Everolimus as first line therapy for pancreatic neuroendocrine tumours: current knowledge and future perspectives
urpose Everolimus has been shown to be effective for advanced pancreatic neuroendocrine tumours (pNETs), but its positioning in the therapeutic algorithm for pNETs is matter of debate. Methods With the aim to shed light on this point, we performed an up-to-date critical review taking into account the results of both retrospective and prospective published studies, and the recommendations of international guidelines. In addition, we performed an extensive search on the Clinical Trial Registries databases worldwide, to gather information on the ongoing clinical trials related to this specific topic. Results We identified eight retrospective published studies, two prospective published studies…
Predictive factors of response to mTOR inhibitors in neuroendocrine tumours
Medical treatment of neuroendocrine tumours (NETs) has drawn a lot of attention due to the recent demonstration of efficacy of several drugs on progression-free survival, including somatostatin analogs, small tyrosine kinase inhibitors and mTOR inhibitors (or rapalogs). The latter are approved as therapeutic agents in advanced pancreatic NETs and have been demonstrated to be effective in different types of NETs, with variable efficacy due to the development of resistance to treatment. Early detection of patients that may benefit from rapalogs treatment is of paramount importance in order to select the better treatment and avoid ineffective and expensive treatments. Predictive markers for th…
Early prediction of pancreatic cancer from new-onset diabetes: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper
Pancreatic cancer (PC) is a common cause of cancer-related death, due to difficulties in detecting early-stage disease, to its aggressive behaviour, and to poor response to systemic therapy. Therefore, developing strategies for early diagnosis of resectable PC is critical for improving survival. Diabetes mellitus is another major public health problem worldwide. Furthermore, diabetes can represent both a risk factor and a consequence of PC: nowadays, the relationship between these two diseases is considered a high priority for research. New-onset diabetes can be an early manifestation of PC, especially in a thin adult without a family history of diabetes. However, even if targeted screening…
Impact of the SARS-CoV2 pandemic dissemination on the management of neuroendocrine neoplasia in Italy: a report from the Italian Association for Neuroendocrine Tumors (Itanet)
Introduction The organization of the healthcare system has significantly changed after the recent COVID-19 outbreak, with a negative impact on the management of oncological patients. The present survey reports data collected by the Italian Association for Neuroendocrine Tumors on the management of patients with neuroendocrine neoplasia (NEN) during the pandemic dissemination. Methods A survey with 57 questions was sent to NEN-dedicated Italian centers regarding the management of patients in the period March 9, 2020, to May 9, 2020 Results The main modification in the centers’ activity consisted of decreases in newly diagnosed NEN patients (− 76.8%), decreases in performed surgical procedure…
Corticosteroids in oncology: Use, overuse, indications, contraindications. An Italian Association of Medical Oncology (AIOM)/ Italian Association of Medical Diabetologists (AMD)/ Italian Society of Endocrinology (SIE)/ Italian Society of Pharmacology (SIF) multidisciplinary consensus position paper
Corticosteroids (CSs) are widely used in oncology, presenting several different indications. They are useful for induction of apoptosis in hematological neoplasms, for management of anaphylaxis and cytokine release/hypersensitivity reaction and for the symptomatic treatment of many tumour- and treatment-related complications. If the employment of CSs in the oncological setting results in several benefits for patients and satisfaction for clinicians, on the other hand, many potential adverse events (AEs), both during treatment and after withdrawal of CSs, as well as the duality of the effects of these compounds in oncology, recommend being cautious in clinical practice. To date, several gray…
Efficacy and safety of everolimus in extrapancreatic neuroendocrine tumor: a comprehensive review of literature
BACKGROUND Everolimus, an oral mTOR (mammalian target of rapamycin) inhibitor, is currently approved for the treatment of progressive pancreatic neuroendocrine tumors (NETs). Although promising, only scattered data, often from nondedicated studies, are available for extrapancreatic NETs. PATIENTS AND METHODS A systematic review of the published data was performed concerning the use of everolimus in extrapancreatic NET, with the aim of summarizing the current knowledge on its efficacy and tolerability. Moreover, the usefulness of everolimus was evaluated according to the different sites of the primary. RESULTS The present study included 22 different publications, including 874 patients and 4…
Metabolic disorders and gastroenteropancreatic-neuroendocrine tumors (GEP-NETs): How do they influence each other? An Italian Association of Medical Oncology (AIOM)/ Italian Association of Medical Diabetologists (AMD)/ Italian Society of Endocrinology (SIE)/ Italian Society of Pharmacology (SIF) multidisciplinary consensus position paper
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of malignancies derived from neuroendocrine cells that can occur anywhere along the gastrointestinal tract. GEP-NETs incidence has been steadily increasing over the past decades, in parallel with the increasing incidence of the metabolic syndrome (MetS). It is not yet fully known whether the MetS components (such as obesity, dyslipidemia and type 2 diabetes) could be involved in the etiology of GEP-NETs or could influence their outcomes. In this review, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Endocrinology…
Antineoplastic dosing in overweight and obese cancer patients: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper
Most anticancer molecules are administered in body-size-based dosing schedules, bringing up unsolved issues regarding pharmacokinetic data in heavy patients. The worldwide spread of obesity has not been matched by improved methods and strategies for tailored drug dosage in this population. The weight or body surface area (BSA)-based approaches may fail to fully reflect the complexity of the anthropometric features besides obesity in cancer patients suffering from sarcopenia. Likewise, there is a lack of pharmacokinetic data on obese patients for the majority of chemotherapeutic agents as well as for new target drugs and immunotherapy. Therefore, although the available findings point to the …
ENDOCRINE TUMOURS: Calcitonin in thyroid and extra-thyroid neuroendocrine neoplasms: the two-faced Janus.
An increased calcitonin serum level is suggestive of a medullary thyroid cancer (MTC), but is not pathognomonic. The possibility of false positives or other calcitonin-secreting neuroendocrine neoplasms (NENs) should be considered. Serum calcitonin levels are generally assessed by immunoradiometric and chemiluminescent assays with high sensitivity and specificity; however, slightly moderately elevated levels could be attributable to various confounding factors. Calcitonin values >100 pg/mL are strongly suspicious of malignancy, whereas in patients with moderately elevated values (10–100 pg/mL) a stimulation test may be applied to improve diagnostic accuracy. Although the standard protoco…
Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor
Abstract Purpose To evaluate the antiproliferative activity and safety of nonconventional high doses of somatostatin analogs (HD-SSA) in patients with well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NET) with radiological disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria on a previous treatment. Methods A retrospective analysis of prospectively maintained databases from 13 Italian NET-dedicated centers was performed. Main inclusion criteria were: well-differentiated G1 or G2 GEP-NET, progressive disease on a previous treatment, and subsequent treatment with HD-SSA (either by increased administered dose [dose intensity] or…
Safety of high doses of somatostatin analogs in well differentiated NENs in elderly
Abstract Background Neuroendocrine neoplasms (NENs) are a group of heterogeneous neoplasms which can be treated with different therapies: in well differentiated (WD) NENs analogs of somatostatin (SSA) can be used considering their proved antineoplastic and antisecretory effects. This is a multicenter study to investigate the safety of high doses (HDD) analogs of somatostatin (SSA) in WD NENs with particular attention for patients over 70 years of age. Methods We collected clinical data from 13 Italian NENs dedicated Units. Patients with WD NENs, in progression on previous treatments, included SSA, and subsequently treated with HDD-SSA, were considered. Results 170 pts were included: 61.76% …
A rare rarity: neuroendocrine tumor of the esophagus
Abstract Esophageal Neuroendocrine tumors (NETs) are rare, aggressive and lacking specific symptoms. This causes a diagnostic delay, worsening the prognosis. Numerous cases are reported in literature, without a consensus on the management. Our aim was to clarify epidemiology, clinical presentation, diagnostic, therapeutic management of esophageal NETs. Extensive literature search identified a total of 226 articles. One hundred twenty-five articles (n = 1676) met the inclusion criteria, showing that: the incidence of esophageal NET varies geographically; men (60–70 years) are more affected; smoking and alcohol abuse are the major risk factors; dysphagia, weight loss, appetite loss are the mo…
Lanreotide Therapy vs Active Surveillance in MEN1-Related Pancreatic Neuroendocrine Tumors2 Centimeters.
Abstract Purpose Pancreatic neuroendocrine tumors (pNETs) are frequent in multiple endocrine neoplasia type 1 (MEN1) syndrome. They are usually not surgically treated unless larger than 1 to 2 cm or a growth rate > 0.5 cm per year. Somatostatin analogues represent one of the main therapeutic options in pNETs, but they have never been prospectively investigated in MEN1-related pNETs. The aim of this study was to prospectively evaluate the effectiveness of lanreotide in patients with MEN1-related pNETs < 2 cm. Methods MEN1 patients with 1 or more pNETs < 2 cm of maximal diameter were considered. Study design was prospective observational, comparing patients treated with l…
Neuroendocrine Tumors: A Comprehensive Review on Nutritional Approaches.
Simple Summary Neuroendocrine neoplasms and their main subtype neuroendocrine tumors have an increasing incidence worldwide, associated with a high survival and prevalence rate. Both the tumor itself and systemic therapy can have an impact on patients' nutrition. Conversely, preliminary data suggest that malnutrition has a negative impact on the development and prognosis of neuroendocrine tumors, as does obesity. The aim of this review is to condense the latest evidence on the role of the most widely used dietary patterns, the Mediterranean diet, the ketogenic diet and intermittent fasting, in the context of neuroendocrine tumors. Nutritional plans are an integral part of the multidisciplin…
Case Report: Unmasking Hypercalcemia in Patients With Neuroendocrine Neoplasms. Experience From Six Italian Referral Centers
BackgroundHypercalcemia is a common paraneoplastic syndrome which can occur in up to 10% of patients with advanced neoplasms. Paraneoplastic parathyroid hormone-related protein (PTHrP) represents the most frequent cause of this syndrome. In neuroendocrine neoplasms (NENs) paraneoplastic hypercalcemia is rare.Case SeriesThe present series includes all patients with NENs and paraneoplastic hypercalcemia from four Italian centres: (I) A 40-year-old man was hospitalized for repeated episodes of falls, hyposthenia and drowsiness. Severe hypercalcemia was found. Metastatic pancreatic G2 NEN and PTHrP-related hypercalcemia were diagnosed. The patient started therapy with somatostatin analogs (SSA)…
From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell?
AbstractGut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host’s metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host’s immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microb…
The Zollinger-Ellison syndrome: is there a role for somatostatin analogues in the treatment of the gastrinoma?
Purpose: Analyze the role of somatostatin analogues (SSAs) in the treatment of sporadic and MEN1-related gastrinomas, trying to define whether recent trials have changed the landscape of gastrinoma therapy. Methods: We evaluate the rationale of SSA use in the treatment of gastrinomas, summarize the current literature concerning the effect of SSAs on the control of Zollinger-Ellison syndrome (ZES) and gastrinomas tumor progression and discuss their role in the most recent guidelines. Results: The medical treatment of gastrinoma and related ZES is aimed at controlling acid hypersecretion and tumor progression, in inoperable patients. The use of proton pump inhibitors (PPIs) to control the syn…
Sunitinib in patients with pre-treated pancreatic neuroendocrine tumors: A real-world study.
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…
Therapeutic sequences in patients with grade 1−2 neuroendocrine tumors (NET): an observational multicenter study from the ELIOS group
Purpose: Many different treatments are suggested by guidelines to treat grade 1−2 (G1−G2) neuroendocrine tumors (NET). However, a precise therapeutic algorithm has not yet been established. This study aims at identifying and comparing the main therapeutic sequences in G1−G2 NET. Methods: A retrospective observational Italian multicenter study was designed to collect data on therapeutic sequences in NET. Median progression-free survival (PFS) was compared between therapeutic sequences, as well as the number and grade of side effects and the rate of dose reduction/treatment discontinuation. Results: Among 1182 patients with neuroendocrine neoplasia included in the ELIOS database, 131 G1–G2 ga…