Roberta Modica

Hepatic arterial embolization in patients with neuroendocrine tumors

Liver metastases occur in 46-93% of patients with neuroendocrine neoplasms (NENs). Presence and extension of liver metastases are considered important prognostic factors, as they may significantly impair the patient’s quality of life, because of either tumor bulk or hormonal hypersecretion. Therapies for NEN liver metastases include surgical resection, liver transplantation, chemotherapy and biotherapy. Surgery is the gold standard for curative therapy, but in most of NEN patients with liver metastases, when surgery can not be applied, minimally invasive therapeutic approaches are adopted. They include trans-arterial embolization (TAE), trans-arterial chemoembolization (TACE), radiofrequency thermal ablation and new emerging techniques.TAE is based on selective infusion of particles in the branch of the hepatic artery supplying the tumor lesions. The goal of TAE is to occlude tumor blood vessels resulting in ischemia and necrosis. Many reports have shown that TAE can reduce tumor size and hormone output, resulting in palliation of symptoms without the use of cytotoxic drugs, resulting in better tolerability. This review will focus on TAE performance and safety in NEN patients with liver metastases.

Second-line sunitinib as a feasible approach for iodine-refractory differentiated thyroid cancer after the failure of first-line sorafenib

About 5 % of patients with differentiated thyroid cancer (DTC) show RAI-refractory disease, thus having a poor prognosis [1, 2]. Tyrosine-kinase inhibitors (TKIs) has represented a revolution in the management of iodinerefractory DTC [3]. Sorafenib has been the most studied TKI in this field, showing encouraging results in several retrospective and phase II studies [4–8]. Effectiveness of sorafenib in RAI-refractory DTC has been definitely demonstrated in the phase III trial DECISION, where a significant improvement of median progression-free survival (PFS) in the treatment group, as compared with placebo, was reported (10.8 vs 5.8 months; HR 0.58, 95 % CI 0.45–0.75, p\ 0.0001) [9]. Following this finding, sorafenib has became the first TKI approved by the US Food and Drug Administration (FDA) for the treatment of RAIrefractory DTC. Given that the study cohort of the DECISION trial included only TKIs-naive patients, sorafenib can be fully considered the first-line systemic therapy for this clinical setting. Nevertheless, sorafenib has some crucial limits. As reported for all TKIs, it is never curative and has a temporally limited effect. Furthermore, sorafenib induced the development of adverse events leading to drug withdrawal in about 20 % of patients [9]. To date, clear indications about management of RAI-refractory DTC patients after the failure of first-line sorafenib are lacking. Sunitinib is a TKI with a pharmacodynamic profile similar to sorafenib, but broader, targeting RET, c-Kit, VEGFR1, -2, PDGFR-a and -b [10]. Despite few studies have been performed so far, sunitinib seems to be effective for the treatment of RAI-refractory DTC [11–14]. Furthermore, several trials of renal cancer have showed that sunitinib was effective in achieving clinical benefit in the majority of patients who experienced the failure of first-line sorafenib [15], even inducing a longer median PFS. Hence, sunitinib may represent a feasible option as salvage treatment after sorafenib failure also in iodine-refractory DTC. Here we report clinical histories of 3 patients (followed at Federico II University, Department of Clinical Medicine and Surgery, Section of Endocrinology, Naples) with iodinerefractory DTC who were treated with sunitinib after the failure of first-line sorafenib.

The safety of available treatments options for neuroendocrine tumors

ABSTRACT Introduction: Neuroendocrine neoplasms (NEN) represent a heterogeneous group of malignancies generally characterized by low proliferation and indolent course. However, about half of the newly diagnosed cases are metastatic and require long-term systemic therapies. Areas covered: This review revises the literature to summarize the current knowledge upon safety of all systemic treatment options available. Thirty three different clinical studies have been considered, including 4 on somatostatin analogues (SSA), 5 on targeted therapies, 10 on peptide receptor radionuclide therapy (PRRT), and 14 on chemotherapy. Expert opinion: SSA are safe and well tolerated without any relevant severe adverse event and very low treatment discontinuation rate. Targeted therapies show a satisfying safety profile. Most adverse events are grade 1–2 and easy manageable with dose reduction or temporary interruption. PRRT is manageable and safe with a low rate of grade 3–4 adverse events. However, severe renal and hematologic toxicity may occur. Chemotherapy is usually considered after previous therapeutic lines. Therefore, these subjects are more susceptible to experience adverse events due to cumulative toxicities or poor performance status. The available systemic treatment options are generally well tolerated and suitable for long-term administration. Cumulative toxicity should be taken in account for the definition of therapeutic sequence.

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 456 extrapancreatic NETs treated with everolimus. Nine different primary sites of extrapancreatic NETs were found. The median progression-free survival ranged from 12.0 to 29.9 months. The median time to progression was not reached in a phase II prospective study, and the interval to progression ranged from 12 to 36 months in 5 clinical cases. Objective responses were observed in 7 prospective studies, 2 retrospective studies, and 2 case reports. Stabilization of the disease was obtained in a high rate of patients, ranging from 67.4% to 100%. The toxicity of everolimus in extrapancreatic NETs is consistent with the known safety profile of the drug. Most adverse events were either grade 1 or 2 and easy manageable with a dose reduction or temporary interruption and only rarely requiring discontinuation. CONCLUSION Treatment with everolimus in patients with extrapancreatic NETs appears to be a promising strategy that is safe and well tolerated. The use of this emerging opportunity needs to be validated with clinical trials specifically designed on this topic. IMPLICATIONS FOR PRACTICE The present study reviewed all the available published data concerning the use of everolimus in 456 extrapancreatic neuroendocrine tumors (NETs) and summarized the current knowledge on the efficacy and safety of this drug, not yet approved except for pancreatic NETs. The progression-free survival rates and some objective responses seem promising and support the extension of the use of this drug. The site-by-site analysis seems to suggest that some subtypes of NETs, such as colorectal, could be more sensitive to everolimus than other primary NETs. No severe adverse events were usually reported and discontinuation was rarely required; thus, everolimus should be considered a valid therapeutic option for extrapancreatic NETs.

Potential role of cinacalcet hydrochloride in sporadic primary hyperparathyroidism without surgery indication

Primary hyperparathyroidism (PHPT) is characterized by the chronic elevation of serum calcium (Ca) levels induced by a long-standing increase of PTH concentrations [1]. Surgical removal of the hyperfunctioning parathyroid tissue represents the only curative approach in this field [2, 3]. Besides symptomatic forms [4], parathyroidectomy (PTx) is indicated in asymptomatic PHPT subjects who have a more advanced disease status. According to the latest update [5], criteria for surgical intervention in asymptomatic PHPT are as follows: (a) serum Ca levels [ 1 mg/dl (0.25 mmol/l) above upper limits of normal; (b) a calculated creatinine clearance \ 60 ml/min; (c) a BMD T score of -2.5 or less at any site or previous fragility fracture (or both); or (d) age \ 50 years. Nevertheless, the management of those patients not having surgery indication is still a point of discussion. Indeed, the 15-year observational study by Rubin et al. [3] has found disease progression in 38 % of this subgroup. This suggests that current surgery criteria are effective in identifying a population with more advanced disease, but cannot effectively predict disease evolution. Cinacalcet hydrochloride is an allosteric modulator of the Ca-sensing receptor (CaSR), where it acts by mimicking an increase in levels of extracellular Ca [6]. In PHPT, this should result in the suppression of PTH secretion [7]. Cinacalcet has been approved in Europe and USA for the management of moderate-to-severe hypercalcemia in patients with PHPT who fulfill surgery indication but are unable to undergo parathyroidectomy [8]. Hence, careful monitoring represents the only indication in PHPT without surgery criteria. We here reported a retrospective, single-center analysis of sporadic PHPT patients who were subjected to treatment with cinacalcet, independently of the surgical indication. Our objective was to provide preliminary insights about the role of cinacalcet in PHPT patients without surgery indication by performing a comparative assessment with PHPTs fitting surgery criteria.

Nutrition and neuroendocrine tumors: An update of the literature

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms with worldwide increasing incidence, high prevalence and survival. Both the tumor itself and the systemic therapy may have an impact on patients’ nutrition. Malnutrition negatively impacts on outcome in NETs patients. Moreover, it has been demonstrated that body mass index was a risk factor for NET development and that metabolic syndrome was associated with worse prognosis in these patients. Of note, food could also interact with the metabolism of oral target therapy and antineoplastic agents used for the treatment of progressive NETs. Therefore, the nutritional assessment, based on body composition, and lifestyle modifications should be an integral component of management of the NET patients. The nutrition care plans are an integral part of the multidisciplinary management team for patients with NETs. Nutritionists with expertise in NETs can provide dietary approaches to improve the quality of life and nutritional status during various therapeutic modalities used in patients with NETs. The aim of this review is to critically discuss the importance of nutrition and body composition in patients with NETs.

The antiproliferative effect of pasireotide LAR alone and in combination with everolimus in patients with medullary thyroid cancer: a single-center, open-label, phase II, proof-of-concept study

PurposeMedullary thyroid cancer (MTC) is a neuroendocrine tumour of the thyroid C cells. Pasireotide, a multi-receptor targeted somatostatin analogue, and everolimus, an inhibitor of mTOR, showed antitumour properties in neuroendocrine tumours. Aim of this study was to evaluate pasireotide alone and in combination with everolimus in patients with MTC.MethodsPatients with progressive metastatic or persistent postoperative MTC received pasireotide LAR 60 mg/m for at least 6 months. Patients exhibiting progressive disease received everolimus 10 mg/d as combination therapy. Primary endpoint was progression free survival (PFS). Secondary endpoints included, overall survival, objective response rates, change in circulating markers, safety. Study registration no. NCT01625520.ResultsNineteen consecutive patients were enrolled. Median follow-up was 31 months. Median PFS with pasireotide was 36 months (95% CI: 19.5–52.5). Nine patients (47%) had tumour progression: seven of them started everolimus in combination with pasireotide, achieving a median PFS of 9.0 months (95% CI: 0–21.83). Five of them (71%) had further tumour progression, one objective response (14.3%), one stopped treatment because of pulmonary embolism. Pasireotide alone and with everolimus was safe and required withdrawal only in one case. Diarrhoea and hyperglycaemia were the most frequent adverse events with pasireotide (grade 3 in 5.3% each). Hyperglycaemia was the most frequent grade 3 toxicity with the combination therapy (28.6%).ConclusionsPasireotide therapy shows antiproliferative effects in persistent postoperative MTC suggesting further investigation on larger series of patients. In progressive MTC lesions, the combination pasireotide plus everolimus may be of benefit. Both schemes were safe and well tolerated.

Tumor Detection in Syndromic NET: Zollinger-Ellison Syndrome

The Zollinger-Ellison syndrome (ZES) is a clinical disorder characterized by recurrent peptic ulcers due to hypergastrinemia induced by a gastrinoma, a gastrin-secreting neuroendocrine tumor. ZES is sporadic in 60–75% of cases, whereas in the remaining patients, it is associated with multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder resulting in hyperplasia and/or tumors of endocrine and non-endocrine organs. Here we present a case of a 40-year-old female, presented with recurrent epigastric pain and acid reflux, uncontrolled with proton pump inhibitors. A MEN1-related ZES was hypothesized on the basis of early age of onset and the evidence of multifocal tumors within the pancreas and duodenum, despite the absence of primary hyperparathyroidism. The diagnostic workup included endoscopic ultrasound, contrast-enhanced multi-detector computed tomography, and somatostatin-receptor scintigraphy.

Gestione integrata del tumore della prostata: il ruolo dell’endocrinologo

SommarioIl carcinoma della prostata (CP) è una patologia di grande interesse endocrinologico sotto diversi aspetti. Dai fattori di rischio, prevalentemente endocrino-metabolici, alle terapie, basate in gran parte sulla soppressione dell’asse gonadico, agli effetti collaterali delle terapie che incidono sul metabolismo, il tessuto osseo, la funzione sessuale, c’è grande necessità di includere l’endocrinologo nel team multidisciplinare del paziente con CP. D’altro lato, la ricerca endocrinologica di base e traslazionale può contribuire alla genotipizzazione molecolare del CP e all’elaborazione di terapie a bersaglio molecolare mirate.

Nuove strategie terapeutiche per il trattamento dei NET

SommarioLa strategia terapeutica dei tumori neuroendocrini (NET) comprende la chirurgia per le forme localizzate e le terapie sistemiche per quelle metastatiche o inoperabili. La peculiarità biologica dei NET vede utilizzati in prima linea gli analoghi della somatostatina, anche ad alto dosaggio o in combinazione con gli altri farmaci, gli inibitori delle tirosinochinasi e di mTOR e la terapia radiorecettoriale. Chemioterapia e immunoterapia sono riservate ai NET più aggressivi. Nuovi studi clinici valuteranno, insieme a efficacia e sicurezza, le migliori sequenze terapeutiche.