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Background: Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 ((177)Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods: We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either (177)Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) ((177)Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results: At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the (177)Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the (177)Lu-Dotatate group versus 3% in the control group (PConclusions: Treatment with (177)Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the (177)Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

Many management strategies exist for neuroendocrine liver metastases. These strategies range from surgery to ablation with various interventional radiology procedures, and include both regional and systemic therapy with diverse biological, cytotoxic, or targeted agents. A paucity of biological, molecular, and genomic information and an absence of data from rigorous trials limit the validity of many publications detailing management. This Review represents the views from an international conference, for which 15 expert working groups prepared evidence-based assessments addressing specific questions, and from which an independent jury derived final recommendations. The aim of the conference was to review the existing approaches to neuroendocrine liver metastases, assess the evidence on which management decisions were based, develop internationally acceptable recommendations for clinical practice (when evidence was available), and make recommendations for clinical and research endeavours. This report represents the final clinical statements and proposals for future research. © 2014 Elsevier Ltd.

a Department of Gastroenterology, Beaujon Hospital, Clichy , France; b Department of Oncology, Institut Catala d’Oncologia, Barcelona , Spain; c Department of Surgery, Verona University, Verona , Italy; d Department of Endocrinology and Metabolism, Genimatas Hospital, Athens , Greece; e Department of Gastroenterology, Beaujon Hospital, Clichy , France; f Department of Endocrinology, Erasmus MC University, Rotterdam , The Netherlands; g Department of Internal Medicine, Martin University, Martin , Slovakia; h Department of Propaedeutic Internal Medicine, Laiko Hospital, Athens , Greece; i Department of Nuclear Medicine, Erasmus MC University, Rotterdam , The Netherlands; j Department of Gastroenterology, Beaujon Hospital, Clichy , France; k Department of Gastroenterology, Royal Free Hospital, London , UK; l Department of Cell Biology, National Institute of Health, Bethesda, Md. , USA; m Department of Endocrinology, University Hospital, Uppsala , Sweden

a DRK Kliniken Westend, Berlin , Germany; b UFR Bichat-Beaujon-Louis Mourier, Service de Chirurgie Digestive, Hopital Louis Mourier, Colombes , France; c Medicine and Surgery, General Surgery Section, MED/18 – General Surgery and d Department of Pathology, University of Verona, Verona , Italy; e Netherlands Cancer Centre, Amsterdam , and f Department of Nuclear Medicine, Erasmus University Medical Center, Rotterdam , The Netherlands

Consensus guidelines for the management of patients with digestive neuroendocrine tumors : well-differentiated jejunal-ileal tumor/carcinoma

a Department of Pathology, Gothenburg University, Gothenburg , Sweden; b Department of Gastroenterology, Gasthuisberg University, Leuven , Belgium; c Department of Gastroenterology, Ospedale S. Andrea, Rome , Italy; d Department of Oncology, University of Texas, Houston, Tex. , USA; e Department of Endocrinology, Erlangen University, Erlangen , Germany; f Department of Oncology and Pathology, Royal Infirmary Hospital, Glasgow , UK; g Department of Oncology, Virgen de la Victoria Hospital, Malaga , Spain; h Department of Nuclear Medicine, Medizinische Hochschule Hannover, Hannover , Germany; i Department of Endocrinology, Erciyes University, Kayseri , Turkey; j Department of Surgery, Beaujon Hospital, Clichy , France; k Department of Nuclear Medicine, Catholique de Louvain University, Brussels , Belgium; l Department of Nuclear Medicine, Erasmus MC University, Rotterdam , The Netherlands; m Department of Gastroenterology, Royal Free Hospital, London , UK

Octreotide LAR is indicated for treatment of malignant carcinoid syndrome and has been studied at doses of 10 to 30 mg intramuscularly every 4 weeks. In clinical practice, higher doses are often prescribed for patients who experience refractory carcinoid syndrome (flushing and/or diarrhea) or tumor growth while on the maximum label-recommended dose.We performed a retrospective, longitudinal review of octreotide LAR administration at a tertiary institution to determine the frequency of above-label dosing and outcomes.Three hundred thirty-eight patients were considered evaluable, among whom 100 (30%) underwent at least 1 increase in dose or frequency of octreotide-LAR above the standard label dose. The most common maximum doses were 40 mg every 4 weeks (n = 37 patients), 60 mg every 4 weeks (n = 34), and 30 mg every 3 weeks (n = 18). The indications for dose increase were worsening carcinoid syndrome (n = 60), radiographic progression (n = 33), and rising urine 5-HIAA (n = 6). Of the patients whose doses were increased for refractory carcinoid syndrome, 62% (n = 34) experienced improvement in diarrhea, and 56% (n = 28) experienced improvement in flushing.In conclusion, octreotide LAR is commonly prescribed in doses or schedules above the recommended dose and frequency. Patients with refractory carcinoid syndrome appear to experience a clinical benefit from this change. Prospective data may be used to further evaluate this strategy.

a Department of Internal Medicine, Section of Endocrinology, Erasmus MC, Rotterdam, The Netherlands; b Division of General Surgery, Department of Surgery, Medical University of Vienna, Vienna , Austria; c Hospices Civils de Lyon, Hopital Edouard-Herriot Service Central d‘Anatomie et Cytologie Pathologiques, Lyon , France; d Centre de Medecine Nucleaire, Universite Catholique de Louvain, Brussels , Belgium; e Department of Pathology, University of Kiel, Kiel , Germany; f B Unit of Surgery, Department of Surgery, University of Verona, Verona , Italy; g Department of Nuclear Medicine, Erasmus MC, Rotterdam , The Netherlands; h Department of Endocrine Oncology, University Hospital, Uppsala , Sweden; i Department of Internal Medicine, Division of Hepatology and Gastroenterology, Interdisciplinary Center of Metabolism and Endocrinology, Charite, Campus Virchow Hospital, University for Medicine Berlin, Berlin , Germany; j Service de Gastroenterologie-Pancreatologie, Pole des Maladies de l‘Appareil Digestif, Hopital Beaujon, Clichy , France; k Department of Pathology and Laboratory Medicine, Universita degli Studi, Parma, Italy; l Department of Endocrinology, Genoa University, Genoa , Italy

a Digestive Diseases Branch, NIDDK, NIH, Bethesda, Md. , USA; b Dipartimento di Patologia e Medicina di Laboratorio, Universita di Parma, Parma , Italy; c Division of Gastroenterology and Endocrinology, Department of Internal Medicine, Philipps University, Marburg , Germany; d Department of Pathology, IPATIMUP Hospital, Porto , Portugal; e Dipartimento di Fisiopatologia Clinica, Universita di Firenze, Firenze , Italy; f Department of Surgery, Johann-Wolfgang-Goethe-Universitat, Frankfurt , Germany; g E. Christ, Department of Endocrinology, Inselspital, Bern , Switzerland; h Department of Oncology, Netherlands Cancer Centre, Amsterdam , The Netherlands; i Department of Surgery, Rigshospitalet Blegdamsvej Hospital, Copenhagen , Denmark; j Department of Surgery, Gothenburg University, Gothenburg , Sweden; k Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam , The Netherlands; l Service de Gastroenterologie-Pancreatologie, Pole des Maladies de l’Appareil Digestif, Hopital Beaujon, Clichy , France

The presence of transcripts for somatostatin receptor (SSTR) subtypes 1, 2, 3, and 4 was probed by reverse transcription and polymerase chain reaction in ribonucleic acid isolated from 46 malignant and 9 nonmalignant breast tissues, 15 carcinoid tumor tissues, and 13 renal cell carcinoma tissues. The transcripts for SSTR2 were amplified in all but 2 tissue samples, whereas transcripts for SSTR1, SSTR3, and SSTR4 were detected sporadically. In renal cell tumors, SSTR3 transcripts were completely absent. In breast cancer tissue, SSTR subtypes were transcribed independently of patient age, menstrual status, diagnosis, histological grade, and levels of estrogen receptor and progesterone receptor. The probability of finding transcripts for SSTR subtypes, P, was ranked differently for the three types of tumor tissues. For breast cancer, P2 > P3 = P1 > P4 ; for carcinoid tumors, P2 > P1 > P3 = P4 ; and for renal cell tumors, P2 > P1 > P4 > P3.