CT with 68Gallium-DOTA-peptides in NET: An overview

European Journal of Radiology 80 (2011) e116–e119

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Review

PET/CT with 68Gallium-DOTA-peptides in NET: An overview Valentina Ambrosini a , Davide Campana b , Paola Tomassetti b , Gaia Grassetto c , Domenico Rubello c,∗ , Stefano Fanti a a b c

Department of Nuclear Medicine, Sant’ Orsola-Malpighi University Hospital, Bologna, Italy Department of Internal Medicine, Sant’ Orsola-Malpighi University Hospital, Bologna, Italy Department of Radiology, Nuclear Medicine, Medical Physics, Santa Maria della Misericordia Hospital, Via Tre Martiri 140, 45100 Rovigo, Italy

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Article history: Received 29 June 2010 Accepted 29 July 2010 Keywords: NET 68Gallium-DOTA-peptides DOTA-TOC DOTA-NOC DOTA-TATE

a b s t r a c t In the present review article we presented the major technical innovations regarding the diagnosis of NET with PET/CT 68Ga-DOTA-peptides compounds over conventional radiologic and scintigraphic imaging, discussing both the different types of radiopharmaceuticals commercially available, trying to making a comparison on the possible advantages and drawbacks of these radiopharmaceuticals, and providing also some technical recommendations to the radiologists and nuclear physicians for using these new methodology in an appropriate manner in the clinical setting. © 2010 Elsevier Ireland Ltd. All rights reserved.

Neuroendocrine tumours (NET) are heterogeneous slowgrowing neoplasms, occurring in 1–4/100,000 people per year [1,2]. NET cells origin from endocrine cells that derive from the neural crest [3] and are characterized by an endocrine metabolism and a typical pathologic pattern. Belonging to the APUD cells system (amine precursor uptake and decarboxylation), NET can produce a large variety of substances since they take up, accumulate and decarboxylate amine precursors such as dihydroxy-phenylalanine (DOPA) and hydroxyl-tryptophane. The presence of hormone syndromes related to amine/hormone production, allows the differentiation of NET in functional (33–50% of cases) or nonfunctional tumours. Another typical feature of NET cells is the expression of several receptors in high quantities [3]. Although NET may virtually arise everywhere (NE cells are widely dispersed in the human body), the most common sites of NET onset are the bronchus/lungs and gastro-entero-pancreatic (GEP) tract. Less frequent localizations are the skin, the adrenal glands, the thyroid and the genital tract [4]. NET of the gastro-entero-pancreatic tract can be classified depending on their origin in NET of the foregut (pancreas, stomach, duodenum), midgut (ileum, appendix) or hindgut (colon, rectum). A TNM staging system has been proposed for the tumours of the foregut, midgut and hindgut [5,6] by the European Neuroendocrine

∗ Corresponding author at: Service of Nuclear Medicine, PET/CT Centre, Santa Maria della Misericordia Hospital, Rovigo, Italy. Tel.: +39 0425 39 4428: fax: +39 0425 39 4434. E-mail addresses: [email protected], [email protected] (D. Rubello). 0720-048X/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2010.07.022

Tumour Society (ENETS), taking into account the most recent WHO classifications and the need for a better prognostic assessment of NET. Histologic grading identifies three categories based on the Ki67 levels (G1: Ki67 < 2%, G2: Ki67 between 3 and 20%, G3: Ki67 > 20%) [5,6]. Although traditionally the TNM staging classification has not been applied to lung NET, the TNM has been demonstrated to be useful in these patients therefore the International Association for the Study of Lung Cancer (IASLC) recently recommended that the TNM be applied to pulmonary NET [7]. NET slow metabolic rate, small lesions size and variable anatomical localization have represented the major limits for lesions diagnosis. The diagnostic work up has relied on conventional morphological imaging procedures including computed tomography (CT), ultrasound (US) and magnetic resonance imaging (MRI) combined with gamma camera functional imaging, namely whole-body somatostatin receptor scintigraphy (SRS) [8,9]. However, although SRS showed a higher accuracy than CT [10] for NET diagnosis at both the primary and metastatic site, the development of novel PET tracers specific for NET has revolutioned the diagnostic approach. In the past decade, several beta emitting tracers have been developed for NET imaging, mainly as a consequence the marginal role of FDG for the assessment of these tumours [11]. In fact well differentiated NET are characterized by a low metabolic rate and therefore low glucose consumption, rendering FDG not suitable for the evaluation of well differentiated forms while its role may still be valuable in highly proliferating undifferentiated tumours or in cases of lesions presenting a low expression of somatostatin receptors (e.g. medullary thyroid carcinoma).

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68Ga-DOTA-peptides are a group of PET tracers that specifically bind to somatostatin receptors (sst) that are over-expressed on NET cells. Somatostatin receptors are G-protein-coupled receptors and are internalized after specific ligand-binding [12]. Six different sst have been identified (sst1, 2A, 2B, 3, 4, 5) in humans. 68Ga-DOTApeptides structure can be summarized in (1) the active part binding to sst (TOC, NOC, TATE), (2) the chelant (DOTA) and (3) the isotope (68Ga). The most relevant difference among these compounds relies in a variable affinity to sst receptors subtypes [13]: all can bind to sst2 and sst5, only DOTA-NOC presents a good affinity also for sst3. The observed differences in receptors binding affinity have not yet found a direct clinical correlate and at present there is no indication that such differences are associated with advantages in clinical employment. Antunes et al. also reported how the labelling with 68Ga also presents advantages over other employed isotopes [13]. The high accuracy of the results obtained using 68Ga-DOTApeptides in NET is represented by the rapidly growing number of papers published in the past few years. From a practical point of view, 68Ga-DOTA-peptides presents several advantages. First of all the labelling with 68Ga does not require an onsite cyclotron since 68Ga can be easily eluted from a commercially available Ge-68/Ga-68 generator. The long half-life of the mother radionuclide 68Ge (270.8 days) makes it possible to use the generator for approximately 9–12 months depending on requirement. 68Ga (t1/2 = 68 min) is a positron emitter with 89% positron emission and negligible gamma emission (1077 keV) of 3.2% only. For labelling, the 68Ga eluate is first concentrated and purified using a micro chromatography method [14]. Radiolabelling yields of >95% can usually be achieved within 15 min. Other advantages include the fact that 68Ga-DOTA-peptides are not dependent on cells metabolism (as compared for example to 18F-DOPA), have an easy and economic synthesis process and provide relevant information of sst expression, with direct therapeutic implications. Indications to perform 68Ga-DOTA-peptides studies in NET patients include: staging, re-staging after therapy, identification of the site of the unknown primary tumour in patients with proven NET secondary lesions and selection of cases eligible for therapy with either cold or hot (peptide receptor radionuclide therapy) somatostatin analogues. Recently, the assessment of SUVmax has been reported to present also prognostic implications [15]. At present the most commonly employed DOTA-peptides are 68GaDOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE.

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reported especially for small lesions, particularly at node and bone level [21], or in cases with an unusual anatomical localization [22]. 68Ga-DOTA-NOC PET/CT was also reported to be more helpful than CT and SRS for the detection of unknown primary tumour (CUP) in patients with confirmed NET secondary lesions [23]. This clinical application may be particularly relevant since the unknown primary in a patient with metastasis occurs even more often than for other carcinomas and its identification is associated with a better prognosis [24]. Although most studies reported the superiority of 68GaDOTANOC PET/CT to conventional imaging (CI) for the assessment of neuroendocrine tumours (NET), the detection of a higher number of lesions is not necessarily followed by a modification of disease stage or therapeutic approach. On the contrary the detection of unsuspected metastatic disease or local relapse (as compared to conventional imaging), the identification of the occult primary tumour or the confirmation or exclusion of SSR expression on tumour cells are all conditions that can modify the therapeutic approach. The impact on clinical management of DOTANOC PET/CT, on either modification of therapy or stage, was recently reported in a population of 90 subjects. 68Ga-DOTA-NOC PET/CT affected either stage or therapy in half the patients. The most frequent impact on management was regarding the therapeutic approach (initiation/continuance of ‘hot’ or ‘cold’ somatostatin analogues, 36 pts) followed by surgical indication/exclusion (referral to surgery, 6 pts; exclusion for surgical treatment, 6 pts). Less frequent impacts on management included the initiation of radiotherapy (1 patient), further diagnostic investigation (1 patient), and liver transplantation (1 patient) [25]. The observation that well differentiated lesions are associated with slower growth rate and with higher likely-wood of response to targeted therapy (either with hot or cold somatostatin analogues) and that 68Ga-DOTA-peptides uptake reflects sst expression on tumour cells, raises the issue of weather it is possible to define PET/CT parameters that can predict patients outcome. 68Ga-DOTANOC PET/CT was recently reported to be to provide prognostic data [15] in a population of 44 pts with NET: the SUVmax was significantly higher in cases with stable disease or partial response at followup. The best SUVmax cut-off to differentiate between patients with stable disease/partial response at follow-up from those with progressive disease was reported to range between 17.6 and 19.3. SUVmax values higher than 19.3 permitted the selection of patients with slower disease progression. 3. 68Ga-DOTA-TATE

1. 68Ga-DOTA-TOC 68Ga-DOTA-TOC was the first tracer to be employed in NET imaging and was reported to present a high tumour to non-tumour contrast and a higher sensitivity compared to SRS [16,17]. The study with the largest patients population (84 pts with NET), reported sensitivity (97%) for DOTA-TOC was superior to CT (61%) and SRS (52%) for the detection of NET lesions, especially in case of small tumours at nodal or bone level [18]. In particular, in a comparison study of 51 patients with well differentiated NET, PET with 68Ga-DOTA-TOC performed better than CT and SRS for the early detection of bone NET secondary lesions (sensitivity of 97%, specificity of 92%) [19]. 2. 68Ga-DOTA-NOC 68Ga-DOTA-NOC is also increasingly used in several centres: compared to DOTA-TOC, DOTA-NOC is able to bind with good affinity also to sst3 [13] and was reported to have a more favourable dosimetry [20]. The good sensitivity of 68Ga-DOTA-NOC was

68Ga-DOTA-TATE is characterized by a very high affinity for sst2 [13] with a considerably higher affinity than 111In-DTPAoctreotide [26]. In a recent paper, 51 patients (35 negative and 16 equivocal for uptake on SRS) were studied by 68Ga-DOTA-TATE PET. 68GaDOTA-TATE PET identified significantly more lesions than SRS and changed management in 36 patients (70.6%), who were subsequently deemed suitable for PRRT [27]. 4. Comparison studies A few studies in the literature compared the sensitivity of 68GaDOTA-peptides with metabolic tracers in NET patients, namely 18FFDG and 18F-DOPA. The only available study of direct comparison between 68GaDOTA-NOC and 18F-DOPA studied a limited patients population (13 pts): DOTA-NOC showed a higher number of lesions (71 vs. 45) and in more cases identified the site of the occult primary (6 vs. 2 of 8 non-operated cases) [28].

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68Ga-DOTA-TATE was also compared with 18F-DOPA [29] and showed similar results: in 25 patients with well differentiated NET studied with both tracers reported sensitivity for 68Ga-DOTA-TATE were higher (96% vs. 56%). Different pattern of tracer uptake (68Ga-DOTA-peptides vs. 18FFDG) has been described in the clinical practise within areas of the same tumour lesion or in different lesions within the same patient [30]. Therefore much interest is currently devoted to the use of both a receptor based tracer and a metabolic one in order to ascertain weather the tumour has some undifferentiated component (with high glucose metabolism) that may benefit from standard chemotherapy instead of targeted therapy only. 68Ga-DOTA-TATE was found to be superior to 18F-FDG for the assessment of well differentiated NET [31]. In particular there was a higher uptake of 68Ga-DOTA-TATE in low-grade versus highgrade NET. On the contrary there was significantly higher uptake of 18F-FDG in high-grade versus low-grade lesions. It is interesting to notice that in 3 patients the tumour exhibited variable affinity for 68Ga-DOTA-TATE and for FDG: the use of tracers with different mechanism of uptake may provide more accurate information on the tumour biology and therefore provide useful data that could have a relevant impact on the patients management. 68Ga-DOTA-TOC was also reported to provide more accurate information in well differentiated NET as compared to FDG, detecting a higher number of positive lesions [32]. 5. PET/CT imaging protocol using 68GA-DOTA-peptides PET/CT acquisition starts at 60 min after intravenous injection of approximately 100 MBq (75–250 MBq) of the radiolabeled peptide (such as 68Ga-DOTA-NOC, 68Ga-DOTA-TOC, etc.). The amount of injected radioactivity strictly depends on the daily production of the generator for each single elution (usually ranging between 300 and 700 MBq) and, of course, by the number of patients scanned per day. Since sst are widely dispersed within the human body, different organs may be imaged by tracers binding to somatostatin receptors including the liver, spleen, pituitary, thyroid, kidneys, adrenal glands, salivary glands, stomach wall, bowel. The pancreas shows variable uptake of 68 Ga-DOTA-peptides. Though all 5 subtypes of sst are present in the pancreas, they are preferably found in the islets (located in the endocrine pancreas). However, interestingly a focal uptake in esocrine pancreas (head) may be detected on 68Ga-DOTA-peptides images and may represent a potential pitfall in image interpretation since it is not necessarily associated with the presence of active disease. Its clinical significance and the mechanism of uptake in the pancreatic head is still debated. Regarding potential pitfalls in image interpretation it is important to notice that the presence of inflammation may be a cause of false positive results, due to the expression of somatostatin receptors on activated lymphocites. Other reasons for falsely positive PET include the presence of accessory spleen or physiologic activity at adrenal level. 6. Conclusions The recent introduction of 68Ga-DOTA-peptides completely revolutioned the diagnostic approach to NET imaging with a direct impact on clinical management. All described compounds (68Ga-DOTA-TOC, -NOC, -TATE) have been reported to be accurate for the localization of well differentiated NET lesions, performing better than CT and SRS. PET assessment of NET with 68Ga-DOTA-peptides not only provides an accurate detection of even small-sized lesions, but

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