Management Of Neuroendocrine Tumors Research Articles

Natural History of Localized and Locally Advanced Atypical Lung Carcinoids after Complete Resection: A Joined French-Italian Retrospective Multicenter Study

Background: The natural history and the best modality of follow-up of atypical lung carcinoids (AC) remain ill defined. The aim of this study was to analyze recurrence-free survival (RFS) after complete resection (R0) of stage I-III pulmonary AC. Secondary objectives were prognostic parameters, the location of recurrences, and the modality of follow-up. Methods: A retrospective review of 540 charts of AC patients treated between 1998 and 2008 at 10 French and Italian centers with experience in lung neuroendocrine tumor management was undertaken. The exclusion criteria were MEN1-related tumor, history of another cancer, referral after tumor relapse, and being lost to follow-up. A central pathological review was performed in each country. Results: Sixty-two patients were included. After a median follow-up time of 91 months (mean 85, range 6-165), 35% of the patients experienced recurrence: 16% were regional recurrences and 19% were distant metastases. Median RFS was not reached. The 1-, 3-, and 5-year RFS rate was 90, 79, and 68%, respectively. In univariate analysis, lymph node involvement (p = 0.0001), stage (p = 0.0001), mitotic count (p = 0.004), and type of surgery (p = 0.043) were significantly associated with RFS. In multivariate analysis, lymph node involvement was significantly associated with RFS (HR 95% CI: 0.000-0.151; p = 0.004). During follow-up, somatostatin receptor scintigraphy, fibroscopy, and abdominal examination results were available for 22, 12, and 25 patients, respectively. The median time interval for imaging follow-up was 10 months. Conclusions: After complete resection of AC, recurrences were observed mostly within the first 5 years of follow-up, within bronchi, mediastinal nodes, the liver, and bones. In R0 patients, lymph node involvement could help to stratify follow-up intervals. Suboptimal imaging is evidenced.

Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers part 2: Neuroendocrine tumours, hepatocellular carcinoma, and gastro-intestinal stromal tumours.

Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the cancer cell molecular biology has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents, being more specific to cancer cells, were expected to be less toxic than conventional cytotoxic agents. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings, illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. Targeted agents have provided clinical benefit in many GI cancer types. Particularly, some GI tumours are considered chemoresistant and targeted therapies have offered a new therapeutic base for their management. Hence, somatostatin receptor-directed strategies, sorafenib, and imatinib have revolutioned the management of neuroendocrine tumours (NET), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), respectively, and are now used as first-line treatment in many patients affected by these tumours. However, these agents face problems of resistances and identification of predictive biomarkers from imaging and/or biology. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this second part, we will focus on NET, HCC, and GIST, whose treatment relies primarily on targeted therapies.

Diagnostic, Surgical, and Postoperative Challenges of Neuroendocrine Tumors of the Neck: Clinical Experience and Literature Review

Neuroendocrine tumors of the neck are rare swellings, which constitute about 0.03% of all tumors. Most are sporadically arising paragangliomas. Over 50% arise from the carotid bodies and pose difficulties in diagnosis and surgical management, which may result in disabling complications. To determine the diagnostic, surgical, and postoperative challenges, and how to overcome them, in the management of neuroendocrine tumors of the neck. Descriptive case series. A retrospective analysis of 19 patients who presented to our surgery clinics between 2010 and 2015 with neck swelling and suspicion of neurogenic tumors were included in the study. All patients received preoperative evaluation with Doppler studies and neck computed tomography scan, with the finding of suspicion of neurogenic tumor. Preoperative tissue diagnosis was not attempted as this usually required excisional biopsy. All tumors were surgically excised. Data regarding mean tumor size, neurovascular invasion, postoperative complications, and histopathologicalfindings were recorded and statistically analyzed. Nineteen patients (7 male) with median age of 45years were included. Mean size of the tumor was 7.5cm (range: 4.0-11.8cm). Six of the tumors were right sided and 13 left sided. Clinical findings often were nonspecific and mimicked other conditions. Operative challenges were encountered in 11 (57.9%) patients, who had tumors of more than 5cm. Vascular invasion was found in 2 (10.5%) patients, but bleeding requiring preoperative transfusion was not required in any patient. Neurological complications occurred in 11 (57.8%) patients; 3 had transit hypoglossal nerve palsy, with full recovery; 2 had complete nerve palsy, with reasonable rehabilitation without further surgical intervention; and 5 developed neurological deficits (hoarseness, dysphagia, or Horner's syndrome) but recovered and compensated well without further operation. Two patients who had vascular invasion required vascular reconstruction. Histopathology in 14 (73.7%) cases was carotid body tumor and 5 were Schwannomas (1 vagal and 4 sympathetic chain). All 4 patients with Schwannomas of cervical sympathetic chain developed Horner's syndrome; 2 of them have compensated well with reasonable recovery; 2 have had tarsorrhaphy for cosmetic reasons. The patient with vagal Schwannoma developed hoarseness and swallowing difficulties, which resolved without intervention. No malignancy was encountered in this series, and there was no mortality. Neuroendocrine tumors of the neck present diagnostic challenges because of nonspecific clinical findings mimicking other conditions. Preoperative tissue diagnosis is mostly unsuccessful, and exact diagnosis requires excisional biopsy. Surgical excision, which is the main treatment, often has associated technical difficulties and unavoidable complications requiring further intervention.

Management of gastric neuro-endocrine tumours in a large French national cohort (GTE).

Gastric neuro-endocrine tumours are rare. European guidelines for the management of neuro-endocrine tumours have been published in 2012. The aim of our survey was to study the management of gastric neuro-endocrine tumours registered in the national cohort. A prospective national cohort registers the Neuro-endocrine tumours in France since January 2003 (GTE network). We reviewed all the individual medical reports of gastric neuro-endocrine tumours in order to collect data on treatment. One hundred and ninety seven gastric neuro-endocrine tumours diagnosed between 1964 and 2013 in 20 centres were registered. For 181 cases data were considered complete for our survey. Eighty four tumours were type 1 (46.4%); five types 2 (2.8%); 52 types 3 (28.7%) and 40 types 4 (22.1%). Types 1 and 2 were first endoscopically managed in 93 and 60% of cases, respectively, whereas surgery was first done in 45 and 42%, respectively, of types 3 and 4. Systemic treatment, chemotherapy and/or somatostatin analogue, was first administered exclusively for types 3 and 4. Near 3% of types 1 and 40% of types 2 received at a time somatostatin analogue treatment. Five-year survival rates were 98.3, 100, 63.2 and 31.8% for types 1, 2, 3 and 4, respectively. The great majority of gastric neuro-endocrine tumours registered in this national cohort are treated in accordance with the current guidelines. The survival rates we reported must be interpreted with caution, because this cohort registered preferentially selected patients eligible for treatment. The registration of all the gastric neuro-endocrine tumours, in particular type 1 considered as benign and type 4 not eligible for specific anti-cancer treatment must be encouraged.

Gastroduodenal neuroendocrine neoplasms, including gastrinoma - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

This paper presents the updated Polish Neuroendocrine Tumour Network expert panel recommendations on the management of neuroendocrine neoplasms (NENs) of the stomach and duodenum, including gastrinoma. The recommendations discuss the epidemiology, pathogenesis, and clinical presentation of these tumours as well as their diagnosis, including biochemical, histopathological, and localisation diagnoses. The principles of treatment are discussed, including endoscopic, surgical, pharmacological, and radionuclide treatments. Finally, there are also recommendations on patient monitoring.

Principles of diagnosis and management of neuroendocrine tumours.

Neuroendocrine tumours (NETs) are a unique group of malignant growths, best known for their ability to secrete bioactive peptides, which may cause symptoms such as flushing and diarrhea. Although NETs traditionally have been considered uncommon, a recent population-based study reported that the

Additional value of hybrid SPECT/CT systems in neuroendocrine tumors, adrenal tumors, pheochromocytomas and paragangliomas

The aim of this review was to evaluate the potential advantages of SPECT/CT hybrid imaging in the management of neuroendocrine tumors, adrenal tumors, pheochromocytomas and paragangliomas. From the collected data, the superiority of fused images was observed as providing both functional/molecular and morphological imaging compared to planar imaging. This provided an improvement in diagnostic imaging, with significant advantages as regards: (1) precise locating of the lesions; (2) an improvement in characterization of the findings, resulting higher specificity, improved sensitivity, and overall greater accuracy, (3) additional anatomical information derived from the CT component; (4) CT-based attenuation correction and potential for volumetric dosimetry calculations, and (5) improvement on the impact on patient management (e.g. in better defining treatment plans, in shortening surgical operating times). It can be concluded that SPECT/CT hybrid imaging provides the nuclear medicine physician with a powerful imaging modality in comparison to planar imaging, providing essential information about the location of lesions, and high quality homogeneous images.

Neuroendocrine differentiation in prostate cancer: key epigenetic players.

A recent publication by Dardenne et al . (1) in Cancer Cell (October 10, Vol. 30: 563–577, 2016) demonstrate N-Myc overexpression and its stabilization by Aurora-A (AURKA) and AKT1 Kinase induces enhancer of zeste homolog 2 (EZH2)-mediated transcriptional reprogramming repressing androgen receptor (AR) and driving neuroendocrine prostate cancer (1). This has important clinical implication proposing combinatorial therapy using inhibitors of phosphatidylinositol 3-kinase (PI3K)-AKT and AURKA as future trials in the management of neuroendocrine tumors.

Escalated dose somatostatin analogues (SSAs) in management of neuroendocrine tumors (NETs): A systematic review.

422 Background: SSAs are effective in controlling NET symptoms and more recently have been shown to have anti-proliferative properties. PROMID and CLARINET have established “standard” doses of octreotide and lanreotide, but dose escalation is often employed both for symptom relief and tumor control. Methods: We searched MEDLINE, EMBASE, Cochrane CENTRAL and abstracts of major conferences. Studies investigating patients treated with doses of octreotide higher than 30mg/28d or lanreotide higher than 120mg/28d were eligible for inclusion. Data extracted included patient population, interventions and prior SSA use. The primary endpoint was disease control rate; secondary endpoints included response rate, symptom control, biochemical response, progression-free survival and toxicity. Results: 19 studies (12 prospective; 981 patients) were identified from 609 search results. Of the 13 studies that mandated prior treatment, the reasons for dose escalation were tumor progression (5), symptoms (3), either (2) and not listed (3). SSAs used were octreotide LAR (10), lanreotide ATG (1), short-acting octreotide (3), short-acting lanreotide (3), and mixtures (2). Significant heterogeneity existed in dosing schedules as well as reporting of efficacy data. Disease control rates ranged from 40-100% (pooled rate 248/396) with response rates from 0-42% (pooled rate 24/396). Dose escalation was associated with improvement in carcinoid symptoms in at least 50% of patients. Biochemical response was variably defined but reported rates ranged from 33% to 100% (pooled rate 55/78). Median PFS ranged from 6 months to 30 months. Dose escalation was generally well tolerated with side effect profile and frequency comparable to normal dose SSA. Conclusions: Escalated dose SSA is well tolerated and results in significant rates of disease control and symptomatic improvement. Compared to a prior systematic review (Broder WJG 2015), this review includes studies of lanreotide, includes 721 additional patients, and restricts inclusion to clinical studies. Prospective randomized trials of escalated SSA therapy are warranted.

The role of 68Ga-DOTA-NOC PET/CT in evaluating neuroendocrine tumors: real-world experience from two large neuroendocrine tumor centers.

Our aim was to assess the role of Ga-DOTA-NOC PET/CT as a tool for the management of neuroendocrine tumors (NETs), evaluating the clinical impact on patients from two large NET centers in different geopolitical settings. This is a retrospective study of patients with NETs who underwent Ga-DOTA-NOC PET/CT at Royal Liverpool University Hospital (UK) and at Mount Lebanon Hospital (Lebanon). Indications for imaging and findings of the PET/CT along with demographic and clinical outcome data were recorded and evaluated. Four hundred and forty-five patients fulfilled the inclusion criteria, with a median age at the time of diagnosis of 56 (range: 3-90) years; 248 (55.7%) patients were male.Ga-DOTA-NOC PET/CT was indicated for staging in 193 (43.4%) patients, for diagnosis in 124 (27.9%) patients, for follow-up in 97 (21.7%) patients, and for identification of a primary NET site in 31 (7%) patients.One hundred and four (27.9%) patients underwent Ga-DOTA-NOC PET/CT for the primary diagnosis of NET, of whom 66 (52.7%) patients presented with a clinical suspicion of NET, 10 (8.3%) patients presented with a biochemical suspicion of NET only, and 48 (38.8%) patients presented with a suspicious NET lesion discovered on another imaging modality. The most common clinical presentation was typical carcinoid syndrome [4 (33%) patients].Results on the basis of histology were used as the gold standard for the diagnosis in 57% of patients and the remaining on the basis of follow-up as per established clinical consensus. Sensitivity, specificity, negative-predictive value, and positive-predictive value of PET/CT were 87.1, 97.7, 79.6, and 98.7%, respectively, for the entire sample. Accuracy was measured using the receiver operating characteristic curve analysis with an area under the curve of 0.924 (95% confidence interval: 0.874-0.974). Ga-DOTA-NOC PET/CT is a highly sensitive and specific study for the diagnosis and follow-up of patients with neuroendocrine tumors. These results support the use of Ga-DOTA-NOC PET/CT contributing significantly toward the clinical management of NET patients.

Guidelines for the management of neuroendocrine tumours by the Brazilian gastrointestinal tumour group.

Neuroendocrine tumours are a heterogeneous group of diseases with a significant variety of diagnostic tests and treatment modalities. Guidelines were developed by North American and European groups to recommend their best management. However, local particularities and relativisms found worldwide led us to create Brazilian guidelines. Our consensus considered the best feasible strategies in an environment involving more limited resources. We believe that our recommendations may be extended to other countries with similar economic standards.

The Impact of Somatostatin Receptor-Directed PET/CT on the Management of Patients with Neuroendocrine Tumor: A Systematic Review and Meta-Analysis.

Somatostatin receptor (SSTR) imaging is widely used for guiding the management of neuroendocrine tumor (NET) patients. 68Ga-DOTATATE approval by the U.S. Food and Drug Administration has triggered widespread clinical interest in SSTR PET/CT throughout the United States. Here, we performed a systematic review and meta-analysis to evaluate the impact of SSTR PET/CT on the management of patients with NETs. Methods: A comprehensive literature search was performed using The National Center for Biotechnology Information PubMed online database, applying the following key words: "management" AND "PET" AND "neuroendocrine". Fourteen of 190 studies were deemed suitable based on the following inclusion criteria: original research, cohort study, number of patients 10 or more, and reported change in management after SSTR PET/CT. Change in management across studies was determined by a random-effects model. Results: A total of 1,561 patients were included. Overall, change in management occurred in 44% (range, 16%-71%) of NET patients after SSTR PET/CT. In 4 of 14 studies, SSTR PET/CT was performed after an 111In-Octreotide scan. In this subgroup, additional information by SSTR PET/CT led to a change in management in 39% (range, 16%-71%) of patients. Seven of 14 studies differentiated between inter- and intramodality changes, with most changes being intermodality (77%; intramodality, 23%). Conclusion: The management was changed in more than one third of patients undergoing SSTR PET/CT even when performed after an 111In-Octreotide scan. Intermodality changes were 3 times more likely than intramodality changes, underlining the clinical impact of SSTR PET/CT.

417P Availability and Utility of Functional Imaging (FI) and Peptide Receptor Radionuclide Therapy (PRRT) in the CommNETS Collaboration (Australia, Canada and New Zealand)

Background The use of FI and PRRT is integral to the management of neuroendocrine tumors (NETs). Considerable global variability exists in access to and utility of FI and PRRT. Methods A survey of PRRT centres within CommNETS was conducted to explore the use of FI and PRRT. Two companion surveys were completed by the lead in nuclear medicine and medical oncology per site. Descriptive and inferential statistical methods including nonparametric analyses were performed to evaluate differences in accessibility and availability, models of care, protocols and funding. Results 16 surveys were sent to the 8 PRRT centres across CommNETS (Aust: 6, Canada: 2, NZ: 0). Response rate was 100%. All were academic centres reviewing 110 new and 140 followup patients per month. All centres had access to Octreotide scans, but in Australia this has been superseded by tandem Gallium68 (Ga) and 18Fluorine (FDG) positron emission tomography (PET) scans to stage and assess biology and heterogeneity of NETs. GaPET scans were not available in Canada. Although FDGPET was unfunded for NETs within CommNETS, it was routinely ordered (63%) for grade 2 or 3 NETs. To assess response, 63% used GaPET scans at 6month intervals and 38% ordered both Ga and FDGPET scans. PRRT was only available on clinical trial in Canada. Lutetium177 was the standard PRRT isotope at all centres for most indications. Radiosensitising chemotherapy was used in 5 centres (not in Canada) capecitabine (45%) or capecitabine and temozolomide (36%). Four cycles of PRRT was universal but intervals varied between every 8 weeks (50%), 6 weeks (25%) or 10 weeks (25%), usually without maintenance therapy (63%). Considerable variation existed regarding concurrent somatostatin analogue usage, determination of renal function, dosimetry, dose adjustments and minimum haematological parameters. Only five sites recorded quality of life outcomes. Conclusions This is the first survey to assess the availability and utility of FI and PRRT within CommNETS. Future collaborative efforts will try to improve access and share knowledge between experienced and upcoming PRRT centres to develop standard operating procedures and cooperative trials. Legal entity responsible for the study CommNETs Collaboration Funding CommNETs Collaboration Disclosure All authors have declared no conflicts of interest.

Additional value of hybrid SPECT/CT systems in neuroendocrine tumors, adrenal tumors, pheochromocytomas and paragangliomas.

The aim of this review was to evaluate the potential advantages of SPECT/CT hybrid imaging in the management of neuroendocrine tumors, adrenal tumors, pheochromocytomas and paragangliomas. From the collected data, the superiority of fused images was observed as providing both functional/molecular and morphological imaging compared to planar imaging. This provided an improvement in diagnostic imaging, with significant advantages as regards: (1) precise locating of the lesions; (2) an improvement in characterization of the findings, resulting higher specificity, improved sensitivity, and overall greater accuracy, (3) additional anatomical information derived from the CT component; (4) CT-based attenuation correction and potential for volumetric dosimetry calculations, and (5) improvement on the impact on patient management (e.g. in better defining treatment plans, in shortening surgical operating times). It can be concluded that SPECT/CT hybrid imaging provides the nuclear medicine physician with a powerful imaging modality in comparison to planar imaging, providing essential information about the location of lesions, and high quality homogeneous images.

Somatastatin analogue tolerability testing in the management of neuro endocrine tumours (NETs), a single centre review of practice

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Collaborative Practice in the Management of Neuroendocrine Tumors

Collaborative Practice in the Management of Neuroendocrine Tumors

Gastric Neuroendocrine Tumor Management with Endoscopic Mucosal Resection

Introduction: Gastric carcinoid tumors are rare lesions that account for 7% of all GI carcinoids and if diagnose in early stage, could be manage completely by endoscopic procedures. Case report: During evaluation ofA 58 y old diabetic woman due to iron deficiency anemia, a localized neuroendocrine tumor found and successfully managed by endoscopic mucosal resection. Conclusion: successful management of these lesions during early stages by endoscopic procedures,further emphasize on importance ofscreening and awareness of responsible physicians to keep in mind their possibility.

Overview of pancreatic neuroendocrine tumor management and survival in the Netherlands.

e15660Background: Pancreatic neuroendocrine tumors (pNETs) are classified as rare diseases with a prevalence of 2/100.000. As a result of improved recognition and imaging incidence rises over the p...

Safety and Efficacy of 68Ga-DOTATATE PET/CT for Diagnosis, Staging, and Treatment Management of Neuroendocrine Tumors.

Our purpose was to evaluate the safety and efficacy of (68)Ga-DOTATATE PET/CT compared with (111)In-pentetreotide imaging for diagnosis, staging, and restaging of pulmonary and gastroenteropancreatic neuroendocrine tumors. (68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were obtained for 78 of 97 consecutively enrolled patients with known or suspected pulmonary or gastroenteropancreatic neuroendocrine tumors. Safety and toxicity were measured by comparing vital signs, serum chemistry values, or acquisition-related medical complications before and after (68)Ga-DOTATATE injection. Added value was determined by changes in treatment plan when (68)Ga-DOTATATE PET/CT results were added to all prior imaging, including (111)In-pentetreotide. Interobserver reproducibility of (68)Ga-DOTATATE PET/CT scan interpretation was measured between blinded and nonblinded interpreters. (68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were significantly different in impact on treatment (P < 0.001). (68)Ga-DOTATATE PET/CT combined with CT or liver MRI changed care in 28 of 78 (36%) patients. Interobserver agreement between blinded and nonblinded interpreters was high. No participant had a trial-related event requiring treatment. Mild, transient events were tachycardia in 1, alanine transaminase elevation in 1, and hyperglycemia in 2 participants. No clinically significant arrhythmias occurred. (68)Ga-DOTATATE PET/CT correctly identified 3 patients for peptide-receptor radiotherapy incorrectly classified by (111)In-pentetreotide. (68)Ga-DOTATATE PET/CT was equivalent or superior to (111)In-pentetreotide imaging in all 78 patients. No adverse events requiring treatment were observed. (68)Ga-DOTATATE PET/CT changed treatment in 36% of participants. Given the lack of significant toxicity, lower radiation exposure, and improved accuracy compared with (111)In-pentetreotide, (68)Ga-DOTATATE imaging should be used instead of (111)In-pentetreotide imaging where available.

ENETS 2016 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: An Update

The participants at the conference were asked to focus on the relevant literature published between 2011 and 2015. They met over two and a half days, in which data and new evidence were presented. The participants then retreated to break-out sessions according to their disciplines and were required to answer questions listed in a workbook created by the session chairs and the organizing committee. The workbook questions were tailored on the text of the initial guidelines framework [2, 4] , focusing on the new available evidence. All relevant areas were updated via a thorough literature review and the questions that the chairpersons considered appropriate to discuss the new evidence. All participants were encouraged to challenge the document. Recent data on new evidence and insights were intensely discussed in working-group sessions as well as during the plenary session. Notes were taken continuously, so that the final agreement on each question was noted and returned to each session chair for preparation of the consensus statements. The magnitude of the consensus for each answer was estimated to achieve unanimity. In addition to providing textual guidelines, delegates were requested to elaborate accurate but simple Several guidelines and standards of care on the management of neuroendocrine tumors (NETs) have been published by expert national and international groups in recent years [1–9] ; additional changes in how these patients are managed are evolving rapidly, and since the last European Neuroendocrine Tumor Society (ENETS) Guidelines in 2011/12 [8] , new important data have become available pertaining to novel diagnostic tools and therapies. On October 30th and 31st, 2014, the ENETS held an Advisory Board meeting in Vienna aiming at critically discussing and updating the ENETS Guidelines on the Diagnosis and Treatment of Neuroendocrine Tumors generated initially in 2005–2006 [2, 4] and revised in 2011 [8] . The consensus sessions covered the following neuroendocrine neoplasm-related topics by sites of origin or stage: gastroduodenal, midgut (including appendix), hindgut, functional pancreatic, non-functional pancreatic, and two final sessions that covered liver and other distant metastases from neuroendocrine neoplasms of any origin and a separate session devoted to neuroendocrine high-grade tumors and carcinomas. Published online: January 6, 2016