapy has a role in terms of clinical benefit and symptoms palliation, more than survival advantage. Gemcitabine as a single agent is the first-line standard treatment since 1997. Several trials failed to demonstrate a survival advantage of chemotherapy doublets or gemcitabine combined with biological agents versus gemcitabine alone in phase III trials. Erlotinib was the only agent to produce a statistically significant improvement of survival when combined with gemcitabine versus gemcitabine alone. Nevertheless, the clinical application of these literature data remains controversial. However, a meta-analysis showed that combination chemotherapy is superior to gemcitabine alone in terms of survival and clinical benefit in selected subgroups of patients. In unresectable locally advanced disease chemotherapy is active, whereas no high level evidence exists about a possible superiority of chemoradiation. Chemotherapy followed by chemoradiation represents a promising treatment schedule, resulting better than chemotherapy alone in a retrospective analysis. Adjuvant chemotherapy is nowadays a standard treatment, with both 5-FU and gemcitabine resulted superior to observation. Instead adjuvant chemoradiation is not a standard, even though it can be suggested in selected subgroups of patients. In resectable locally advanced disease neoadjuvant therapy is still investigational. Chemoradiation or chemotherapy followed by chemoradiation produced promising results in phase II trials. Possible future gain in terms of survival could come from better neoadjuvant treatments in potentially resectable pancreatic carcinoma. Therefore, this setting should stimulate studies with new drugs and combinations and potential biological predictive factors.

12 Review Molecular target therapy for gastroenteropancreatic endocrine tumours: biological rationale and clinical perspectives. 2009

Capurso, Gabriele / Fazio, Nicola / Festa, Stefano / Panzuto, Francesco / De Braud, Filippo / Delle Fave, Gianfranco. ·Digestive and Liver Disease Unit, S. Andrea Hospital, II Medical School, University "La Sapienza", Via Di Grottarossa 1035-1039, 00189, Rome, Italy. ·Crit Rev Oncol Hematol · Pubmed #19249226.

ABSTRACT: Gastroenteropancreatic endocrine tumours (GEP ETs) represent a relatively rare and heterogeneous group of neoplasms whose therapy can be challenging. The poorly differentiated, fast-growing cases are treated with chemotherapy. In the slow-growing ones, biotherapy is usually performed. Several categories of targeted therapies have been studied for their treatment in vitro and in vivo. A critical review of molecular alterations suggests a rationale for targeting angiogenesis, and the phosphatidylinositol 3 kinase (PI(3)K)/AKT/mammalian target of rapamycin (mTOR) pathway. Accordingly, antiangiogenic agents and mTOR inhibitors are presently the most tested agents in phase II and III studies. Bevacizumab, some multitarget inhibitors, and mTOR inhibitors showed promising results in patients with advanced GEP ETs. A limited activity has been reported for imatinib and epidermal growth factor receptor (EGFR) inhibitors. Combinations of molecular targeted therapies with different sites of action, and somatostatin analogues may be relevant to avoid molecular escape pathways. Future trials should include more homogeneous groups of patients and pay more attention to the subgroup with progressive disease.

13 Clinical Trial A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial. 2017

Kulke, M H / Ruszniewski, P / Van Cutsem, E / Lombard-Bohas, C / Valle, J W / De Herder, W W / Pavel, M / Degtyarev, E / Brase, J C / Bubuteishvili-Pacaud, L / Voi, M / Salazar, R / Borbath, I / Fazio, N / Smith, D / Capdevila, J / Riechelmann, R P / Yao, J C. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA. · Department of Gastroenterology and Pancreatology University of Paris VII and Beaujon Hospital, Paris, France. · Department of Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium. · Department of Medical Oncology, Edouard Herriot Hospital, Lyon, France. · Department of Medical Oncology, University of Manchester/The Christie Hospital, Manchester, UK. · Department of Endocrine Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Hepatology and Gastroenterology, Charité University of Medicine, Berlin, Germany. · Department of Oncology, Novartis AG, Basel, Switzerland. · Department of Oncology, Novartis Pharmaceuticals Corporation, East Hanover, USA. · Department of Medical Oncology, Catalan Institute of Oncology, IDIBELL, Hospital of Barcelona, Barcelona, Spain. · Department of Gastroenterology Saint-Luc University Hospital, Brussels, Belgium. · Department of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy. · Department of Oncology, St. Andrew Hospital, Bordeaux, France. · Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. · Department of Oncology, Cancer Institute of the State of São Paulo, São Paulo, Brazil. · Department of Gastrointestinal and Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA. ·Ann Oncol · Pubmed #28327907.

ABSTRACT: Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET. Patients and methods: Patients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker response was evaluated in an exploratory analysis. Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm versus 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar (77.2% versus 82.7%, respectively). No significant improvement was observed in median overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively. Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

14 Clinical Trial A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours. 2016

Fazio, Nicola / Buzzoni, Roberto / Baudin, Eric / Antonuzzo, Lorenzo / Hubner, Richard A / Lahner, Harald / DE Herder, Wouter W / Raderer, Markus / Teulé, Alexandre / Capdevila, Jaume / Libutti, Steven K / Kulke, Matthew H / Shah, Manisha / Dey, Debarshi / Turri, Sabine / Aimone, Paola / Massacesi, Cristian / Verslype, Chris. ·European Institute of Oncology, Milan, Italy nicola.fazio@ieo.it. · IRCCS National Tumor Institute, Milan, Italy. · Institut Gustave Roussy, Villejuif, France. · Careggi University Hospital, Florence, Italy. · The Christie NHS Foundation Trust, Manchester, U.K. · University of Duisburg-Essen, Essen, Germany. · Erasmus MC, Rotterdam, the Netherlands. · University Hospital of Vienna, Vienna, Austria. · Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain. · Montefiore Medical Center and Albert Einstein College of Medicine, New York, NY, U.S.A. · Dana-Farber Cancer Institute, Boston, MA, U.S.A. · The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, U.S.A. · Novartis Healthcare Private Limited, Hyderabad, India. · Novartis Pharma AG, Basel, Switzerland. · Novartis Oncology, Paris, France. · University Hospitals Leuven, Leuven, Belgium. ·Anticancer Res · Pubmed #26851029.

ABSTRACT: BACKGROUND: This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436). PATIENTS AND METHODS: In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1. RESULTS: As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7-67.3%). CONCLUSION: BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2.

15 Clinical Trial Real-world study of everolimus in advanced progressive neuroendocrine tumors. 2014

Panzuto, Francesco / Rinzivillo, Maria / Fazio, Nicola / de Braud, Filippo / Luppi, Gabriele / Zatelli, Maria Chiara / Lugli, Francesca / Tomassetti, Paola / Riccardi, Ferdinando / Nuzzo, Carmen / Brizzi, Maria Pia / Faggiano, Antongiulio / Zaniboni, Alberto / Nobili, Elisabetta / Pastorelli, Davide / Cascinu, Stefano / Merlano, Marco / Chiara, Silvana / Antonuzzo, Lorenzo / Funaioli, Chiara / Spada, Francesca / Pusceddu, Sara / Fontana, Annalisa / Ambrosio, Maria Rosaria / Cassano, Alessandra / Campana, Davide / Cartenì, Giacomo / Appetecchia, Marialuisa / Berruti, Alfredo / Colao, Annamaria / Falconi, Massimo / Delle Fave, Gianfranco. ·Digestive and Liver Disease, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy; Unit of Gastrointestinal and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Oncology and Hematology, Policlinico di Modena, Italy; Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Departments of Endocrinology and Oncologia Medica, Università Cattolica del S. Cuore, Rome, Italy; Departments of Medical and Surgical Sciences and Medical Oncology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; Oncology, Antonio Cardarelli Hospital, Naples, Italy; Division of Medical Oncology and Endocrinology Unit, Regina Elena National Cancer Institute Rome, IRCCS, Rome, Italy; Oncology, San Luigi Gonzaga Hospital, Orbassano, Torino, Italy; Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy; Oncology, Fondazione Poliambulanza, Brescia, Italy; Oncology, Istituto Oncologico Veneto, Padova, Italy; Departments of Medical Oncology and Pancreatic Surgery, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy; Oncology, S. Croce e Carle Hospital, Cuneo, Italy; Department of Medical Oncology A, IRCCS AOU San Martino-IST, Genova, Italy; Oncologia Medica 1, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy; Oncologia, Spedali Civili di Brescia, University of Brescia, Brescia, Italy. · Digestive and Liver Disease, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy; Unit of Gastrointestinal and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Oncology and Hematology, Policlinico di Modena, Italy; Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Departments of Endocrinology and Oncologia Medica, Università Cattolica del S. Cuore, Rome, Italy; Departments of Medical and Surgical Sciences and Medical Oncology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; Oncology, Antonio Cardarelli Hospital, Naples, Italy; Division of Medical Oncology and Endocrinology Unit, Regina Elena National Cancer Institute Rome, IRCCS, Rome, Italy; Oncology, San Luigi Gonzaga Hospital, Orbassano, Torino, Italy; Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy; Oncology, Fondazione Poliambulanza, Brescia, Italy; Oncology, Istituto Oncologico Veneto, Padova, Italy; Departments of Medical Oncology and Pancreatic Surgery, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy; Oncology, S. Croce e Carle Hospital, Cuneo, Italy; Department of Medical Oncology A, IRCCS AOU San Martino-IST, Genova, Italy; Oncologia Medica 1, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy; Oncologia, Spedali Civili di Brescia, University of Brescia, Brescia, Italy gianfranco.dellefave@uniroma1.it. ·Oncologist · Pubmed #25117065.

ABSTRACT: Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3-4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3-4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs.

16 Clinical Trial Everolimus in combination with octreotide long-acting repeatable in a first-line setting for patients with neuroendocrine tumors: an ITMO group study. 2014

Bajetta, Emilio / Catena, Laura / Fazio, Nicola / Pusceddu, Sara / Biondani, Pamela / Blanco, Giusi / Ricci, Sergio / Aieta, Michele / Pucci, Francesca / Valente, Monica / Bianco, Nadia / Mauri, Chiara Maria / Spada, Francesca. ·Institute of Oncology, Polyclinic Hospital, Monza, Italy. ·Cancer · Pubmed #24752410.

ABSTRACT: BACKGROUND: Preclinical and clinical studies suggest synergistic activity between somatostatin analogues and mammalian target of rapamycin inhibitors. The activity and safety of everolimus was assessed in combination with octreotide long-acting repeatable (LAR) in patients with neuroendocrine tumors (NETs) of gastroenteropancreatic and lung origin. METHODS: This was a phase 2, multicenter trial using a Simon's 2-stage minimax design. Treatment-naive patients with advanced well-differentiated NETs of gastroenteropancreatic tract and lung origin received everolimus 10 mg daily, in combination with octreotide LAR 30 mg every 28 days. The primary endpoint was objective response rate (ORR). RESULTS: A total of 50 patients (median age, 60.5 years) were enrolled. Primary tumor sites were: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum and duodenum (2 patients), and unknown (14 patients). Thirteen patients (26%) had carcinoid syndrome. Treatment-related adverse events (AEs) were mostly grade 1 or 2; the only grade 4 AE was mucositis in 1 patient, whereas grade 3 AEs included skin rash in 1 case (2%), stomatitis in 4 cases (8%), and diarrhea in 11 cases (22%). The ORR was 18%; 2% of patients had a complete response (CR), 16% a partial response (PR) and 74% achieved stable disease (SD). All CRs and all PRs as well as 92% of SDs had a duration ≥ 6 months. The clinical benefit (CR+PR+SD) was 92%. At a median follow-up of 277 days, median time to progression and overall survival were not reached. CONCLUSIONS: The everolimus-octreotide LAR combination was active and well tolerated in these previously treated patients with advanced NETs, suggesting a possible role as first-line treatment in patients with NET.

17 Clinical Trial Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the XELBEVOCT study. 2014

Berruti, Alfredo / Fazio, Nicola / Ferrero, Anna / Brizzi, Maria Pia / Volante, Marco / Nobili, Elisabetta / Tozzi, Lucia / Bodei, Lisa / Torta, Mirella / D'Avolio, Antonio / Priola, Adriano Massimiliano / Birocco, Nadia / Amoroso, Vito / Biasco, Guido / Papotti, Mauro / Dogliotti, Luigi. ·Oncologia Medica, Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Università degli Studi di Brescia, Azienda Ospedaliera Spedali Civili Piazzale Spedali Civili 1, 25123 Brescia, Italy. alfredo.berruti@gmail.com. ·BMC Cancer · Pubmed #24628963.

ABSTRACT: BACKGROUND: We assessed the activity and toxicity of the XELBEVOCT regimen in patients with metastatic well-to-moderately differentiated neuroendocrine neoplasms (WMD-NEN). Ancillary studies evaluated hypertension, proteinuria, and vascular endothelial growth factor (VEGF) polymorphisms in predicting progression-free survival (PFS) and the predictive role of serum vitamin D in progression-free survival and proteinuria onset. METHODS: This prospective phase 2 study included 45 patients with WMD-NEN arising from various primary sites. The treatment regimen was octreotide long-acting release (LAR), 20 mg monthly, metronomic capecitabine, 2000 mg/daily, and intravenous bevacizumab, 5 mg/kg every 2 weeks, without interruption for 9 months. Bevacizumab was continued until disease progression. RESULTS: Partial response was obtained in 8 patients (17.8%, 95% confidence interval [CI], 6.4%-28.2%); tumor response was more frequent in pancreatic than in non-pancreatic malignancies. The median PFS was 14.9 months; median overall survival was not attained. Biochemical and symptomatic responses were observed in 52.9% and 82.3% of cases, respectively. The treatment was well tolerated. Grade 3 toxicities included hand and foot syndrome (11.1%), proteinuria (4.4%), and renal toxicity (2.2%). Proteinuria (all grades) was correlated with longer PFS (p = 0.017). There was an inverse relationship between proteinuria and vitamin D levels. VEGF polymorphisms were not associated with patient outcome. CONCLUSION: The XELBEVOCT regimen is active and well tolerated in patients with metastatic WMD-NEN. Proteinuria correlated with hypovitaminosis D status and was the best predictive factor of treatment efficacy. TRIAL REGISTRATION: Trial registration number NCT01203306.

18 Article Should platinum-based chemotherapy be preferred for germline BReast CAncer genes (BRCA) 1 and 2-mutated pancreatic ductal adenocarcinoma (PDAC) patients? A systematic review and meta-analysis. 2019

Rebelatto, Taiane F / Falavigna, Maicon / Pozzari, Marta / Spada, Francesca / Cella, Chiara A / Laffi, Alice / Pellicori, Stefania / Fazio, Nicola. ·Department of Medical Oncology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. · National Institute for Heath Technology Assessment, Postgraduate Program in Epidemiology, Porto Alegre, Brazil. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy. Electronic address: nicola.fazio@ieo.it. ·Cancer Treat Rev · Pubmed #31542591.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Recent studies have shown that 4-20% of patients with PDAC have a germline BReast CAncer (gBRCA) genes 1 and 2 mutation (m). Because homologous recombination is impaired in patients with gBRCAm, some reports suggested that these tumors may be more sensitive to platinum compounds. Therefore, this systematic review and meta-analysis focused on benefit of patients with gBRCAm receiving a platinum-based chemotherapy (PtCh) compared with those treated with a non-platinum-based chemotherapy (NPtCh). MATERIAL AND METHODS: The following electronic databases were searched from inception to May 12, 2018: PubMed (MEDLINE), EMBASE, and Cochrane Library. Abstracts from conferences were also reviewed for inclusion. Cohort, case-control and randomized studies of patients with PDAC and gBRCAm were eligible for inclusion if they provided data to compare patients receiving PtCh vs NPtCh. The primary endpoint was overall survival (OS) in the PtCh group vs the NPtCh group in patients with clinical stage III (locally advanced) or IV (metastatic) (CS III-IV) PDAC. RESULTS: Of 112 studies identified, 6 were included (total of 108 patients); of these, 4 provided sufficient data for meta-analysis. Half of the patients were males, with a mean age ranging from 58 to 63 years. The OS in the 85 patients with CS III-IV PDAC was higher in the PtCh group (23.7 vs 12.2 months; mean difference of 10.21 months, 95% confidence interval [CI] 5.05-15.37; P < 0.001; very low quality of evidence). PtCh was associated with a lower mortality (62.3 vs 87.5%; relative risk of 0.80, 95%CI 0.66-0.97; P = 0.021; very low quality of evidence). CONCLUSION: Our study confirmed the hypothesis that patients with CS III-IV gBRCAm preferably benefit from a PtCh compared with NPtCh. However the very low quality of evidence should induce to be careful about the risk of potential biases. The generated hypothesis should be prospectively investigated in homogenous clinical settings.

19 Article Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study. 2019

Carlsen, Esben Andreas / Fazio, Nicola / Granberg, Dan / Grozinsky-Glasberg, Simona / Ahmadzadehfar, Hojjat / Grana, Chiara Maria / Zandee, Wouter T / Cwikla, Jaroslaw / Walter, Martin A / Oturai, Peter Sandor / Rinke, Anja / Weaver, Andrew / Frilling, Andrea / Gritti, Sara / Arveschoug, Anne Kirstine / Meirovitz, Amichay / Knigge, Ulrich / Sorbye, Halfdan. ·Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen, Denmark. · Department of Biomedical Sciences, Cluster for Molecular Imaging, University of Copenhagen, Copenhagen, Denmark. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy. · Department of Medical Sciences, Uppsala University, Uppsala, Sweden. · Neuroendocrine Tumor Unit, Department of Endocrinology & Metabolism, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. · Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany. · Division of Nuclear Medicine, IEO, European Institute of Oncology IRCCS, Milan, Italy. · Erasmus Medical Center, Rotterdam, The Netherlands. · Medical School, University of Warmia and Mazury, Olsztyn, Poland. · Department of Nuclear Medicine, University Hospital of Geneva, Geneva, Switzerland. · Department of Gastroenterology, University Hospital Gießen and Marburg, Marburg, Germany. · Department of Oncology, Churchill Hospital, Oxford, UK. · Department of Surgery and Cancer, Imperial College London, London, UK. · Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark. · Department of Oncology and Radiation Therapy Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. · Departments of Surgical Gastroenterology and Clinical Endocrinology, Rigshospitalet, Copenhagen, Denmark. · Department of Oncology, Haukeland University Hospital, Bergen, Norway. · Department of Clinical Science, University of Bergen, Bergen, Norway. ·Endocr Relat Cancer · Pubmed #30540557.

ABSTRACT: Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1-2 (G1-G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21-54% (n = 125) vs Ki-67 ≥55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3-4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.

20 Article Unmet Needs in Functional and Nonfunctional Pancreatic Neuroendocrine Neoplasms. 2019

Jensen, Robert T / Bodei, Lisa / Capdevila, Jaume / Couvelard, Anne / Falconi, Massimo / Glasberg, Simona / Kloppel, Günter / Lamberts, Steven / Peeters, Marc / Rindi, Guido / Rinke, Anja / Rothmund, Mathias / Sundin, Anders / Welin, Staffan / Fazio, Nicola / Anonymous7711249 / Anonymous7721249. ·Cell Biology Section, NIDDK, National Institutes of Health, Bethesda, Maryland, USArobertj@bdg10.niddk.nih.gov. · Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Department of Medical Oncology, Vall d'Hebron University Hospital, Vall Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain. · Service de Pathologie, Hôpital Bichat, Paris, France. · Chirurgia del Pancreas, Università Vita e Salute, San Raffaele Hospital IRCCS, Milan, Italy. · Neuroendocrine Unit, Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. · Institute of Pathology, Technische Universität München, Munich, Germany. · Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Oncology, Antwerp University Hospital, Edegem, Belgium. · Institute of Anatomic Pathology, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy. · Department of Gastroenterology, UKGM Marburg and Philipps University, Marburg, Germany. · Department of Surgery, Philipps University, Marburg, Germany. · Department of Radiology, Institute of Surgical Sciences, Uppsala University, Uppsala, Sweden. · Endocrine Oncology Unit, Department of Medical Sciences, University Hospital, Uppsala, Sweden. · Gastrointestinal and Neuroendocrine Oncology Unit, European Institute of Oncology (IEO), Milan, Italy. ·Neuroendocrinology · Pubmed #30282083.

ABSTRACT: 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.

21 Article Unmet Needs in Appendiceal Neuroendocrine Neoplasms. 2019

Toumpanakis, Christos / Fazio, Nicola / Tiensuu Janson, Eva / Hörsch, Dieter / Pascher, Andreas / Reed, Nicholas / O Apos Toole, Dermot / Nieveen van Dijkum, Els / Partelli, Stefano / Rinke, Anja / Kos-Kudla, Beata / Costa, Frederico / Pape, Ulrich-Frank / Grozinsky-Glasberg, Simona / Scoazec, Jean-Yves / Anonymous7581249 / Anonymous7591249. ·Neuroendocrine Tumour Unit, Royal Free Hospital, London, United Kingdomc.toumpanakis@ucl.ac.uk. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, Milan, Italy. · Endocrine Oncology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. · Center for Neuroendocrine Tumors Bad Berka, Bad Berka, Germany. · Department of Surgery, Campus Charité Mitte/Campus Virchow-Klinikum, Charité University Medicine Berlin, Berlin, Germany. · Beatson Oncology Centre, Gartnavel General Hospital, Glasgow, United Kingdom. · Department of Clinical Medicine, St. James's Hospital, Trinity College Dublin, Dublin, Ireland. · Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. · Department of Gastroenterology, UKGM, Marburg, Marburg, Germany. · Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Katowice, Poland. · Hospital Sírio-Libanês, São Paulo, Brazil. · Division of Hepatology and Gastroenterology, Medical Department, Charité Campus Charité Mitte/Campus Virchow-Klinikum, Charité University Medicine Berlin, Berlin, Germany. · Neuroendocrine Tumor Unit, Department of Endocrinology, Hadassah-Hebrew University Medical Centre, Jerusalem, Israel. · Department of Pathology, Gustave Roussy Cancer Campus, Villejuif, France. ·Neuroendocrinology · Pubmed #30235454.

ABSTRACT: 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".

22 Article Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours. 2018

Raymond, Eric / Kulke, Matthew H / Qin, Shukui / Yu, Xianjun / Schenker, Michael / Cubillo, Antonio / Lou, Wenhui / Tomasek, Jiri / Thiis-Evensen, Espen / Xu, Jian-Ming / Croitoru, Adina E / Khasraw, Mustafa / Sedlackova, Eva / Borbath, Ivan / Ruff, Paul / Oberstein, Paul E / Ito, Tetsuhide / Jia, Liqun / Hammel, Pascal / Shen, Lin / Shrikhande, Shailesh V / Shen, Yali / Sufliarsky, Jozef / Khan, Gazala N / Morizane, Chigusa / Galdy, Salvatore / Khosravan, Reza / Fernandez, Kathrine C / Rosbrook, Brad / Fazio, Nicola. ·Department of Medical Oncology, Paris Saint-Joseph Hospital Group, Paris, France. · Program in Neuroendocrine and Carcinoid Tumors, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, China. · Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. · Centrul de Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania. · Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain. · Zhongshan Hospital, Fudan University, Shanghai, China. · Faculty of Medicine, Masaryk Memorial Cancer Institute, Masaryk University, Brno, Czech Republic. · Department of Gastroenterology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. · No. 307 Hospital, Academy of Military Medical Sciences, Beijing, China. · Department of Medical Oncology, Fundeni Clinical Institute, Bucharest, Romania. · Andrew Love Cancer Center, Geelong Hospital, Victoria, Victoria, Australia. · Všeobecné Fakultní Nemocnice v Praze Onkologická Klinika, Prague, Czech Republic. · Hepato-Gastroenterology Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium. · Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. · Division of Hematology/Oncology, Columbia University Medical Center, New York, New York, USA. · Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · China-Japan Friendship Hospital, Beijing, China. · Service d'Oncologie Digestive, Hôpital Beaujon, Clichy, France. · Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University Cancer Hospital and Institute, Beijing, China. · GI and HPB Surgical Oncology, Tata Memorial Hospital, Mumbai, India. · West China Hospital of Sichuan University, Chengdu, China. · 2nd Department of Oncology, Faculty of Medicine, Comenius University, Bratislava, Slovakia. · Henry Ford Health System, Detroit, Michigan, USA. · National Cancer Center, Tokyo, Japan. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, Milan, Italy. · Pfizer Oncology, Pfizer Inc., San Diego, California, USA. · Pfizer Oncology, Pfizer Inc., Cambridge, Massachusetts, USA. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, Milan, Italynicola.fazio@ieo.it. ·Neuroendocrinology · Pubmed #29991024.

ABSTRACT: BACKGROUND: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. METHODS: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). CONCLUSIONS: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.

23 Article Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues. 2018

Pusceddu, Sara / Vernieri, Claudio / Di Maio, Massimo / Marconcini, Riccardo / Spada, Francesca / Massironi, Sara / Ibrahim, Toni / Brizzi, Maria Pia / Campana, Davide / Faggiano, Antongiulio / Giuffrida, Dario / Rinzivillo, Maria / Cingarlini, Sara / Aroldi, Francesca / Antonuzzo, Lorenzo / Berardi, Rossana / Catena, Laura / De Divitiis, Chiara / Ermacora, Paola / Perfetti, Vittorio / Fontana, Annalisa / Razzore, Paola / Carnaghi, Carlo / Davì, Maria Vittoria / Cauchi, Carolina / Duro, Marilina / Ricci, Sergio / Fazio, Nicola / Cavalcoli, Federica / Bongiovanni, Alberto / La Salvia, Anna / Brighi, Nicole / Colao, Annamaria / Puliafito, Ivana / Panzuto, Francesco / Ortolani, Silvia / Zaniboni, Alberto / Di Costanzo, Francesco / Torniai, Mariangela / Bajetta, Emilio / Tafuto, Salvatore / Garattini, Silvio Ken / Femia, Daniela / Prinzi, Natalie / Concas, Laura / Lo Russo, Giuseppe / Milione, Massimo / Giacomelli, Luca / Buzzoni, Roberto / Delle Fave, Gianfranco / Mazzaferro, Vincenzo / de Braud, Filippo. ·Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy. Electronic address: sara.pusceddu@istitutotumori.mi.it. · Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy. · Dipartimento di Oncologia, Università degli Studi di Torino, A. O. Ordine Mauriziano, Turin, Italy. · Dipartimento di Oncologia, Santa Chiara Hospital, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. · IEO - Istituto Europeo di Oncologia, ENETS Center of Excellence, Milan, Italy. · Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. · Centro di Osteoncologia e Tumori Rari, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. · Azienda Ospedaliera Universitaria San Luigi Gonzaga, Orbassano, Italy. · Policlinico Sant'Orsola Malpighi, Bologna, Italy. · Unità di chirurgia tiroidea e paratiroidea, Istituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy. · IOM- Istituto Oncologico del Mediterraneo, Catania, Italy. · Azienda Ospedaliera Universitaria Sant'Andrea, ENETS Center of Excellence, Rome, Italy. · Azienda Ospedaliera Universitaria, Verona, Italy. · Fondazione Poliambulanza, Brescia, Italy. · A. O. U. Careggi, Firenze, Italy. · Azienda Ospedaliero Universitaria Ospedali Riuniti, Ancona, Italy. · Policlinico di Monza, Monza, Italy. · IRCCS Fondazione Pascale, ENETS Center of Excellence, Naples, Italy. · Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine, Italy. · Fondazione IRCCS Policlinico San Matteo, SC oncologia, Pavia, Italy. · Policlinico di Modena, Italy. · Unit of Endocrinology, Ospedale Mauriziano, Torino, Italy. · Istituto Clinico Humanitas, Rozzano, ENETS Center of Excellence, Italy. · Ospedale Policlinico Borgo Roma, Verona, Italy. · Ospedale S Croce e Carle, Cuneo, Italy. · Ospedale Valduce Como, Italy. · Endocrinology Section, Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Italy. · Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy. · Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Medical-Surgical Science and Traslational Medicine Departement, Sapienza University, Rome, Italy. · Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Italy. · Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Universita' degli Studi di Milano, Milan, Italy. ·Gastroenterology · Pubmed #29655834.

ABSTRACT: BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

24 Article Sunitinib in patients with pre-treated pancreatic neuroendocrine tumors: A real-world study. 2018

Rinzivillo, Maria / Fazio, Nicola / Pusceddu, Sara / Spallanzani, Andrea / Ibrahim, Toni / Campana, Davide / Marconcini, Riccardo / Partelli, Stefano / Badalamenti, Giuseppe / Brizzi, Maria Pia / Catena, Laura / Schinzari, Giovanni / Carnaghi, Carlo / Berardi, Rossana / Faggiano, Antongiulio / Antonuzzo, Lorenzo / Spada, Francesca / Gritti, Sara / Femia, Daniela / Gelsomino, Fabio / Bongiovanni, Alberto / Ricci, Sergio / Brighi, Nicole / Falconi, Massimo / Delle Fave, Gianfranco / Panzuto, Francesco. ·Digestive and Liver Disease, ENETS Center of Excellence Sant'Andrea Hospital - Sapienza University of Rome, Italy. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, ENETS Center of Excellence IEO, Milan, Italy. · Department of Medical Oncology, Fondazione IRCCS Istituto Tumori Milano, ENETS Center of Excellence, Milan, Italy. · Division of Oncology, Department of Oncology and Haematology, University Hospital of Modena, Modena, Italy. · Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. · Department of Medical and Surgical Sciences, S.Orsola-Malpighi University Hospital, Bologna, Italy. · Department of Oncology, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Istituto Toscano Tumori, Santa Chiara Hospital, Pisa, Italy. · Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Vita e Salute University, Milan, Italy. · Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy. · Medical Oncology, AOU S. Luigi Gonzaga Regione Gonzole 10, Orbassano, Italy. · Struttura di Oncologia Policlinico di Monza, Monza, MB, Italy. · Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy. · Oncology Unit, Humanitas Clinical and Research Centre, Rozzano, Italy. · Medical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, Ancona, Italy. · Divisione di Endocrinologia, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli Federico II, ENETS Center of Excellence Naples, Italy. · S.C di Oncologia Medica, AOU Careggi Florence, Italy. · Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, Bologna, Italy. · Digestive and Liver Disease, ENETS Center of Excellence Sant'Andrea Hospital - Sapienza University of Rome, Italy. Electronic address: fpanzuto@ospedalesantandrea.it. ·Pancreatology · Pubmed #29361429.

ABSTRACT: INTRODUCTION: Besides data reported in a Phase-III trial, data on sunitinib in pancreatic Neuroendocrine Tumors (panNETs) are scanty. AIM: To evaluate sunitinib efficacy and tolerability in panNETs patients treated in a real-world setting. PATIENTS AND METHODS: Retrospective analysis of progressive panNETs treated with sunitinib. Efficacy was assessed by evaluating progression-free survival, overall survival, and disease control (DC) rate (stable disease (SD) + partial response + complete response). Data are reported as median (25th-75th IQR). RESULTS: Eighty patients were included. Overall, 71.1% had NET G2, 26.3% had NET G1, and 2.6% had NET G3 neoplasms. A total of 53 patients (66.3%) had received three or more therapeutic regimens before sunitinib, with 24 patients (30%) having been treated with four previous treatments. Median PFS was 10 months. Similar risk of progression was observed between NET G1 and NET G2 tumors (median PFS 11 months and 8 months, respectively), and between patients who had received ≥ 3 vs ≤ 2 therapeutic approaches before sunitinib (median PFS 9 months and 10 months, respectively). DC rate was 71.3% and SD was the most frequent observed response, occurring in 43 pts (53.8%). Overall, 59 pts (73.8%) experienced AEs, which were grade 1-2 in 43 of them (72.9%), grade 3 in 15 pts (25.4%), and grade 4 in one patient (1.7%). Six pts (7.5%) stopped treatment due to toxicity. CONCLUSIONS: The present real-world experience shows that sunitinib is a safe and effective treatment for panNETs, even in the clinical setting of heavily pre-treated, progressive diseases.

25 Article Peptide receptor radionuclide therapy as neoadjuvant therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms. 2018

Partelli, Stefano / Bertani, Emilio / Bartolomei, Mirco / Perali, Carolina / Muffatti, Francesca / Grana, Chiara Maria / Schiavo Lena, Marco / Doglioni, Claudio / Crippa, Stefano / Fazio, Nicola / Zamboni, Giuseppe / Falconi, Massimo. ·Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. · Surgery Department, European Institute of Oncology, Milan, Italy. · Nuclear Medicine Department, "S. Anna" Hospital, Ferrara, Italy. · Nuclear Medicine Department, European Institute of Oncology, Milan, Italy. · Pathology Department, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. · Oncology Department, European Institute of Oncology, Milan, Italy. · Pathology Department, "Sacro Cuore-Don Calabria" Hospital, Negrar, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. Electronic address: falconi.massimo@hsr.it. ·Surgery · Pubmed #29284590.

ABSTRACT: BACKGROUND: Peptide receptor radionuclide therapy is a valid therapeutic option for pancreatic neuroendocrine neoplasms. The aim of this study was to describe an initial experience with the use of peptide receptor radionuclide therapy as a neoadjuvant agent for resectable or potentially resectable pancreatic neuroendocrine neoplasms. METHODS: The postoperative outcomes of 23 patients with resectable or potentially resectable pancreatic neuroendocrine neoplasms at high risk of recurrence who underwent neoadjuvant peptide receptor radionuclide therapy (peptide receptor radionuclide therapy group) were compared with 23 patients who underwent upfront surgical operation (upfront surgery group). Patients were matched for tumor size, grade, and stage. Median follow-up was 61 months. RESULTS: The size (median greatest width) of the primary pancreatic neuroendocrine neoplasms decreased after neoadjuvant peptide receptor radionuclide therapy (59 to 50 mm; P=.047). There were no differences in intraoperative and postoperative outcomes and there were no operative deaths, but the risk of developing a pancreatic fistula tended to be less in the peptide receptor radionuclide therapy group when compared to the upfront surgery group (0/23 vs 4/23; P < .02). The incidence of nodal metastases at the time of resection was also less in the peptide receptor radionuclide therapy group (n= 9/23 vs 17/23; P<.02). Neither median disease-specific survival (not reached in either group; P=.411) nor progression-free survival (52 vs 37 months; P>.2) differed between groups, but progression-free survival in the 31 patients who had an R0 resection seemed to be greater in the 15 patients in the peptide receptor radionuclide therapy group versus 16 patients the upfront group (median progression-free survival not reached vs 36 months; P<.05). CONCLUSION: Neoadjuvant peptide receptor radionuclide therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms in patients with high-risk features of recurrence seems to be beneficial, but well-designed and much larger prospective trials are needed to confirm the safety and the oncologic value of this approach.

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