Christos Toumpanakis

Chemotherapy with 5-fluorouracil, cisplatin and streptozocin for neuroendocrine tumours

Background:The role of chemotherapy for neuroendocrine tumours remains controversial and there is no standard regimen.Method:We report the outcome for a consecutive series of chemonaive patients with metastatic or locally advanced neuroendocrine tumours treated with a combination of 5-fluorouracil (500 mg m−2), cisplatin (70 mg m−2) and streptozocin (1000 mg m−2) (FCiSt) administered three weekly for up to six cycles. Patients were assessed for radiological response, toxicity and survival.Results:In the 79 patients assessable for response, treatment with FCiSt was associated with an overall response rate of 33% (38% for pancreatic primary sites and 25% for non-pancreatic primary sites). Stable disease occurred in a further 51%, with progression in 16%. The median time to progression was 9.1 months and median overall survival was 31.5 months. The most common grade 3–4 toxicity was neutropaenia (28% patients) but grade 3–4 infection was rare (7%). The most frequent non-haematological grade 3–4 toxicity was nausea and vomiting (17%). Prognostic factors included Ki-67, mitotic index, grade and chromogranin A, whereas response to chemotherapy was predicted by mitotic index, grade and α-fetoprotein.Conclusions:FCiSt is an effective regimen for neuroendocrine tumours with an acceptable toxicity profile. Grade and mitotic index are the best predictors of response.

A comparison of Ki-67 and mitotic count as prognostic markers for metastatic pancreatic and midgut neuroendocrine neoplasms

Background:The aim of this study was to compare mitotic count (MC) and Ki-67 proliferation index as prognostic markers in pancreatic and midgut neuroendocrine neoplasms (NENs).Methods:Two hundred eighty-five patients with metastatic NENs were recruited. Concordance between histological grade according to either Ki-67 or MC as defined by the European Neuroendocrine Tumour Society guidelines was assessed and the prognostic significance of Ki-67 or MC were evaluated.Results:There was a discrepancy of 44 and 38% in grade assignment when using Ki-67 or MC in pancreatic and midgut NENs, respectively. In multivariate analysis, grade using Ki-67, but not MC, was a significant prognostic factor in determining overall survival (hazard ratios: midgut G2 2.34, G3 15.1, pancreas G2 2.08, G3 11.3). The prognostic value of Ki-67 was improved using a modified classification (hazard ratios: midgut G2 3.02, for G3 22.1, pancreas G2 5.97, G3 33.8).Conclusion:There is a lack of concordance between Ki-67 and MC in assigning tumour grade. Grade according to Ki-67 was a better prognostic marker than MC for metastatic pancreatic and midgut NENs. We suggest that Ki-67 alone should be used for grading pancreatic and midgut NENs and that the current threshold for classifying G1/G2 tumours should be revised from 2 to 5%.

ENETS Consensus Guidelines Update for Neuroendocrine Neoplasms of the Jejunum and Ileum.

a Department of Surgery, Medical University of Vienna, Vienna , Austria; b Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin , Germany; c Centro de Oncologia, Hospital Sírio Libanês, São Paulo , Brazil; d Department of Endocrinology and Metabolism, Hadassah University Hospital, Mevasseret Tsion , Israel; e Department of Endocrinology, Erciyes University Medical School, Kayseri , Turkey; f Neuroendocrine Tumor Center of Excellence, Rigshospitalet, Copenhagen University Hospital, Copenhagen , Denmark; g Department of Medical Sciences, Endocrine Oncology Unit, University Hospital, Uppsala , Sweden; h Institute of Pathology, University of Bern, Bern , Switzerland; i Neuroendocrine Tumour Unit, Royal Free Hospital, London , UK; j Department of Clinical Oncology, Institute Alexander Fleming, Buenos Aires , Argentina; k National NET Centre, St. Vincent’s University and Department of Clinical Medicine, St. James Hospital and Trinity College, Dublin , Ireland; l Department of Internal Medicine, Division of Nuclear Medicine, Erasmus Medical Center, Rotterdam , The Netherlands; m Beatson Oncology Centre, Gartnavel General Hospital, Glasgow , UK; n Department of Surgery, CHU Robert Debré, Reims , France

Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues

In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27–1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89–4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 – not reached) with pasireotide versus 6.8 months (5.6 – not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20–0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.

ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas

a Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid , Spain; b Department of Oncology, Haukeland University Hospital, Bergen , Norway; c Institut Gustave Roussy, Villejuif , and d Oncologie Médicale, Hôpitaux Universitaires Paris Nord Val de Seine, Paris , France; e Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin , Germany; f Department of Surgery, Medical University of Vienna, Vienna , Austria; g Department of Oncology, First Faculty of Medicine and General Teaching Hospital, Prague , Czech Republic; h Neuroendocrine Tumour Unit, Royal Free Hospital, London , UK; i Institut für Pathologie und Zytologie, St. Vincenz Krankenhaus, Limburg , Germany; j Department of Radiology, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn , Poland; k Neuroendocrine Tumour Unit, Royal Free Hospital, London , UK; l NET Centre, St. Vincent’s University and Department of Clinical Medicine, St. James Hospital and Trinity College, Dublin , Ireland; m Institute of Pathology, University of Bern, Bern , Switzerland

Features of Carcinoid Heart Disease Identified by 2- and 3-Dimensional Echocardiography and Cardiac MRI

Background—Carcinoid heart disease is a rare form of valvular heart disease. We sought describe the spectrum of carcinoid heart disease identified by echocardiography and cardiac MRI. Method and Results—Two hundred fifty-two patients with carcinoid syndrome underwent a range of investigations including 2D transthoracic echocardiography, 3D transthoracic echocardiography and transesophageal echocardiography, and cardiac MRI. Fifty-two patients had evidence of carcinoid heart disease. Involvement of the tricuspid, pulmonary, mitral, and aortic valves were found in 47 (90%), 36 (69%), 15 (29%), and 14 (27%), respectively. Myocardial metastases were found in 2 (3.8%) patients. Several patterns of disease were identified depending on the extent and severity to which each leaflet and its associated subvavlular apparatus was affected. Thirteen of 15 (87%) patients with left-sided carcinoid involvement had a patent foramen ovale. Three patients with severe degree of shunting had severe valvular regurgitation. Patients with mild/moderate degree of shunting had mild or moderate valvular regurgitation. Three-dimensional transthoracic echocardiography/transesophageal echocardiography provided detailed anatomic information particularly for the tricuspid and pulmonary valves. Cardiac MRI allowed complementary assessment of valvular heart disease and delineation of myocardial metastases. Gallium-68 octreotide positron emission tomography identified neuroendocrine metastases. Conclusions—Carcinoid heart disease is a heterogeneous disease with a wide spectrum of echocardiographic findings. A multimodality approach is needed in patients with this complex pathology.

Update on the Role of Somatostatin Analogs for the Treatment of Patients With Gastroenteropancreatic Neuroendocrine Tumors

Somatostatin analogs (SA) are the standard of care for controlling symptoms of patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). SA control symptoms in more than 70% of patients with carcinoid syndrome. Similar results are obtained in patients with functional, hormone-secreting, pancreatic NETs. The use of SA as antiproliferative agents has been established only recently. Retrospective studies have shown stabilization of tumor growth in >50% of patients with progressive disease. The results of a recent randomized phase III trial (PROMID) demonstrated that the median time to progression in patients with midgut carcinoid tumors treated with octreotide LAR (Long-Acting-Repeatable, Novartis, Basel, Switzerland) was more than twice as long compared to that of patients treated with placebo. The results of a phase III study of lanreotide versus placebo in nonfunctional NETs are not yet available. More studies are needed to determine whether combining SA with novel targeted treatments will result in enhanced antiproliferative activity compared to treatment with a SA alone. Studies are ongoing using pan-receptor agonists (eg, pasireotide) and chimeric dimers, which possess features of somatostatin and dopamine agonists (dopastatins) and are thought to enhance symptom control by binding multiple receptors (somatostatin and dopamine receptors). Somatostatin receptor antagonists are also currently being developed for clinical use. Peptide receptor radionuclide therapy (PRRT), consisting of yttrium-90 and lutetium-177 isotopes conjugated with SA appear to be efficacious in advanced NETs. Randomized studies are needed to definitively establish the safety and efficacy of this strategy compared to other available treatments, and to determine which radiolabeled isotopes or combinations are most effective.

Molecular Genetics of Gastroenteropancreatic Neuroendocrine Tumors

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are usually sporadic; however, familial (inherited) syndromes, such as the multiple endocrine neoplasia 1 (MEN-1) syndrome, von Hippel-Lindau (VHL) syndrome, neurofibromatosis (NF-1), as well as tuberous sclerosis, may be associated with proximal intestinal and pancreatic NETs. For example, 25% of gastrinoma patients have MEN-1 syndrome. Over the last two decades, the genetic basis of tumorigenesis for these familial syndromes has been clearly identified, providing clinicians with useful screening tools for affected families. Also, over the last few years, advanced molecular genetic techniques, such as comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses, have detected some differences in genomic aberrations among various types of NETs. Whether these chromosomic alterations have implications in the treatment of patients and the outcome of the disease is still unclear.

Features of Carcinoid Heart Disease Identified By Two- and Three- Dimensional Echocardiography and Cardiac Magnetic Resonance Imaging

Background—Carcinoid heart disease is a rare form of valvular heart disease. We sought describe the spectrum of carcinoid heart disease identified by echocardiography and cardiac MRI. Method and Results—Two hundred fifty-two patients with carcinoid syndrome underwent a range of investigations including 2D transthoracic echocardiography, 3D transthoracic echocardiography and transesophageal echocardiography, and cardiac MRI. Fifty-two patients had evidence of carcinoid heart disease. Involvement of the tricuspid, pulmonary, mitral, and aortic valves were found in 47 (90%), 36 (69%), 15 (29%), and 14 (27%), respectively. Myocardial metastases were found in 2 (3.8%) patients. Several patterns of disease were identified depending on the extent and severity to which each leaflet and its associated subvavlular apparatus was affected. Thirteen of 15 (87%) patients with left-sided carcinoid involvement had a patent foramen ovale. Three patients with severe degree of shunting had severe valvular regurgitation. Patients with mild/moderate degree of shunting had mild or moderate valvular regurgitation. Three-dimensional transthoracic echocardiography/transesophageal echocardiography provided detailed anatomic information particularly for the tricuspid and pulmonary valves. Cardiac MRI allowed complementary assessment of valvular heart disease and delineation of myocardial metastases. Gallium-68 octreotide positron emission tomography identified neuroendocrine metastases. Conclusions—Carcinoid heart disease is a heterogeneous disease with a wide spectrum of echocardiographic findings. A multimodality approach is needed in patients with this complex pathology.

Analysis of 150 Patients With Carcinoid Syndrome Seen in a Single Year at One Institution in the First Decade of the Twenty-First Century

Carcinoid heart disease (CHD), reported in 50% to 70% of patients with carcinoid syndrome, is thought to be related to the production of 5-hydroxytryptamine by the tumor. The development of new therapeutic modalities designed to reduce tumor hormone production may have altered the development of CHD. Currently, echocardiography is performed when clinical suspicion of CHD exists. The aim of this study was to establish the prevalence of CHD in the setting of modern treatment regimens and delineate whether a screening program for CHD is needed. One hundred fifty patients with carcinoid syndrome were screened for CHD by transthoracic echocardiography. The functional status of patients was classified according to New York Heart Association class. Thirty patients (20%) were found to have CHD. Of those with CHD, 14 (47%) had left- and right-sided valvular lesions. Patent foramen ovale was present in all patients with left-sided CHD. Forty-three percent of patients were in New York Heart Association class I, 40% in class II, 13% in class III and 3% in class IV. Eight patients (27%) with moderate or severe valvular lesions were in class I. Thirty-seven percent of patients with CHD had no physical signs. In conclusion, the presence of symptoms or abnormalities on clinical examination has a low sensitivity for the presence of CHD. Therefore, screening with echocardiography, even in patients who are asymptomatic, should be advocated.