Neuroendocrine tumours (NETs) and endocrine tumours

Principal investigator: Anders Sundin

Neuroendocrine tumours (NETs) and endocrine tumours are challenging in the sense that they vary considerably in their characteristics. They may be functioning, producing hormones giving rise to clinical syndromes, and non-functioning without hormonal symptoms. The former usually present at an early stage when the tumour is small whereas the non-functioning tumours usually present with local symptoms and are usually larger at diagnosis. Bowel NETs may cause obstruction and venous ischemia. Most of the NETs are slow grooving with low proliferation but a subgroup has higher proliferation rate and more aggressive clinical behaviour. Because of all these various characteristics the NET patients present at many varying tumour stages and, consequently, require very different imaging strategies utilising radiological and nuclear medicine imaging methods.

Based on the generally high somatostatin receptor expression in NETs and the high metabolic rate in the high grade NETs, imaging by positron emission tomography (PET) with 68Ga-lablled somatostatin receptor analogues and (18F]fluoro-deoxy-glucose, respectively, has become a standard during the last few years. PET is currently always performed together with diagnostic CT (PET/CT) allowing for simultaneous functional and anatomical imaging work-up. Another PET tracer available for PET/CT is the amine precursor 11C-5-hydroxy-tryptophan, which is taken up by the NET cells and converted to serotonin, and is valuable in patients with tumours with low or absent somatostatin receptor expression.

A second area that has expanded during the last few years is Magnetic Resonance Imaging (MRI) especially with diffusion weighted imaging (DWI) and the development of whole-body imaging examination protocols. DWI in the area of NETs basically allows for imaging of high cellularity tissues, which is malignant tumours and increases the sensitivity for especially small tumour lesions. MRI has traditionally, for the sake of examination time, been restricted to examination of limited body-areas but with the current whole-body MRI protocols examination from the top of the head to the thighs may be completed within 45-60 minutes including intravenous contrast-enhancement and DWI.

Peptide receptor radio therapy (PRRT) with 177Lu-labelled somatostatin receptor analogues has become an important therapy option in patients with disseminated disease in whom conventional therapies fail. The number of therapy cycles that may be administered rely on the absorbed dose in the dose limiting normal organs – kidneys and bone marrow – and may be determined by dose calculations (dosimetry). Because 177Lu not only emits therapeutic beta radiation but also gamma that allows for gamma-camera examination (scintigraphy including SPECT) the absorbed doses to normal organs and tumours may be calculated. The original PRRT protocol of 4 cycles may because of this dosimetry whereby the accumulated absorbed doses in kidneys and bone marrow are registered, instead be personalized and about half of the patients receive more than 4 and up to about 10 PRRT cycles.

Organization

The group comprise radiologists, nuclear medicine physicians and physicists. The work is performed at the Departments of Nuclear Medicine, PETcentre and Radiology, Uppsala University Hospital involving Institutions of Surgical Sciences and Hospital Physics, Uppsala University.
 

Four projects:

Project 1: PET/CT and PET/MR diagnosis and therapy monitoring of neuroendocrine tumours

PET/CT with 68Ga-labelled somatostatin analogues, mainly 68Ga-DOTATOC, has replaced previous nuclear imaging of NETs with scintigraphy because of the better spatial resolution of the PET camera, the faster kinetics of the tracer and the better tumour-to-normal tissue image contrast. The well-established PET tracer 11C-5-hydroxy-tryptophan still has a role for patients with tumours with low or no somatostatin receptor expression. The tracers have, however, never been examined in the same patients in a head to head comparison.

The first study in this project is a retrospective evaluation of PET/CT with 11C-5-hydroxy-tryptophan in NET patients to assess its impact on primary tumour diagnosis, tumour staging and diagnosis of recurrent disease in comparison with results of surgery, histopathology, and follow-up imaging.

The second study utilises PET/MRI to compare the PET tracers 68Ga-DOTATOC and 11C-5-hydroxy-tryptophan in NET patients also in comparison with whole body MRI including DWI.

The third study constitutes a therapy monitoring trial. Firstly, a retrospective comparison is performed between 11C-5-hydroxy-tryptophan-PET/CT in patients before start and during treatment somatostatin analogue therapy to measure the therapy effects on PET as changes in 11C-5-hydroxy-tryptophan-tumour uptake (SUV) in correlation to conventional radiology (CT/MRI) with RECIST 1.1 criteria, biochemisty and clinical status. Secondly, in a prospective study patients undergoing PRRT with 177Lu-DOTATATE are examined by dynamic and static PET/CT with 68Ga-DOTATOC before therapy start and before the third cycle of PRRT in order to measure the changes in tumour transport rate (Ki) and the uptake (SUV) between examinations as a means to assess the therapy effect in relation to conventional radiology (CT/MRI) using the RECIST 1.1. criteria, biochemistry and clinical status.

Members of the group during 2015

Nicoleta Casta, PhD student

Anders Sundin, MD, PhD, Professor


Project 2: Imaging and dosimetry in PRRT with 177Lu-DOTATATE

In the first part of this project the absorbed tumour dose is related to various factors during PRRT mainly tumour shrinkage as evaluated by CT. Other aspects are the administered peptide (TATE), the specific activity of the 177Lu-DOTATATE preparation. This is performed for different NET types (pancreatic NETs, Small bowel NETs etc.)

In the second part, 68Ga-DOTATATE-PET/CT will be added to the dosimetry calculations based on repeated scintigraphy (including SPECT) during 177Lu-DOTATATE therapy. In order to assess the respective kinetics of the 177Lu-DOTATATE and the 68Ga-DOTATATE preparations, respectively, patients will receive both preparations and undergo scintigraphy and PET/CT during blood sampling for whole-blood and plasma pharmacokinetics. Because of the more precise absolute quantification and better spatial resolution provided by PET as compared to scintigraphy, higher precision in the dosimetry is anticipated as well as better appreciation of organ and tumour heterogeneity in this respect.

Members of the group during 2015

Ulrika Jahn, PhD student

Anders Sundin, MD, PhD, Professor            

Mark Lubberink, PhD Ass Professor

Mattias Sandström, PhD

Ezgi Elan, PhD student
 

Project 3: PRRT in neuroendocrine tumours

The results of PRRT with 177Lu-DOTATE as monitored by organ dosimetry in order to administer the maximum number of therapy cycles to each patient are promising. A manuscript on a large study comprising 200 patients with various NETs is soon to be submitted for publication. However, many more patients have undergone PRRT that those in the study and it is therefore of great interest to assess also the results for these patients and to perform this for each NET type separately (pancreatic NETs, small bowel NETs etc.).

In the first study the results of PRRT with 177Lu-DOTATE will be assessed in patients with pancreatic NETs and secondly, small bowel NETs. Results are assessed according to RECIST 1.1. (CT/MRI) to determine best response, time to progression, progression free survival and overall survival etc.

Members of the group during 2015

Katarzyna Fröss-Baron, Researcher

Anders Sundin, Professor

Ulrike Garske, MD, PhD

Barbro Eriksson, MD, PhD, Ass Professor

Dan Granberg, MD, PhD, Ass Professor


Project 4: Radiological and nuclear medicine imaging in adrenal tumours

Adrenal tumours are subject to imaging examinations for several reasons. CT or MRI of the abdomen/thorax, for reasons unrelated to adrenal disease, results in diagnosis of an adrenal tumour in approximately 1/25 patients and these, so called adrenal incidentalomas, needs to be assessed regarding malignancy (typically by imaging) and hormonal function (biochemistry).

One of the rare but feared tumours in the adrenals is adrenocortical cancer (ACC). In a large cohort of patients with ACC at the Uppsala and Karolinska University Hospitals, patients who all had undergone preoperatiove CT were evaluated for primary tumour size, heterogeneity, contrast-enhancement, tumour invasion and patterns of metastasis.

A large cohort of ACC patients having undergone 11C-metomidate-PET/CT will be similarly assessed and the diagnostic accuracy compared to that of contrast-enhanced CT and MRI.

In patients with hypertension a subgroup suffers from aldosteronism because of adrenal hyperplasia or an adrenal tumour (Conn adenoma). In order to determine the treatment (systemic and surgical resection, respectively) the reason for aldosteronism needs to be established. Adrenal venous sampling of blood for hormonal analyses is the standard procedure to determine whether the increased aldosterone production relates to a unilateral adenoma or bilateral hyperplasia. This is an invasive, technically demanding and extremely operator dependent procedure and therefore often needs to be repeated because of failure to sample blood from both adrenals.

PET/CT with 11C-metomidate, that accumulates in adrenocortical tissues has been tried in several studies to characterise adrenal tumours and to localise Conn adenomas but is hampered by the approximately 0,5cm resolution of the PET camera that makes detection of small tumours difficult. Suppression of the normal adrenocortical tissue by cortisone premedication has partially increased the imaging yield but further studies are necessary.

Future studies will concentrate on further developing 11C-metomidate-PET/CT, firstly in a joint project with Cambridge University, GB, to develop a 18F-labelled analogue 18F-etomidate with theoretically better imaging characteristics.

Members of the group during 2015

Sorgul Guven, PhD student

Anders Sundin, MD, PhD, Professor

Per Hellman, MD, PhD, Professor