ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Follow-Up and Documentation

The documentation of patients with neuroendocrine tumors should include the most relevant data characterizing an individual patient from the first contact with their physician/hospital until their last presentation during follow-up. The documentation should be both simple but nevertheless as complete as possible and should include basic demographic details to identify a specific patient, tumor histology and biology, disease history, course of the disease, diagnostic tests and therapeutic interventions. This information is essential for treatment and follow-up strategies adjusted to the specific features of the tumor of the patient. Furthermore, standardized documentation acts as a key precondition to learn more about patients with specific tumor subtypes and regarding the impact of treatment modalities on the course of the disease. In the present clinical setting, the timing of data collection and content of documented data vary considerably. Therefore, comparison of data from different centers is frequently hampered by lack of data uniformity.During the ENETS Standards of Care Conference organized in Mallorca in 2007, a group of physicians with extensive experience in the clinical care of patients with benign and malignant gastro-entero-pancreatic (GEP) neuroendocrine tumors met to produce proposals for the unified collection of data and suggested time intervals for follow-up investigations. These guidelines recognize the diversity of tumor subtypes, the actual WHO and TNM tumor classifications, the individual clinical course of the disease as well as the resource implications relevant to the growing costs of the European healthcare systems. Particular attention was paid to recommend only those investigations which would have a significant impact on further therapeutic strategies.The panel agreed that the following 5 categories best define the different tumor entities observed in the clinical setting. The categories follow the recent WHO classification 1, 2 as well as the ENETS recommendations for TNM staging 3, 4 in order to better compare data from different centers.Insulinomas and small, benign tumors (T1 endocrine tumors of the stomach, rectum and appendix, ‘carcinoids’) were categorized separately. They belong to the most frequent benign endocrine tumor entities and require a less intensive follow-up compared to malignant variants.• Benign insulinoma (T1 1 cm invading muscularis propria or subserosa• T2 (>1 cm) tumors of the duodenum/ampulla/proximal jejunum; duodenal gastrinomas and midgut carcinoids which are usually 2 cm) tumors limited to the pancreas• Appendiceal carcinoid 1–2 cm(a) G1: well-differentiated, Ki-67 3 mm) invading subserosa/mesoappendix is a matter of debate. Most surgeons recommend right-sided hemicolectomy. Following this procedure and providing that no metastatic lymph node involvement is present, no routine follow-up investigations are indicated. The beneficial effect of follow-up studies recommended in IV.4 for patients with a T2 endocrine tumor and simple appendicectomy remains controversial. There is no indication for tumor markers in patients with T1 or T2 appendiceal tumors.The respective tumors have been defined in III.2. In general, their grading is G1. After surgical tumor resection the following investigations are recommended.V.4.1.1 US/CT/MRI• 6 months postoperatively: US or CT or MRI (depending on availability and experience); if negative:• Repeat after further 6 months; if negative:• Repeat at yearly intervals postoperatively; the time intervals can be reconsidered according to (1) the tumor growth characteristics of an individual patient and/or when (2) tumor resection is Nx due to the lack of any nodal sampling at the time of surgery• In the case of stable disease, longer intervals may be justifiedV.4.1.2 Octreotide Scintigraphy (Octreoscan®)• At baseline, then every 2 years. Reconsider the time intervals according to the tumor growth characteristics of an individual patient. When the disease shows stability or no recurrence, according to US, CT or MRI, the octreotide scan may not be necessary. If a change in the strategy of treatment is considered a new scan may be justifiedV.4.1.3 Comments(a) There was no formal agreement in the panel discussion concerning the duration of follow-up investigations: 4 years – indefinitely(b) Octreoscan® may be substituted in future by 68Gallium-DOTA-DOC PET due to its higher sensitivity. See IV.2.Plasma CgA should only be determined in the presence of a tumor visualized by imaging, except in very occasional patients. In the presence of a tumor repeat every 6 months. For further comments see IV.2.2.The respective tumors have been defined in III.3. After surgical resection of a probably malignant tumor according to the WHO classification the following investigations are recommended.See recommendations suggested for V.4.V.5.2.1 General CommentTumors graded as G2 or G3 are much rarer than G1 tumors. In case of doubt with either very slow progression of tumors classified as G2 or G3 or very fast progression of tumors classified as G1 or G2 consider re-biopsy.V.5.2.2 ImagingV.5.2.2.1 US/CT/MRI. 3 months postoperatively US or CT or MRI (depending on availability and experience); if negative: repeat at 3-month intervals indefinitely.V.5.2.2.2 Octreoscan®. 3 months postoperatively; if negative: repeat 12 months postoperatively or if new lesions appear during US/CT/MRI imaging.For further comments see V.4.1.2.V.5.2.2.3 Comment. Octreoscan may be substituted in future by 68Gallium-DOTA-DOC PET due to its higher sensitivity. For further comment see IV.2.V.5.3.3 Tumor Markers• See V.4.2.• Intervals: 3 monthsThe respective tumors have been defined in III.3. Surgical intervention should always be considered as therapeutic option. For follow-up the following investigations are recommended.See recommendations suggested for V.4.In patients with carcinoid syndrome echocardiography should be performed at diagnosis. If positive at diagnosis repeat every 6 months; if negative, every 12 months.See recommendations suggested for V.5.2.In patients who are not members of a MEN-1 or VHL family but whose clinical spectrum of symptoms and pathohistological findings is suggestive of the MEN-1 or VHL syndromes, mutational analysis of the appropriate genes should be arranged. If positive, predictive genetic testing of family members should be performed according to the country-specific guidelines. Surveillance programs can be stopped in family members who are negative for the identified mutation, but biochemical and clinical surveillance is required for patients at risk. Patients with MEN-1 syndrome and patients with VHL disease should be referred to and followed up in specialized centers.In non-parathyroidectomized subjects: serum-calcium and plasma PTH levels at 12-month intervals. Most experts agree that in case of confirmed biochemical diagnosis of a primary hyperparathyroidism no further imaging studies are indicated to demonstrate the mostly asymmetric hyperplasia of the parathyroid glands.In patients with subtotal parathyroidectomy or with total parathyroidectomy and autotransplantation with or without substitution of calcium and 1,25-dihydroxycholecalciferol, the control of serum calcium should be determined according to the individual situation.Patients with recurrent hyperparathyroidism should be transferred to specialized centers with experience in MIBI scintigraphy and selective vein catheters.In general, pancreatico-duodenal neuroendocrine tumors are multiple. The resection of an insulinoma (usually pancreatic) should always be actively sought to avoid life-threatening hypoglycemic events.The resection of a gastrinoma (usually multiple and duodenal) is dependent on factors such as the patient’s individual situation (general health status, patient’s preference and the policy of the surgical institution). The consequences of hypergastrinemia can usually also be well managed by proton pump inhibitors, although high doses may need to be used.Most pancreatic neuroendocrine tumors are non-functioning and small tumors can be best visualized by endoscopic ultrasound, larger tumors by conventional ultrasound, CT and MRI. However, this will be contingent on the radiological expertise of the center. Follow-up investigations must be individualized and depend on the size and growth behavior of individual tumors. The same is true for metastatic tumors. In general, imaging intervals are between 1 and 2 years. Most experts agree that tumors >2 cm should be resected due to a ≈30% probability of metastatic spread.Tumor markers for pancreatic and duodenal tumors include plasma CgA and serum gastrin for gastrinoma. They can be used to detect a relapsing gastrinoma or tumor growth and should be determined during visits for imaging.In patients with and without adenomas of the hypophysis screening should be performed in intervals between 1 and 2 years.The follow-up investigations which should be documented to visualize the specific course of the disease in an individual patient are summarized in table 1.Göran Åkerström, Department of Surgery, University Hospital, Uppsala (Sweden); Bruno Annibale, University Sapienza Roma, Rome (Italy); Emilio Bajetta, Medical Oncology Unit B, Istituto Nazionale Tumori, Milan (Italy); Jaroslava Barkmanova, Department of Oncology, University Hospital, Prague (Czech Republic); Anne Couvelard, Service de Gastroentérologie, Hôpital Beaujon, Clichy (France); Joseph Davar, Department of Cardiology, Royal Free Hospital, London (UK); Wouter de Herder, Department of Internal Medicine, Section of Endocrinology, Erasmus MC, Rotterdam (The Netherlands); Gianfranco Delle Fave, Ospedale S. Andrea, Rome (Italy); Barbro Eriksson, Medical Department, Endocrine Unit, University Hospital, Uppsala (Sweden); Diego Ferone, Departments of Internal Medicine and Endocrinological and Metabolic Sciences, University of Genoa, Genoa (Italy); Björn Gustafsson, Medisinsk avd, Gastroseksjon, St Olavs Hospital, Trondheim (Norway); Diana Ivan, Endocrinology and Diabetology, Klinikum der Philipps-Universität, Marburg (Germany); Gregory Kaltsas, G. Genimatas Hospital, Athens (Greece); Reza Kianmanesh, UFR Bichat-Beaujon-Louis Mourier, Service de Chirurgie Digestive, Hôpital Louis Mourier, Colombes (France); Günter Klöppel, Institut für Pathologie, TU München, Munich (Germany); Ulrich-Peter Knigge, Department of Surgery, Rigshospitalet, Copenhagen (Denmark); Paul Komminoth,Institute for Pathology, Stadtspital Triemli, Zürich (Switzerland); Dik Kwekkeboom, Department of Nuclear Medicine, Erasmus University Medical Center, Rotterdam (The Netherlands); Rachida Lebtahi, Nuclear Medicine Department, Bichat Hospital, Paris (France); Val Lewington, Royal Marsden, NHS Foundation Trust, Sutton (UK); Anne Marie McNicol, Division of Cancer Sciences and Molecular Pathology, Pathology Department, Royal Infirmary, Glasgow (UK); Emmanuel Mitry, Hepatogastroenterology and Digestive Oncology, Hôpital Ambroise-Paré, Boulogne (France); Ola Nilsson, Department of Pathology, Sahlgrenska sjukhuset, Gothenburg (Sweden); Kjell Öberg, Department of Internal Medicine, Endocrine Unit, University Hospital, Uppsala (Sweden); Juan O’Connor, Instituto Alexander Fleming, Buenos Aires (Argentina); Dermot O’Toole, Department of Gastroenterology and Clinical Medicine, St. James’s Hospital and Trinity College Dublin, Dublin (Ireland); Ulrich-Frank Pape, Department of Internal Medicine, Division of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin (Germany); Mauro Papotti, Department of Biological and Clinical Sciences, University of Turin/St. Luigi Hospital, Turin (Italy); Marianne Pavel, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin (Germany); Aurel Perren, Institut für Allgemeine Pathologie und Pathologische Anatomie der Technischen Universität München, Klinikum r.d. Isar, Munich (Germany); Marco Platania, Istituto Nazionale dei Tumori di Milano, Milan (Italy); Guido Rindi, Department of Pathology and Laboratory Medicine, Università degli Studi, Parma (Italy); Philippe Ruszniewski, Service de Gastroentérologie, Hôpital Beaujon, Clichy (France); Aldo Scarpa, Department of Pathology, University of Verona, Verona (Italy); Klemens Scheidhauer, Klinikum rechts der Isar, TU München, Munich (Germany); Jean-Yves Scoazec, Anatomie Pathologique, Hôpital Edouard-Herriot, Lyon (France); Anders Sundin, Department of Radiology, Uppsala University Hospital, Uppsala (Sweden); Waldemar Szpak, Westville Hospital, Mayville (South Africa); Babs Taal, Netherlands Cancer Centre, Amsterdam (The Netherlands); Pavel Vitek, Institute of Radiation Oncology, University Hospital, Prague (Czech Republic); Marie-Pierre Vullierme, Service de Gastroentérologie, Hôpital Beaujon, Clichy (France); Bertram Wiedenmann, Department of Internal Medicine, Division of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin (Germany).