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Neuroendocrine Tumors: Treatment and Management
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Neuroendocrine Tumors: Treatment and Management

A topical collection in Cancers (ISSN 2072-6694). This collection belongs to the section "Cancer Therapy".

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Editor

Prof. Alessio Imperiale

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Guest Editor
1. Nuclear Medicine and Molecular Imaging Institut de Cancérologie Strasbourg Europe (ICANS) 17, rue Albert Calmette – 67033 Strasbourg, France
2. University Hospitals of Strasbourg Faculty of Medicine - University of Strasbourg Strasbourg, France
3. Molecular Imaging – DRHIM IPHC, UMR7178, CNRS/Unistra Strasbourg, France
Interests: Nuclear medicine, PET, Neuroendocrine tumors, Oncology, Infectious Diseases
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

Neuroendocrine tumors (NET) are rare and heterogeneous epithelial neoplasms with neuroendocrine differentiation commonly originating from the gastrointestinal tract, pancreas, and lung. Patients with suspected or known NET are usually referred to a multidisciplinary skilled team for diagnostic evaluation, treatment, and follow-up. Whenever feasible, surgery is proposed for low-grade tumors. Multiple therapeutic options are available for unresectable advanced disease or metastatic disease, including medical treatment with cold somatostatin analogs, peptide receptor radionuclide therapy (PRRT), chemotherapy, and molecule-targeted therapies such as mammalian target of rapamycin (mTOR) inhibitors and antiangiogenic agents. Moreover, recent advances in understanding the genetic and epigenetic alterations in NET as well as the knowledge of proteomics and metabolomics tumoral features could make available novel targets for future therapeutic options and for the assessment of patient prognosis. In this Special Issue, a panel of internationally recognized experts in this field will focus on the current diagnostic approach, the several available therapeutic approaches, and the future directions for the management of patients with lung and gastroenteropancreatic NET.

Prof. Alessio Imperiale
Guest Editor

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Keywords

  • Neuroendocrine tumor
  • pancreas, small bowel
  • lung
  • positron emission tomography
  • surgery
  • targeted therapy
  • PRRT

Published Papers (19 papers)

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2023

Jump to: 2022, 2021

16 pages, 3007 KiB  
Article
The Surgical and Therapeutic Activities of Non-Functional Pancreatic Neuroendocrine Tumors at a High-Volume Institution
by Wu-Hu Zhang, Jun-Feng Xu, Yu-Heng Hu, Yi Qin, Jie Chen, Xian-Jun Yu, Xiao-Wu Xu and Shun-Rong Ji
Cancers 2023, 15(7), 1955; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15071955 - 24 Mar 2023
Cited by 1 | Viewed by 1811
Abstract
Background: This study aimed to summarize the surgical and therapeutic activities of non-functional pancreatic neuroendocrine tumors (NF-PanNETs) and perform survival analyses of a 15-year single-institutional cohort of NF-PanNETs. Methods: In total, 1001 patients with neuroendocrine neoplasms treated at Fudan University Shanghai Cancer Center [...] Read more.
Background: This study aimed to summarize the surgical and therapeutic activities of non-functional pancreatic neuroendocrine tumors (NF-PanNETs) and perform survival analyses of a 15-year single-institutional cohort of NF-PanNETs. Methods: In total, 1001 patients with neuroendocrine neoplasms treated at Fudan University Shanghai Cancer Center were screened for inclusion, and 509 patients with NF-PanNETs from 2006 to 2020 were included. For time trend analyses, the 15-year study period was randomly divided into three periods. Survival analyses used the Kaplan–Meier method and Cox regression models. Results: The total number of resected NF-PanNETs increased over the 15-year study period, from 5 resections in 2006 to 94 resections in 2020. A significant decrease in the tumor size was observed, from a mean of 4.0 cm to 3.3 cm, and to 3.0 cm in the most recent period (p = 0.006). Minimally invasive techniques gradually increased from 3.5% to 12.9%, and finally to 46.4% in the most recent period (p < 0.001). In non-metastatic and resected tumors, the tumor size (p < 0.001), positive lymph node (p < 0.001), adjuvant treatment (p = 0.048), and tumor grade (p < 0.001) were independent prognostic factors for recurrence-free survival (RFS). The microvascular invasion (p = 0.024) and tumor grade (p = 0.013) were independent prognostic factors for overall survival (OS). A malignant transformation from NET into neuroendocrine carcinoma was observed. Conclusions: An increasing number of NF-PanNETs resection and minimally invasive surgery was shown. In non-metastatic and resected tumors NF-PanNETs, tumor size, positive lymph node, adjuvant treatment, and tumor grade were independent predictors of RFS. Microvascular invasion and tumor grade were independent prognostic factors for OS. Full article
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2022

Jump to: 2023, 2021

12 pages, 1443 KiB  
Article
Amino Acid Solutions for 177Lu-Oxodotreotide Premedication: A Tolerance Study
by Pierre Courault, Agathe Deville, Vincent Habouzit, Frédéric Gervais, Claire Bolot, Claire Bournaud and Elise Levigoureux
Cancers 2022, 14(21), 5212; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14215212 - 24 Oct 2022
Cited by 2 | Viewed by 1548
Abstract
Background: The co-infusion of amino acid solutions during peptide receptor radionuclide therapy reduces the tubular reabsorption of 177Lu-oxodotreotide, thus minimizing nephrotoxicity. In our nuclear medicine department, the patients received two different types of amino acid perfusion over time: a commercial solution (CS) [...] Read more.
Background: The co-infusion of amino acid solutions during peptide receptor radionuclide therapy reduces the tubular reabsorption of 177Lu-oxodotreotide, thus minimizing nephrotoxicity. In our nuclear medicine department, the patients received two different types of amino acid perfusion over time: a commercial solution (CS) containing 10% amino acids, and a 2.5% lysine–arginine (LysArg) hospital preparation, produced by a referral laboratory. The aim of the present study was to analyze the tolerance of the two amino acid solutions. Methods: The patient files were analyzed and double-checked. The study parameters comprised the gender, age, primary tumor site, type of amino acid perfusion, adverse events (AE) and WHO AE grades, antiemetic premedication, creatinine, and serum potassium level. Results: From February 2016 to February 2019, 76 patients were treated, for a total 235 cycles. AEs occurred in 71% of the CS cycles (n = 82/116), versus 18% (n = 21/119) in the LysArg group (p < 0.0001). In the CS group, the AEs were mostly WHO grade 4 (n = 24/82), and mostly grade 1 in the LysArg group (n = 13/21). Poisson regression showed a higher risk of AE overall and of grades 3 and 4 in the females and with CS. The mean creatinine clearance was identical before and after the PRRT cycles, whichever amino acid perfusion was used. Conclusions: The lysine–arginine preparation showed better tolerance than the commercial solution. The change to LysArg reduced the antiemetic premedication from four molecules to one. Full article
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4 pages, 180 KiB  
Editorial
Neuroendocrine Tumors: Treatment and Management
by Alessio Imperiale
Cancers 2022, 14(16), 4048; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14164048 - 22 Aug 2022
Viewed by 1176
Abstract
This Topical Collection consists of a series of articles presented by a panel of internationally recognized experts and compiles several clinical accomplishments in the field of neuroendocrine tumors (NETs) [...] Full article
13 pages, 2514 KiB  
Review
Update on Epidemiology, Diagnosis, and Biomarkers in Gastroenteropancreatic Neuroendocrine Neoplasms
by Daisuke Takayanagi, Hourin Cho, Erika Machida, Atsushi Kawamura, Atsuo Takashima, Satoshi Wada, Takuya Tsunoda, Takashi Kohno and Kouya Shiraishi
Cancers 2022, 14(5), 1119; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051119 - 22 Feb 2022
Cited by 26 | Viewed by 3290
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of malignancies that originate from the diffuse neuroendocrine cell system of the pancreas and gastrointestinal tract and have increasingly increased in number over the decades. GEP-NENs are roughly classified into well-differentiated neuroendocrine tumors and poorly [...] Read more.
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of malignancies that originate from the diffuse neuroendocrine cell system of the pancreas and gastrointestinal tract and have increasingly increased in number over the decades. GEP-NENs are roughly classified into well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas; it is essential to understand the pathological classification according to the mitotic count and Ki67 proliferation index. In addition, with the advent of molecular-targeted drugs and somatostatin analogs and advances in endoscopic and surgical treatments, the multidisciplinary treatment of GEP-NENs has made great progress. In the management of GEP-NENs, accurate diagnosis is key for the proper selection among these diversified treatment methods. The evaluation of hormone-producing ability, diagnostic imaging, and histological diagnosis is central. Advances in the study of the genetic landscape have led to deeper understanding of tumor biology; it has also become possible to identify druggable mutations and predict therapeutic effects. Liquid biopsy, based on blood mRNA expression for GEP-NENs, has been developed, and is useful not only for early detection but also for assessing minimal residual disease after surgery and prediction of therapeutic effects. This review outlines the updates and future prospects of the epidemiology, diagnosis, and management of GEP-NENs. Full article
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10 pages, 803 KiB  
Communication
Simultaneous Resection of Pancreatic Neuroendocrine Tumors with Synchronous Liver Metastases: Safety and Oncological Efficacy
by Pietro Addeo, Caterina Cusumano, Bernard Goichot, Martina Guerra, François Faitot, Alessio Imperiale and Philippe Bachellier
Cancers 2022, 14(3), 727; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030727 - 30 Jan 2022
Cited by 6 | Viewed by 1999
Abstract
Whether the simultaneous resection of pancreatic neuroendocrine tumors (PNET) with synchronous liver metastases (LM) is safe and oncologically efficacious remains to be debated. We retrospectively reviewed clinical data from patients who underwent the simultaneous resection of PNETs with LMs over the last 25 [...] Read more.
Whether the simultaneous resection of pancreatic neuroendocrine tumors (PNET) with synchronous liver metastases (LM) is safe and oncologically efficacious remains to be debated. We retrospectively reviewed clinical data from patients who underwent the simultaneous resection of PNETs with LMs over the last 25 years. Fifty-one consecutive patients with a median age of 54 years (range 27–80 years) underwent pancreaticoduodenectomy (PD) (n = 16), distal pancreatosplenectomy (DSP) (n = 32) or total pancreatectomy (n = 3) with synchronous LM resection. There were no differences in the postoperative outcomes in term of mortality (p = 0.33) and morbidity (p = 0.76) between PD and DSP. The median overall survival (OS) was 64.78 months (95% CI: 49.7–119.8), and the overall survival rates at 1, 3, and 5 years were 97.9%, 86.2% and 61%, respectively. The OS varied according to the tumor grade (G): G1 (OS 128 months, 5-year OS 83%) vs. G2 (OS 60.5 months, 5-year OS 58%) vs. G3 (OS 49.7 months, 5-year OS 0%) (p = 0.03). Multivariate Cox analysis identified G as the only prognostic factor (HR: 5.56; 95% CI: 0.91–9.60; p = 0.01). Simultaneous PNETS with LMs can be performed safely with acceptable morbidity and mortality at tertiary centers. Well-differentiated PNETs had longer survival and might benefit the most from these extended surgeries. Full article
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2021

Jump to: 2023, 2022

17 pages, 1886 KiB  
Review
The Role of Conventionally Fractionated Radiotherapy and Stereotactic Radiotherapy in the Treatment of Carcinoid Tumors and Large-Cell Neuroendocrine Cancer of the Lung
by Mateusz Bilski, Paulina Mertowska, Sebastian Mertowski, Marcin Sawicki, Anna Hymos, Paulina Niedźwiedzka-Rystwej and Ewelina Grywalska
Cancers 2022, 14(1), 177; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010177 - 30 Dec 2021
Cited by 3 | Viewed by 3933
Abstract
The occurrence of neuroendocrine tumors among the diagnosed neoplasms is extremely rare and is associated with difficulties in undertaking effective therapy due to the histopathological differentiation of individual subtypes and the scarce clinical data and recommendations found in the literature. The choice of [...] Read more.
The occurrence of neuroendocrine tumors among the diagnosed neoplasms is extremely rare and is associated with difficulties in undertaking effective therapy due to the histopathological differentiation of individual subtypes and the scarce clinical data and recommendations found in the literature. The choice of treatment largely depends not only on its type, but also on the location and production of excess hormones by the tumor itself. Common therapeutic approaches include surgical removal of the tumor, the use of chemotherapy, targeted drug therapy, peptide receptor radionuclide therapy, and the use of radiation therapy. This article reviews the current knowledge on the classification and application of radiotherapy in the treatment of lung NETs. Case reports were presented in which treatment with conventional radiotherapy, radical and palliative radiochemotherapy, as well as stereotactic fractionated radiotherapy in the treatment of typical (TC) and atypical (AT) lung carcinoids and large cell neuroendocrine carcinoma (LCNC) were used. We hope that the solutions presented in the literature will allow many radiation oncologists to make the best, often personalized decisions about the therapeutic qualifications of patients. Full article
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32 pages, 2544 KiB  
Review
Peptide Receptor Radionuclide Therapy Targeting the Somatostatin Receptor: Basic Principles, Clinical Applications and Optimization Strategies
by Niloefar Ahmadi Bidakhvidi, Karolien Goffin, Jeroen Dekervel, Kristof Baete, Kristiaan Nackaerts, Paul Clement, Eric Van Cutsem, Chris Verslype and Christophe M. Deroose
Cancers 2022, 14(1), 129; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010129 - 28 Dec 2021
Cited by 20 | Viewed by 3787
Abstract
Peptide receptor radionuclide therapy (PRRT) consists of the administration of a tumor-targeting radiopharmaceutical into the circulation of a patient. The radiopharmaceutical will bind to a specific peptide receptor leading to tumor-specific binding and retention. The only target that is currently used in clinical [...] Read more.
Peptide receptor radionuclide therapy (PRRT) consists of the administration of a tumor-targeting radiopharmaceutical into the circulation of a patient. The radiopharmaceutical will bind to a specific peptide receptor leading to tumor-specific binding and retention. The only target that is currently used in clinical practice is the somatostatin receptor (SSTR), which is overexpressed on a range of tumor cells, including neuroendocrine tumors and neural-crest derived tumors. Academia played an important role in the development of PRRT, which has led to heterogeneous literature over the last two decades, as no standard radiopharmaceutical or regimen has been available for a long time. This review provides a summary of the treatment efficacy (e.g., response rates and symptom-relief), impact on patient outcome and toxicity profile of PRRT performed with different generations of SSTR-targeting radiopharmaceuticals, including the landmark randomized-controlled trial NETTER-1. In addition, multiple optimization strategies for PRRT are discussed, i.e., the dose–effect concept, dosimetry, combination therapies (i.e., tandem/duo PRRT, chemoPRRT, targeted molecular therapy, somatostatin analogues and radiosensitizers), new radiopharmaceuticals (i.e., SSTR-antagonists, Evans-blue containing vector molecules and alpha-emitters), administration route (intra-arterial versus intravenous) and response prediction via molecular testing or imaging. The evolution and continuous refinement of PRRT resulted in many lessons for the future development of radionuclide therapy aimed at other targets and tumor types. Full article
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16 pages, 9152 KiB  
Review
Liver-Directed Therapy for Neuroendocrine Metastases: From Interventional Radiology to Nuclear Medicine Procedures
by Roberto Luigi Cazzato, Fabrice Hubelé, Pierre De Marini, Eric Ouvrard, Julien Salvadori, Pietro Addeo, Julien Garnon, Jean-Emmanuel Kurtz, Michel Greget, Luc Mertz, Bernard Goichot, Afshin Gangi and Alessio Imperiale
Cancers 2021, 13(24), 6368; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246368 - 19 Dec 2021
Cited by 12 | Viewed by 2875
Abstract
Neuroendocrine neoplasms (NENs) are rare and heterogeneous epithelial tumors most commonly arising from the gastroenteropancreatic (GEP) system. GEP-NENs account for approximately 60% of all NENs, and the small intestine and pancreas represent two most common sites of primary tumor development. Approximately 80% of [...] Read more.
Neuroendocrine neoplasms (NENs) are rare and heterogeneous epithelial tumors most commonly arising from the gastroenteropancreatic (GEP) system. GEP-NENs account for approximately 60% of all NENs, and the small intestine and pancreas represent two most common sites of primary tumor development. Approximately 80% of metastatic patients have secondary liver lesions, and in approximately 50% of patients, the liver is the only metastatic site. The therapeutic strategy depends on the degree of hepatic metastatic invasion, ranging from liver surgery or percutaneous ablation to palliative treatments to reduce both tumor volume and secretion. In patients with grade 1 and 2 NENs, locoregional nonsurgical treatments of liver metastases mainly include percutaneous ablation and endovascular treatments, targeting few or multiple hepatic metastases, respectively. In the present work, we provide a narrative review of the current knowledge on liver-directed therapy for metastasis treatment, including both interventional radiology procedures and nuclear medicine options in NEN patients, taking into account the patient clinical context and both the strengths and limitations of each modality. Full article
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12 pages, 590 KiB  
Article
Safety and Efficacy of Peptide-Receptor Radionuclide Therapy in Elderly Neuroendocrine Tumor Patients
by Deborah Theiler, Marco Cattaneo, Lawrence O. Dierickx, Peter Igaz, Simona Grozinsky-Glasberg, Claire Bournaud, Thomas O’Dorisio, M. Sue O’Dorisio, Damian Wild, Emanuel Christ and Guillaume P. Nicolas
Cancers 2021, 13(24), 6290; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246290 - 15 Dec 2021
Cited by 5 | Viewed by 2049
Abstract
Peptide receptor radionuclide therapy (PRRT) is a well-established treatment in somatostatin receptor-expressing neuroendocrine tumours (NETs). The safety and efficacy of PRRT in >79 years old patients (EP) have not been systematically investigated. All patients with inoperable/metastatic/progressive G1/G2 NET, >79 years (EP), treated with [...] Read more.
Peptide receptor radionuclide therapy (PRRT) is a well-established treatment in somatostatin receptor-expressing neuroendocrine tumours (NETs). The safety and efficacy of PRRT in >79 years old patients (EP) have not been systematically investigated. All patients with inoperable/metastatic/progressive G1/G2 NET, >79 years (EP), treated with PRRT at the University Hospital of Basel between 2006 and 2018, were enrolled in this retrospective matched cohort study. Each patient was manually matched with ≥1 younger patient (YP = 60–70 years). The primary endpoint was toxicity. Toxicity (subacute, long-term) was graded according to the criteria for adverse events (CTCAE) v5.0. All toxicity grades ≥ 3, or whose delta (Δ) to baseline were ≥2, were considered significant. The odds ratio (OR) for developing toxicity was tested for non-inferiority of EP vs. YP. Clinical response to PRRT and overall survival (OS) were assessed as secondary outcome measures. Forty-eight EP and 68 YP were enrolled. Both cohorts were balanced regarding median time since diagnosis, tumour location, grading, treatment scheme, and baseline biochemical parameters, except for eGFR (EP: 61 ± 16 vs. YP: 78 ± 19; mL/min/1.73 m2). Twenty-two grade ≥ 3 or Δ ≥ 2 subacute hematotoxicities occurred in 10 EP (10.3% of cycles) and 37 in 19 YP (11.6% of cycles; p = NS). Long-term grade ≥ 3 renal toxicity occurred in 7 EP and 2 YP (p = NS). The median OS was 3.4 years (EP) vs. 6.0 years (YP), HR: 1.50 [0.75, 2.98], p = NS. PRRT is a valid therapeutic option in elderly NET patients with similar toxicity and non-inferior survival compared to matched younger patients. Full article
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20 pages, 758 KiB  
Review
Updated Principles of Surgical Management of Pancreatic Neuroendocrine Tumours (pNETs): What Every Surgeon Needs to Know
by Charles de Ponthaud, Fabrice Menegaux and Sébastien Gaujoux
Cancers 2021, 13(23), 5969; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13235969 - 27 Nov 2021
Cited by 6 | Viewed by 2762
Abstract
Pancreatic neuroendocrine tumours (pNETs) represent 1 to 2% of all pancreatic neoplasm with an increasing incidence. They have a varied clinical, biological and radiological presentation, depending on whether they are sporadic or genetic in origin, whether they are functional or non-functional, and whether [...] Read more.
Pancreatic neuroendocrine tumours (pNETs) represent 1 to 2% of all pancreatic neoplasm with an increasing incidence. They have a varied clinical, biological and radiological presentation, depending on whether they are sporadic or genetic in origin, whether they are functional or non-functional, and whether there is a single or multiple lesions. These pNETs are often diagnosed at an advanced stage with locoregional lymph nodes invasion or distant metastases. In most cases, the gold standard curative treatment is surgical resection of the pancreatic tumour, but the postoperative complications and functional consequences are not negligible. Thus, these patients should be managed in specialised high-volume centres with multidisciplinary discussion involving surgeons, oncologists, radiologists and pathologists. Innovative managements such as “watch and wait” strategies, parenchymal sparing surgery and minimally invasive approach are emerging. The correct use of all these therapeutic options requires a good selection of patients but also a constant update of knowledge. The aim of this work is to update the surgical management of pNETs and to highlight key elements in view of the recent literature. Full article
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23 pages, 1156 KiB  
Review
What Are the Place and Modalities of Surgical Management for Pancreatic Neuroendocrine Neoplasms? A Narrative Review
by Samuel Frey, Eric Mirallié, Maëlle Le Bras and Nicolas Regenet
Cancers 2021, 13(23), 5954; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13235954 - 26 Nov 2021
Cited by 3 | Viewed by 1935
Abstract
Pancreatic neuroendocrine neoplasms (panNENs) are a heterogeneous group of tumors derived from cells with neuroendocrine differentiation. They are considered malignant by default. However, their outcomes are variable depending on their presentation in the onset of hereditary syndromes, hormonal secretion, grading, and extension. Therefore, [...] Read more.
Pancreatic neuroendocrine neoplasms (panNENs) are a heterogeneous group of tumors derived from cells with neuroendocrine differentiation. They are considered malignant by default. However, their outcomes are variable depending on their presentation in the onset of hereditary syndromes, hormonal secretion, grading, and extension. Therefore, although surgical treatment has long been suggested as the only treatment of pancreatic neuroendocrine neoplasms, its modalities are an evolving landscape. For selected patients (small, localized, non-functional panNENs), a “wait and see” strategy is suggested, as it is in the setting of multiple neuroendocrine neoplasia type 1, but the accurate size cut-off remains to be established. Parenchyma-sparring pancreatectomy, aiming to limit pancreatic insufficiency, are also emerging procedures, which place beyond the treatment of insulinomas and small non-functional panNENs (in association with lymph node picking) remains to be clarified. Furthermore, giving the fact that the liver is generally the only metastatic site, surgery keeps a place of choice alongside medical therapies in the treatment of metastatic disease, but its modalities and extensions are still a matter of debate. This narrative review aims to describe the current recommended surgical management for pancreatic NENs and controversies in light of the actual recommendations and recent literature. Full article
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10 pages, 1993 KiB  
Article
Principles of Surgical Management of Small Intestinal NET
by Arnaud Pasquer, Thomas Walter, Laurent Milot, Valérie Hervieu and Gilles Poncet
Cancers 2021, 13(21), 5473; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215473 - 30 Oct 2021
Cited by 7 | Viewed by 2058
Abstract
Introduction: Small-intestinal neuroendocrine tumors (siNETs) account for 25% of gastroenteropancreatic NETs. Multiple siNETs appear to develop in a limited segment of the small bowel (SB), 89% of them being located in the ileum, most often within 100 cm of the ileocecal valve (ICV). [...] Read more.
Introduction: Small-intestinal neuroendocrine tumors (siNETs) account for 25% of gastroenteropancreatic NETs. Multiple siNETs appear to develop in a limited segment of the small bowel (SB), 89% of them being located in the ileum, most often within 100 cm of the ileocecal valve (ICV). According to the European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC), all localized siNETs should be considered for radical surgical resection with adequate lymphadenectomy irrespective of the absence of lymphadenopathy or mesenteric involvement. Surgical management of siNETs: The preoperative workout should include a precise evaluation of past medical and surgical history, focusing on the symptoms of carcinoid syndrome (flush, diarrhea, and cardiac failure). Morphological evaluation should include a CT scan including a thin-slice arterial CT, a PET/CT with 68 Ga, and a hepatic MRI in cases of suspected metastasis. Levels of 24 h urinary 5-hydroxyindoleacetic acid are needed. Regarding surgery, the limiting component is the number of free jejunal branches allowing a resection without risk of short small bowel syndrome. The laparoscopic approach has been poorly studied, and open laparotomy remains the gold standard to explore the abdominal cavity and entirely palpate the small bowel through bidigital palpation and compression. An extensive lymphadenectomy is required. A prophylactic cholecystectomy should be performed. In case of emergency surgery, current recommendations are not definitive. However, there is expert agreement that it is not reasonable to initiate resection of the mesenteric mass without comprehensive workup and mapping. Conclusion: The surgery of siNETs is in constant evolution. The challenge lies in the ability to propose a resection without imposing short small bowel syndrome on the patients. The oncological benefits supported in the literature led to recent changes in the recommendations of academic societies. The next steps remain the dissemination of reproducible quality criteria to perform these procedures. Full article
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12 pages, 257 KiB  
Article
Efficacy and Cerebrospinal Fluid Rhinorrhea after Cabergoline Treatment in Patients with Bioactive Macroprolactinoma
by Hae-Kyung Kim, Jae-Won Hong, Ju-Hyung Moon, Sung-Soo Ahn, Eui-Hyun Kim, Seung-Koo Lee, Eun-Jig Lee, Yae-Won Park and Cheol-Ryong Ku
Cancers 2021, 13(21), 5374; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215374 - 26 Oct 2021
Cited by 1 | Viewed by 1697
Abstract
Predicting dopamine agonist resistance in patients with macroprolactinoma is essential for clinicians to prevent treatment failure and subsequent complications such as medication-induced cerebrospinal fluid (CSF) rhinorrhea. We evaluated the features of patients with cabergoline resistance and CSF rhinorrhea in patients with prolactinomas with [...] Read more.
Predicting dopamine agonist resistance in patients with macroprolactinoma is essential for clinicians to prevent treatment failure and subsequent complications such as medication-induced cerebrospinal fluid (CSF) rhinorrhea. We evaluated the features of patients with cabergoline resistance and CSF rhinorrhea in patients with prolactinomas with prolactin levels ≥1000 ng/mL. A total of 140 patients who were newly diagnosed with prolactinoma secreting only prolactin ≥1000 ng/mL and treated with cabergoline for the first time were included in this study. Based on the hormonal and radiologic response of the prolactinoma, the patients were divided into responders and non-responders. Non-responders (36/140, 25.8%) included a higher number of patients receiving hormone replacement than responders (responders, n (%) = 12(11.5) vs. non-responders = 13(36.1), p = 0.001). In propensity score matching analysis, patients who developed CSF rhinorrhea presented more frequent hormone deficiency than responders regardless of initial cabergoline dose. Hormone deficiency was associated with a greater odds ratio for the risk of non-responders (adjusted odds ratio = 5.13, 95% CI 1.96–13.46, p = 0.001). Cabergoline was effective in bioactive macroprolactinoma. Furthermore, initial cabergoline dose was not significantly associated with long-term responsiveness and development of CSF rhinorrhea but the hypopituitarism was independently associated with an increased risk of cabergoline resistance and CSF rhinorrhea. Full article
19 pages, 314 KiB  
Review
PET with Different Radiopharmaceuticals in Neuroendocrine Neoplasms: An Umbrella Review of Published Meta-Analyses
by Giorgio Treglia, Ramin Sadeghi, Francesco Giovinazzo, Federica Galiandro, Salvatore Annunziata, Barbara Muoio and Alexander Stephan Kroiss
Cancers 2021, 13(20), 5172; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205172 - 15 Oct 2021
Cited by 21 | Viewed by 1754
Abstract
Background: Several meta-analyses have reported quantitative data about the diagnostic performance, the prognostic value, the impact on management and the safety of positron emission tomography (PET) including related hybrid modalities (PET/CT or PET/MRI) using different radiopharmaceuticals in patients with neuroendocrine neoplasms. We performed [...] Read more.
Background: Several meta-analyses have reported quantitative data about the diagnostic performance, the prognostic value, the impact on management and the safety of positron emission tomography (PET) including related hybrid modalities (PET/CT or PET/MRI) using different radiopharmaceuticals in patients with neuroendocrine neoplasms. We performed an umbrella review of published meta-analyses to provide an evidence-based summary. Methods: A comprehensive literature search of meta-analyses listed in PubMed/MEDLINE and Cochrane Library databases was carried out (last search date: 30 June 2021). Results: Thirty-four published meta-analyses were selected and summarized. About the diagnostic performance: 68Ga-SSA PET yields high diagnostic performance in patients with NETs and PGL; 18F-FDOPA PET yields good diagnostic performance in patients with intestinal NETs, PGL, NB, being the best available PET method in detecting rMTC; 68Ga-exendin-4 PET has good diagnostic accuracy in detecting insulinomas; 18F-FDG PET has good diagnostic performance in detecting aggressive neuroendocrine neoplasms. About the prognostic value: 68Ga-SSA PET has a recognized prognostic value in well-differentiated NETs, whereas 18F-FDG PET has a recognized prognostic value in aggressive neuroendocrine neoplasms. A significant clinical impact of 68Ga-SSA PET and related hybrid modalities in patients with NETs was demonstrated. There are no major toxicities or safety issues related to the use of PET radiopharmaceuticals in patients with neuroendocrine neoplasms. Conclusions: Evidence-based data support the use of PET with different radiopharmaceuticals in patients with neuroendocrine neoplasms with specific indications for each radiopharmaceutical. Full article
16 pages, 1177 KiB  
Review
Neuroendocrine Carcinomas of the Digestive Tract: What Is New?
by Anna Pellat, Anne Ségolène Cottereau, Benoit Terris and Romain Coriat
Cancers 2021, 13(15), 3766; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153766 - 27 Jul 2021
Cited by 12 | Viewed by 3702
Abstract
Neuroendocrine carcinomas (NEC) are rare tumors with a rising incidence. They show poorly differentiated morphology with a high proliferation rate (Ki-67 index). They frequently arise in the lung (small and large-cell lung cancer) but rarely from the gastrointestinal tract. Due to their rarity, [...] Read more.
Neuroendocrine carcinomas (NEC) are rare tumors with a rising incidence. They show poorly differentiated morphology with a high proliferation rate (Ki-67 index). They frequently arise in the lung (small and large-cell lung cancer) but rarely from the gastrointestinal tract. Due to their rarity, very little is known about digestive NEC and few studies have been conducted. Therefore, most of therapeutic recommendations are issued from work on small-cell lung cancers (SCLC). Recent improvement in pathology and imaging has allowed for better detection and classification of high-grade NEN. The 2019 World Health Organization (WHO) classification has described a new entity of well-differentiated grade 3 neuroendocrine tumors (NET G-3), with better prognosis, that should be managed separately from NEC. NEC are aggressive neoplasms often diagnosed at a metastatic state. In the localized setting, surgery can be performed in selected patients followed by adjuvant platinum-based chemotherapy. Concurrent chemoradiotherapy is also an option for NEC of the lung, rectum, and esophagus. In metastatic NEC, chemotherapy is administered with a classic combination of platinum salts and etoposide in the first-line setting. Peptide receptor radionuclide therapy (PRRT) has shown positive results in high-grade NEN populations and immunotherapy trials are still ongoing. Available therapies have improved the overall survival of NEC but there is still an urgent need for improvement. This narrative review sums up the current data on digestive NEC while exploring future directions for their management. Full article
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19 pages, 12011 KiB  
Review
Digestive Well-Differentiated Grade 3 Neuroendocrine Tumors: Current Management and Future Directions
by Anna Pellat, Anne Ségolène Cottereau, Lola-Jade Palmieri, Philippe Soyer, Ugo Marchese, Catherine Brezault and Romain Coriat
Cancers 2021, 13(10), 2448; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102448 - 18 May 2021
Cited by 11 | Viewed by 2999
Abstract
Digestive well-differentiated grade 3 neuroendocrine tumors (NET G-3) have been clearly defined since the 2017 World Health Organization classification. They are still a rare category lacking specific data and standardized management. Their distinction from other types of neuroendocrine neoplasms (NEN) not only lies [...] Read more.
Digestive well-differentiated grade 3 neuroendocrine tumors (NET G-3) have been clearly defined since the 2017 World Health Organization classification. They are still a rare category lacking specific data and standardized management. Their distinction from other types of neuroendocrine neoplasms (NEN) not only lies in morphology but also in genotype, aggressiveness, functional imaging uptake, and treatment response. Most of the available data comes from pancreatic series, which is the most frequent tumor site for this entity. In the non-metastatic setting, surgical resection is recommended, irrespective of grade and tumor site. For metastatic NET G-3, chemotherapy is the main first-line treatment with temozolomide-based regimen showing more efficacy than platinum-based regimen, especially when Ki-67 index <55%. Targeted therapies, such as sunitinib and everolimus, have also shown some positive therapeutic efficacy in small samples of patients. Functional imaging plays a key role for detection but also treatment selection. In the second or further-line setting, peptide receptor radionuclide therapy has shown promising response rates in high-grade NEN. Finally, immunotherapy is currently investigated as a new therapeutic approach with trials still ongoing. More data will come with future work now focusing on this specific subgroup. The aim of this review is to summarize the current data on digestive NET G-3 and explore future directions for their management. Full article
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15 pages, 2837 KiB  
Systematic Review
Clinical Utility of 18F-FDG PET in Neuroendocrine Tumors Prior to Peptide Receptor Radionuclide Therapy: A Systematic Review and Meta-Analysis
by Emmanouil Alevroudis, Maria-Eleni Spei, Sofia N. Chatziioannou, Marina Tsoli, Göran Wallin, Gregory Kaltsas and Kosmas Daskalakis
Cancers 2021, 13(8), 1813; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081813 - 10 Apr 2021
Cited by 32 | Viewed by 3618
Abstract
The role of 18F-FDG PET in patients with variable grades of neuroendocrine tumors (NETs) prior to peptide receptor radionuclide therapy (PRRT) has not been adequately elucidated. We aimed to evaluate the impact of 18F-FDG PET status on disease control rate (DCR), [...] Read more.
The role of 18F-FDG PET in patients with variable grades of neuroendocrine tumors (NETs) prior to peptide receptor radionuclide therapy (PRRT) has not been adequately elucidated. We aimed to evaluate the impact of 18F-FDG PET status on disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in neuroendocrine tumor (NET) patients receiving PRRT. We searched the MEDLINE, Embase, Cochrane Library, and Web of Science databases up to July 2020 and used the Newcastle-Ottawa scale (NOS) criteria to assess quality/risk of bias. A total of 5091 articles were screened. In 12 studies, 1492 unique patients with NETs of different origins were included. The DCR for patients with negative 18F-FDG PET status prior to PRRT initiation was 91.9%, compared to 74.2% in patients with positive 18F-FDG PET status (random effects odds ratio (OR): 4.85; 95% CI: 2.27–10.36). Adjusted analysis of pooled hazard ratios (HRs) confirmed longer PFS and OS in NET patients receiving PRRT with negative 18F-FDG PET (random effects HR:2.45; 95%CIs: 1.48–4.04 and HR:2.25; 95% CIs:1.55–3.28, respectively). In conclusion, 18F-FDG PET imaging prior to PRRT administration appears to be a useful tool in NET patients to predict tumor response and survival outcomes and a negative FDG uptake of the tumor is associated with prolonged PFS and OS. Full article
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10 pages, 1164 KiB  
Article
Incidence and Survival Outcomes in Patients with Lung Neuroendocrine Neoplasms in the United States
by Shrunjal Shah, Rohit Gosain, Adrienne Groman, Rahul Gosain, Arvind Dasari, Thorvardur R. Halfdanarson and Sarbajit Mukherjee
Cancers 2021, 13(8), 1753; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081753 - 07 Apr 2021
Cited by 28 | Viewed by 3356
Abstract
Background: The incidence and prevalence of neuroendocrine neoplasms (NENs) are rapidly rising. Epidemiologic trends have been reported for common NENs, but specific data for lung NENs are lacking. Methods: We conducted a retrospective analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database. [...] Read more.
Background: The incidence and prevalence of neuroendocrine neoplasms (NENs) are rapidly rising. Epidemiologic trends have been reported for common NENs, but specific data for lung NENs are lacking. Methods: We conducted a retrospective analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Associated population data were utilized to report the annual age-adjusted incidence and overall survival (OS) trends. Trends for large-cell neuroendocrine carcinoma (LCNEC) and atypical carcinoid (AC) were reported from 2000–2015, while those for typical carcinoid (TC) and small cell lung cancer (SCLC) were reported from 1988–2015. Results: We examined a total of 124,969 lung NENs [103,890—SCLC; 3303—LCNEC; 8146—TC; 656—AC; 8974—Other]. The age-adjusted incidence rate revealed a decline in SCLC from 8.6 in 1988 to 5.3 in 2015 per 100,000; while other NENs showed an increase: TC increased from 0.57 in 1988 to 0.77 in 2015, AC increased from 0.17 in 2001 to 0.22 in 2015, and LCNEC increased from 0.16 in 2000 to 0.41 in 2015. The 5-year OS rate among SCLC, LCNEC, AC, and TC patients was 5%, 17%, 64%, and 84%, respectively. On multivariable analyses, OS and disease-specific survival (DSS) varied significantly by stage, sex, histological type, insurance type, marital status, and race, with a better survival noted in earlier stages, females, married, insured, Hispanic and other races, and urban population. Similarly, TC and AC had better survival compared to SCLC and LCNEC. Conclusion: The incidence of lung NENs is rising, possibly in part because of advanced radiological techniques. However, the incidence of SCLCs is waning, likely because of declining smoking habits. Such population-based studies are essential for resource allocation and to prioritize future research directions. Full article
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12 pages, 1140 KiB  
Article
The Prognostic Value of the De Ritis Ratio for Progression-Free Survival in Patients with NET Undergoing [177Lu]Lu-DOTATOC-PRRT: A Retrospective Analysis
by Tristan Ruhwedel, Julian M. M. Rogasch, Kai Huang, Henning Jann, Imke Schatka, Christian Furth, Holger Amthauer and Christoph Wetz
Cancers 2021, 13(4), 635; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040635 - 05 Feb 2021
Cited by 10 | Viewed by 2478
Abstract
Background: The De Ritis ratio (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) has demonstrated prognostic value in various cancer entities. We evaluated the prognostic capability of the De Ritis ratio in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). Methods: Unicentric, [...] Read more.
Background: The De Ritis ratio (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) has demonstrated prognostic value in various cancer entities. We evaluated the prognostic capability of the De Ritis ratio in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). Methods: Unicentric, retrospective analysis of 125 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC (female: 37%; median age: 66 years; G1+G2 NET: 95%). The prognostic value regarding progression-free survival (PFS) was analyzed with univariable and multivariable Cox regression. Prognostic accuracy was determined with Harrell’s C index and a likelihood ratio test. Results: Progression, relapse, or death after PRRT was observed in 102/125 patients. Median progression-free survival (PFS) was 15.8 months. Pancreatic or pulmonary origin, high De Ritis ratio, and high Chromogranin A (CgA) significantly predicted shorter PFS in univariable Cox. In multivariable Cox regression, only high De Ritis ratio >0.927 (HR: 1.7; p = 0.047) and high CgA >twice the upper normal limit (HR: 2.1; p = 0.005) remained independent predictors of shorter PFS. Adding the De Ritis ratio to the multivariable Cox model (age, Eastern Cooperative Oncology Group (ECOG) performance status, primary origin, CgA) significantly improved prognostic accuracy (p < 0.001). Conclusions: The De Ritis ratio is simple to obtain in clinical routine and can provide independent prognostic value for PFS in patients with NET undergoing PRRT. Full article
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