Editorial 18

F-DOPA PET/CT and neuroendocrine tumours

Cristina Nanni1, Domenico Rubello2, Stefano Fanti1 1

Nuclear Medicine Service - PET Unit, Policlinico S. Orsola-Malpighi, Bologna University, Bologna, Italy Nuclear Medicine Service - PET Unit, S. Maria della Misericordia Hospital, Istituto Oncologico Veneto (IOV), Viale Tre Martiri, 140, 45100 Rovigo, Italy

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Published online: 1 April 2006 © Springer-Verlag 2006

Eur J Nucl Med Mol Imaging (2006) 33:509–513 DOI 10.1007/s00259-006-0079-5

Introduction In recent years, 18F-FDG PET/CT has gained importance, such that it has now become one of the most useful imaging methods in oncology. The tracer fluorine-18 fluorodeoxyglucose (18F-FDG) has been shown to be of value in the study of several malignancies, and it is accordingly used for staging, restaging, assessment of therapy response and follow-up. However, while 18F-FDG has been proven to detect most high-grade cancers, it shows poor sensitivity for the identification of some well-differentiated cancers because the tumour glucose metabolism may be insufficiently increased to permit visualisation by 18F-FDG PET. In the latter tumours, 18F-FDG may be useful only when there is de-differentiation and loss of the specific histological characteristics—an event that does not occur in all cancers. The phenomenon of lack of 18F-FDG uptake in differentiated tumours and increased 18F-FDG uptake when de-differentiation starts is well known and is referred to as the “flip-flop phenomenon” (Fig. 1). Among the tumours that frequently show a lack of enhanced 18F-FDG uptake are neuroendocrine tumours (NETs) [1].

docrine markers such as synaptophysin and chromogranin A. The incidence of NETs is around 2/100,000 for men and 2.4/100,000 for women. The aetiology is unknown except for those tumours that arise in patients with genetic syndromes like MEN1, 2 or 3 [2]. NETs arise mainly in the gastrointestinal tract (stomach 2–4%, jejunum 22%, ileum 25%, appendix 20%, colon/ rectum 20%) and the pancreas (glucagonoma, insulinoma, VIP-oma, gastrinoma); these are collectively referred to as gastroenteropancreatic NETs [3]. However, malignancies arising in other anatomical sites are also among the NETs, e.g. phaeochromocytoma, medullary thyroid cancer, bronchial carcinoid and neuroblastoma. All these tumours may cause specific syndromes (carcinoid syndrome, hyperinsulinism, Zollinger-Ellison syndrome, phaeochromocytoma syndrome, etc.) because they frequently secrete biologically active hormones. In this circumstance a relatively early clinical diagnosis is possible. However, an early diagnosis usually corresponds to a very small secreting mass that may be difficult to localise with morphological tests like CT, ultrasound and MRI, especially if the disease is located in the abdomen. CT and MRI are usually performed after biochemical evaluation, to identify the primary secretory mass. They are very sensitive (98%) for adrenal tumours at least 0.5–1 cm in diameter, but extra-adrenal masses are detected in a lower percentage of cases, especially if they are small and occur in patients with previous abdominal surgery. In these cases, functional imaging appears to be more effective [4].

Neuroendocrine tumours Nuclear medicine and NETs NETs are rare malignancies originating from neural crest cells that are characterised by the expression of neuroen-

Domenico Rubello ()) Nuclear Medicine Service - PET Unit, S. Maria della Misericordia Hospital, Istituto Oncologico Veneto (IOV), Viale Tre Martiri, 140, 45100 Rovigo, Italy e-mail: [email protected]

The most common tracers used for NETs are 123I-MIBG and 111In-pentetreotide. Both have high sensitivity and good specificity for detection of the primary mass and secondary lesions, and they are also useful for assessment of response to therapy and during follow-up. 123 I-MIBG is a noradrenaline analogue that is actively transported into neurosecretory granules via the cell membrane noradrenaline transporter system. It is of proven utility for the evaluation of neuroblastoma, with a very high sensitivity (about 90%) [5].

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510 Fig. 1. 18F-DOPA PET/CT (upper row) showing a small area of increased tracer uptake consistent with differentiated primary pancreatic NET. 18 F-FDG PET/CT (lower row) in the same patient fails to show tracer uptake within the neoplastic lesion. CT scans are shown on the left, and the corresponding PET scans on the right

The use of functional imaging with 111In-pentetreotide is based on the observation of enhanced expression of somatostatin receptors in a high percentage of NETs. Somatostatin receptor scintigraphy (SRS) has gained widespread acceptance in the past decade, such that it is now routinely used in the evaluation of NETs (in particular carcinoids and pancreatic NET). It has a major clinical role, in that it leads to a change in patient management in about one-third of cases [6]. The main limitation of SRS is its relatively low spatial resolution and a resultant poor

capability to exactly localise the neoplastic mass, especially if the lesion is small. 18

F-DOPA PET

18

F-Fluoro-L-DOPA has been used to investigate the activity of aromatic L-amino acid decarboxylase in the striatum and to assess the integrity of the dopaminergic system in vivo. 18F-DOPA uptake in the putamen and the caudate nucleus is related to motor and, in some cases,

Fig. 2. 18F-DOPA PET/CT in a patient with carcinoid. An area of increased tracer uptake is consistent with a small secondary lesion in the left femur

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cognitive function. 18F-DOPA has been found to be useful in patients with Parkinson’s disease, and it has an established role in the investigation of movement disorders. 18

F-DOPA PET/CT and NETs

The ability of NETs to accumulate (via the cell membrane noradrenaline transporter system) and decarboxylate both 5-hydroxytryptamine and 3,4-dihydroxyphenylalanine (an intermediate of catecholamine synthesis) is well known and formed the basis for the original concept of APUD (amine precursor uptake and decarboxylation) tumours [7]. NETs demonstrate increased activity of L-DOPA decarboxylase and are therefore characterised by high 18FDOPA uptake on PET scans. The first example of NET visualisation using a DOPA-labelled tracer was obtained in 1995 [8]. Recently some research groups have demonstrated in preliminary studies that 18F-DOPA PET is a useful procedure to detect primary and metastatic neoplastic diseases of neuroendocrine differentiation (carcinoids, glomus tumours, medullary thyroid cancer, small cell lung cancer and phaeochromocytoma) [9–16], but larger studies are needed to assess the sensitivity, specificity and accuracy of this new diagnostic procedure, especially in comparison with the well-established 123I-MIBG scintigraphy and 111In-pentetreotide SRS. 18 F-DOPA integrated PET/CT has an increased spatial resolution compared with conventional nuclear medicine examinations and allows accurate localisation of hot spots thanks to the anatomical map obtained by CT (Fig. 2). These advantages make this a very important field for further study, and additional protocols are needed to elucidate the effective advantages of PET/CT. Although 18F-DOPA and 123I-MIBG are accumulated via the same membrane transporter, no studies on the possible role of 18F-DOPA PET in the evaluation of neuroblastoma have yet been published.

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F-DOPA PET/CT is performed following intravenous injection of about 370 MBq of the tracer, and the uptake time for oncological studies is around 60 min. It has not yet been clarified whether fasting increases the procedure’s sensitivity. Anti-cancer therapies need to be suspended prior to 18F-DOPA PET/CT. No collateral effects are known, even though Koopmans et al. described a carcinoid crisis subsequent to 18F-DOPA injection in a patient with diffuse hepatic carcinoid metastases [17]. 68

Ga-DOTA-NOC vs

18

F-DOPA in NETs

As 111In-pentetreotide has proven high sensitivity for the detection of NETs and treatment with somatostatin analogues is of proven efficacy, the next step is to use radiolabelled somatostatin analogues for metabolic radiotherapy in inoperable patients. 90Y-DOTA-TOC (1,4,7, 10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid, Tyroctreotide) and 177Lu-DOTA-TOC are therapeutic compounds that have been used for NET treatment with encouraging results, the best being a response rate of 33%. 111 In-DTPA-octreotide (Octreoscan) is the diagnostic agent classically used in the preliminary phase to assess the biodistribution of the therapeutic compound, based on binding to the sst2 receptor subtype. For PET studies, 68GaDOTA-TOC has been used as the positron emitter tracer [18]. Recently, 68Ga-DOTA-NOC (tetraazacyclododecanetetraacetic acid-[1-Nal3]-octreotide) has been synthesised by Wild and co-workers [19]. This compound for PET imaging has high affinity for sst2 and sst5and has been used for the detection of NETs in preliminary studies. As in the case of 111In-Octreoscan, the uptake of 68Ga-DOTA-NOC is based on a receptor mechanism and, although this has not yet been adequately assessed, it seems to have higher sensitivity for NETs. Furthermore, it has several advantages over 111In-Octreoscan for both the patient and the physician: increased spatial resolution, the possibility of

Fig. 3. 18F-DOPA PET/CT shows a small area of increased tracer uptake consistent with primary pancreatic NET

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512 Fig. 4. 18F-DOPA PET/CT in a patient with diffuse hepatic metastasis from carcinoid and an unknown primary. Increased tracer uptake within the ileum is consistent with this being the site of the primary lesion

performing whole-body tomographic studies with a short uptake time (60 min), relatively easy synthesis and the possibility of using hybrid PET/CT scanners, thereby increasing diagnostic accuracy [20, 21]. As 68Ga-DOTA-NOC binds to NETs via a receptor mechanism, the sensitivity of this compound could be lower than that of 18F-DOPA, which accumulates via a metabolic mechanism, in some histological types expressing a low number of somatostatin receptors. On the other hand, 68Ga-DOTA-NOC PET is likely to be of higher value prior to metabolic radiotherapy in order to assess the biodistribution of the therapeutic compound. However, to date no studies have been published on this issue. The overall sensitivity and specificity of 68Ga-DOTA-NOC as compared to those of 18F-DOPA have still to be assessed, but it may be realistic to predict a complementary role for the two tracers, as they explore different features of NETs. Conclusion Although 18F-DOPA was first synthesised several years ago, very limited literature is available on this compound, probably because the labelling procedure is difficult. From preliminary studies, it seems that 18F-DOPA PET and PET/ CT have a high sensitivity and accuracy for NET detection. The high spatial resolution of PET tracers compared with conventional nuclear medicine tracers may explain the good preliminary results obtained in 18F-DOPA studies. No extensive papers comparing 18F-DOPA PET and 18F-DOPA PET/CT have been published yet, and, despite the encouraging results, new studies are needed to fully elucidate the role of 18F-DOPA PET/CT in the diagnostic work-up of NETs, especially for the detection of small pancreatic tumours (Fig. 3), tumours arising in unusual sites, small secondary lesions and unknown primaries (Fig. 4).

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