Uppsala Centre of Excellence for Endocrine Tumors
In 2007, the ENETS Executive Committee agreed to form a task force to investigate the feasibility of establishing Centers of Excellence. A network of centers would allow NET patients to seek specialists who could best treat them, and would also unify the care and research being conducted in the NET field across Europe. Link to ENETs
The Uppsala Centre of Excellence for endocrine tumors is today one of the world leading centers for diagnosis and treatment of neuroendocrine tumors (NET's). Since 1977 diagnosis and treatment of endocrine tumors has been a special focus of interest for Uppsala University Hospital.
In order to give the patient an optimal multimodal management, collaboration with other units/specialists such as radiology, clinical chemistry, pathology, nuclear medicine, cardiology, thoracic surgery and the PET-center has been established. We can offer the patients evaluation from combined clinical teams, dedicated to neuroendocrine tumors ("one-stop-shopping").
Uppsala Centre of Excellence for endocrine tumors have expertise in the following fields:
- Diagnosis of NET's
- Medical treatment including new agents, such as tyrosin kinase/angiogenesis and mTOR inhibitors
- Surgical expertise with all methods, except for liver transplantation
- Peptide radio receptor therapy (PRRT)
- Diagnosis with specific PET tracers (11C-5HTP, 11C-metomidat, 11C-hydroxyephedrine, 68Ga-DOTA-Octreotate)
- Development of molecular genetics and tumor biology for personalized treatment
As a result of dedicated treatment of patients with endocrine tumors the survival is significantly better than can be offered as standard of care in many places in other parts of the world.
Read more about resources at Uppsala Centre of Excellence
Since the late 70's, a deliberate effort on research and development of diagnostics and therapeutics of endocrine tumors has been pursued by the endocrine oncology and endocrine surgery units at Uppsala University Hospital.
Thus, new diagnostics have been developed (biochemical markers, somatostatin receptor imaging, PET with specific tracers (5-HTP, 68Ga-PET), advanced radiology) and new therapies have been introduced (somatostatin analogues, interferon, embolization of liver metastases, new surgical techniques for small intestinal tumors). Improved diagnostics with determination of proliferation rate and staging have also enabled individualisation of treatment. As a consequence, quality of life and survival rates are improving.
In order to give patients with endocrine tumors an optimal multimodal management, collaboration with other units/specialties, such as radiology, clinical chemistry, pathology, nuclear medicine, cardiology, thoracic surgery and the PET-centre has been established.
Physicians and scientists at Uppsala Centre of Excellence
Development of specific diagnostic and therapeutic modalities for endocrine tumors have been developed by the Department of Endocrine Oncology and the Endocrine Surgery.
They pioneered specific cytotoxic treatment (streptozotocin + 5FU), therapy with somatostatin analogs and alpha interferons. A more active surgery including wide resections, debulking, radiofrequency ablation was developed at the Department of Endocrine Surgery. Specific biochemical markers, tachykinins and chromogranin A became new diagnostic tools and unique PET-scannings were developed including C11-5HTP, Ga68 PET.
National referral center
Today more than 2500 patients with different forms of neuroendocrine tumors have been managed. The Department of Endocrine Oncology was appointed National referral center for endocrine tumors in 1986 in Sweden. About 20 per cent of current patient referrals are coming from Europe, the United States, South America and Asia. The international referrals have steadily increased and the center is now considered unique of its kind in the world. The center has been involved in establishing Scandinavian, European and North American Networks for patients with neuroendocrine tumors (GETNE, ENETS, NANETS). Furthermore, a European patient's network for patients with neuroendocrine tumors was established at this center (CARPA).
As a result of dedicated treatment of patients with endocrine tumors the survival is significantly better than can be offered as standard of care in many places in other parts of the world.
The Department of Endocrine Surgery is a part of the Department of Surgery at the University Hospital in Uppsala. During the 1970 and 1980s the subspeciality of Endocrine Surgery developed, in the world after initiative taken from Nordic surgeons, and Uppsala has been active in this matter ever since. We have in close collaboration with the Department of Endocrine Oncology developed and pioneered treatmentof different types of endocrine tumors. Our reputation concerning diagnostic procedures and surgical treatment of primary hyperparathyroidism, thyroid cancer, gastro-entero pancreatic neuroendocrine tumours (GEP-NET) and adrenal tumors are well recognized. We have an ongoing active research.
The Endocrine surgical ward 70C1 is situated at the 6th floor in building "70" at The University Hospital / Akademiska Sjukhuset.
Researchgroups at Uppsala Centre of Excellence
Positron emission tomography (PET)
During the last few years PET using 18F-labelled deoxy-glucose (FDG) has evolved as a powerful imaging modality in oncology. The recent introduction of PET-CT and also most recently PET-MRI, leads to several advantages over a standard PET. The anatomic localisation will be significantly improved. The positron-emitting radionuclides are generally produced in a low-energy cyclotron and the half-lives are usually short; 2-110 minutes. In practice the use of 11C and 18F-labelled PET tracers requires a cyclotron in the vicinity of the PET camera, but 18F can be transported within radius of about 2 hours. The PET tracers emit positrons which collides with an electron upon which both are annihilated and converted into high-energy photons. These travel in opposite directions and simultaneously reach the detector ring and the line of decay is registered. By collecting data from all detected decays during the acquisition, transaxial images may be reconstructed. The attenuation-corrected PET-images are regularly recalculated to provide images of standardized uptake values (SUVs).
This tracer is not well-designed for well-differentiated NETs with low proliferation capacity. The uptake of the tracer is very low and therefore not of significant clinical value. However, in poorly differentiated highly malignant tumors, FDG-PET might give valuable information for both tumor localisation, characterisation, staging and therapy monitoring.
Specific tracers for NETs are 18F-DOPA PET, 11C-5HTP-PET, 68Ga-DOTA-octreotate. 18F-L DOPA and 11C-L-DOPA has been used in a number of studies to visualize NETs with a sensitivity of somewhere between 50-70%. 18F-DOPA PET has also been informative in the visualization of medullary thyroid cancer. 11C-5-HTP-PET is more sensitive than 11C-L-DOPA and also 18F-DOPA-PET particularly in endocrine pancreatic tumors. In a comparative study between CT-scan, SRS and 5-HTP-PET the latter shows significant higher sensitivity and could also demonstrate more lesions than the other methods. The draw-back with this technique is that it is only available in very few centers, such as Uppsala and Gronningen. The technique can demonstrate tumors down to 3 mm. (Fig. 5, 6).
68Ga-DOTA-octreotate-PET (Fig. 7)
68Ga is a generator-produced positron emitter, which has come more and more in to clinical praxis and is also called "the poor mans PET". In several studies it demonstrated higher sensitivity than SRS and can be done in "one-stop" procedure. The better spatial resolution by PET speaks in favour of functional imaging by PET compared with SPECT and planar imaging with SRS.
Peptide receptor radionuclide treatment (PRRT)
Peptide radio-receptor radionuclide therapy with radiolabelled somatostatin analogs is an emerging and convincing treatment modality for patients with unresectable somatostatin receptor positive NETs. The somatostatin receptor is strongly over-expressed in most tumors, resulting in high tumor-to-background ratios. In earlier studies 111Indium-DTPA-octreotide were used at high doses for treatment of GEP-NETs, but the responses to these radioactive compounds were very low. During the last years studies have been performed with 90Yttrium labelled somatostatin analogs and most recently 177Lutetium-DOTA-octreotate. A lot of different studies have been published, unfortunately with different treatment protocols, but in general 25-30% of the patients presented objective responses and up to 40% stabilization of a progressive disease. In general PRRT is regarded as a relatively safe treatment with some haematological and renal toxicity in selected cases. The precise role of PRRT has to be defined in forthcoming randomized clinical trials.
Nuclear medicine of neuroendocrine tumors (NETs) includes diagnosis with somatostatin receptor scintigraphy, PET-scanning and MIBG and treatment, so called peptide-radio-receptor treatment (PRRT). NETs are a heterogenous group of neoplasms, comprising at one end of the spectrum well-differentiated and slowly growing tumors, which are the most common, and at the other and less frequent poorly differentiated and malignant neoplasms with aggressive behaviour. The tumors tend to express hormonal activity in accordance with that of the endocrine cell from which they originate and thus the clinical presentation may be diverse. A unique feature of NETs is the expression of peptide hormone receptors, particular somatostatin receptors, the basis for somatostatin receptor scintigraphy. Another specific feature of NETs is the so called APUD- characteristics, which means that they can take up and accumulate amines and precursors for production for various peptides and hormones. This is one of the bases for PET-scanning in these tumors.
Somatostatin receptor scintigraphy (SRS)
SRS is a well-established functional technique for the imaging or NETs. Receptors for somatostatin and analogs have been identified on many cells of neuroendocrine origin. Of the five different subtypes of somatostatin receptors known to date, subtypes 1 and 2 appear to be the most frequent. The latter is the main target for visualization of NETs by SRS. The most commonly used somatostatin analog is octreotide, which is labelled with 111Indium, using the chelator diethylene-triamine-pentaaceticacid (DTPA) to produce 111Indium-DTPA-octreotide which is available as a commercial product - Octreoscan®. Other tracers are 111Indium-DOTA-TOC, 111Indium-DOTA-NOC and 111Indium-DOTA-TATE.
MIBG, a catecholamine analog, labelled with 123I or 131I, is a well-established tracer for scintigraphic visualization and treatment of tumors originating from the neural crest. That includes mainly phaeochromocytomas, paragangliomas, but also NETs, such as carcinoids. The sensitivity is lower than for SRS for GEP-NETs with a sensitivity of somewhere between 40-50%. In comparative studies the sensitivity of SRS to detect NETs exceeded that of MIBG scintigraphy.
Uppsala Care looks after international patients seeking highly specialised healthcare. As we are a fully integrated part of Akademiska sjukhuset, our patients have access to the full range of skills, professionalism and experience that makes up the hospital's 300 years of history. Our services are popular. In 2014 alone, we received more than 350 patients from 42 different countries.
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Clinical trials at Uppsala Centre of Excellence
Collection and organising patient samples (blood and tissue) that are taken before, during and after cancer therapy.
All patients receiving LU-dotatate treatment is included.
Genetic study in smallbowel NET
Genetic analysis in patients with smallbowel NET.
Everolimus and temozolomide as first-line treatment in advanced gastroenteropancreatic neuroendocrine carcinoma (G3) with a Ki67 of 20-55%.
Nordic study on patients with NEC.
Study of Recombinant Adenovirus AdVince in Patients With Neuroendocrine Tumors; Safety and Efficacy (RADNET)
An open-labelled, uncontrolled, single-center Phase I/IIa clinical study to evaluate the safety of repeated infusions of AdVince into the hepatic artery in patients with metastatic neuroendocrine tumors (NETs), and if possible determination of maximum tolerated dose.
Efficacy and Safety of Everolimus and (STZ-5FU) Given One Upfront the Other Upon Progression in Advanced pNET (SEQTOR)
The purpose of this study is to elucidate which sequence of streptozotocin (STZ) based chemotherapy and the mammalian Target of Rapamycin (mTOR) inhibitor, everolimus, gives better results in terms of second Progression Free Survival (PFS) in well differentiated and advanced pancreatic NETs.
This exploratory study aims to evaluate the diagnostic, prognostic and response predictive value of a multi biomarker strategy in patients with Gastroenteropancreatic Neuroendocrine Tumors (GEP NETs) originating from the midgut or pancreas. Using a recently developed methodology enabling the evaluation of 92 concomitant cancer biomarkers will provide an interesting approach to solve this question (Lundberg et al 2011).
Quality of Life, Treatment Experience and Cost of Treatment With Somatostatin Analogues in Patients With Gastroenteropancreatic Neuroendocrine Tumours (STREET)
Data from this study will contribute additional knowledge regarding patient outcomes and direct somatostatin analogue (SSA) treatment related costs in clinical practice in the Nordic countries. Such knowledge can be of importance in a treatment decision, decision support for development of care, follow up and training of both patients and primary care nurses.
The objective of this study is to evaluate the efficacy and safety of oral cabozantinib at a 60 mg dose compared with a 140 mg dose in subjects with progressive, metastatic MTC. It will test if the lower dose results in similar progression free survival (PFS) and overall response rate (ORR) with fewer adverse events compared to the PFS, ORR and adverse events found in previous clinical trials of 140 mg.
The primary objective of this study is to evaluate the long-term safety and tolerability of orally administered telotristat etiprate.
Recently completed studies
Analysis of mRNA in patients receiving LU-dotatate treatment.
Chromogranin is analysed in patients with NET.
Telotristat Etiprate (LX1606) vs placebo to evaluate the effect and safety in patients with carcinoid syndrome already on SSA therapy.
The purpose of this study is to test the effectiveness and safety of Everolimus or Pasireotide LAR alone or in combination in adult patients with advanced (unresectable or metastatic) neuroendocrine carcinoma (typical and atypical) of the lung and thymus.
This study will estimate the treatment effect of everolimus in combination with pasireotide LAR relative to everolimus alone on progression-free survival (PFS) in patients with advanced progressive PNET.
A Multicenter, Randomized, Blinded Efficacy and Safety Study of Pasireotide LAR vs Octreotide LAR in Patients With Metastatic Carcinoid Tumors Whose Disease-related Symptoms Are Inadequately Controlled by Somatostatin Analogues.
An International, Randomized, Double-Blinded, Phase 3 Efficacy Study of XL184 Versus Placebo in Subjects With Unresectable, Locally Advanced, or Metastatic Medullary Thyroid Cancer.
Phase II, Open, Adaptive, Dose Escalating, Multicentre Titration Study to Assess the Efficacy and Safety of Repeated Subcutaneous Administration of Different Doses of BIM 23A760 in Patients With Carcinoid Syndrome.
A nordic observational study in patients with NET. Follow up during two years.
A Randomized, Double-blind Placebo-controlled, Multicenter Phase III Study in Patients With Advanced Carcinoid Tumor Receiving Octreotide Depot and Everolimus 10 mg/Day or Octreotide Depot and Placebo.
An Open Label, Stratified, Single-arm Phase II Study of Everolimus in Patients With Advanced Pancreatic Neuroendocrine Tumor (NET) After Failure of Cytotoxic Chemotherapy.
Patients with carcinoid tumors receiving Interferon-alpha
An International, Phase II, Randomized, Double-Blinded, Placebo-Controlled, Multi-Center Study to Assess the Efficacy of ZD6474 (ZACTIMA™ ) Versus Placebo in Subjects With Unresectable, Locally Advanced or Metastatic Medullary Thyroid Cancer.
A Phase IV, International, Open-label, Randomised, Cross-over Study to Assess Patient Preference and Health Economy in Patients With Neuroendocrine Tumours, Treated With Lanreotide Autogel Given as Self Administration.
Phase III, Randomised, Double-blind, Stratified Comparative, Placebo Controlled, Parallel Group, Multi-centre Study to Assess the Effect of Deep Subcutaneous Injections of Lanreotide Autogel 120mg Administered Every 28 Days on Tumour Progression Free Survival in Patients With Non-functioning Entero-pancreatic Endocrine Tumour.
First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) Etoposide, Doxorubicin, Cisplatin and Mitotane vs Streptozotocin and Mitotane.
Patients with pancreatic NETs, multicenter study.
History of Uppsala Centre of Excellence
Since the late 70's, a deliberate effort on research and development of diagnosis and therapy of endocrine tumors has been pursued by the Department of Endocrine Oncology and Endocrine Surgery at Uppsala University Hospital. Thus, new diagnostic procedures have been developed, including biochemical markers, somatostatin receptor imaging, positron emission tomography with specific tracers such as 11C-5-HTP, 68Ga-DOTATOC. New therapies have been introduced including somatostatin analogs, interferon, peptide receptor radiotherapy, targeted treatment with m-TOR and tyrosine kinase inhibitors as well as anti-angiogenic treatment. Embolization of liver metastases is performed including radio-embolization with radioactive micro-particles. New surgical techniques for small intestinal tumors and other neuroendocrine tumors have been developed as well.
The tumor biology program include biomarkers for early detection and also markers of proliferation and staging of the disease using the most recent staging programs, developed by European Neuroendocrine Tumor Society (TNM staging and grading system), which enables individualization of treatment. As a consequence quality of life and survival rate have significantly improved over the last decades.
In order to give the patient an optimal multimodal management collaboration with other units specialities such as radiology, clinical chemistry, pathology, nuclear medicine, cardiology, thoracic surgery and the PET-centre has been established. Patient's advocacy groups are also involved in the care (CARPA). A Tumor Board including all the specialities mentioned above is regularly discussing the patient management. A large number of patients (around 3000) have been evaluated and treated and since 1986. The Department of Endocrine Oncology has been a national referral centre.
At present 20-30% of patients come from other countries, also outside Scandinavia and Europe indicating that the centre has received the status of a Centre of Excellence. In 2009 Department of Endocrine Oncology was certified by the European Neuroendocrine Tumor Society (ENETS) as an Centre of Excellence for management of neuroendocrine tumors.