Comparison of Different Positron Emission Tomography Tracers in ...

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Several morphological and functional imaging techniques are usually used to detect residual/recurrent medullary thyroid carcinoma (MTC) with variable results ...
Comparison of Different Positron Emission Tomography Tracers in Patients with Recurrent Medullary Thyroid Carcinoma: Our Experience and a Review of the Literature Giorgio Treglia, Paola Castaldi, Maria Felicia Villani, Germano Perotti, Angelina Filice, Valentina Ambrosini, Nadia Cremonini, Annibale Versari, Stefano Fanti, Alessandro Giordano and Vittoria Rufini Abstract

Several morphological and functional imaging techniques are usually used to detect residual/recurrent medullary thyroid carcinoma (MTC) with variable results; currently, there is growing interest in positron emission tomography (PET) methodology. Herein, we report our experience of and a literature review about the comparison of different positron emission tomography (PET) tracers in patients with residual/recurrent MTC. 18F-DOPA PET/CT seems to be the most useful imaging method to detect recurrent MTC lesions, performing better than 18F-FDG and 68Ga-somatostatin analogs PET/CT. 18F-FDG may complement 18F-DOPA in patients with aggressive tumors. 68Ga-somatostatin analogs PET/CT may be useful to select patients who could benefit from radioreceptor therapy. The information provided by the various PET tracers reflects different metabolic pathways, and may help to select the most appropriate treatment.

G. Treglia (&)  P. Castaldi  M. F. Villani  G. Perotti  A. Giordano  V. Rufini Institute of Nuclear Medicine, Catholic University of the Sacred Heart, Largo Gemelli 8, 00168 Rome, Italy e-mail: [email protected] A. Filice  A. Versari Nuclear Medicine Unit, Santa Maria Nuova Hospital, Reggio Emilia, Italy V. Ambrosini  S. Fanti Nuclear Medicine Unit, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy N. Cremonini Unit of Endocrinology, Ospedale Maggiore, Bologna, Italy

R. P. Baum and F. Rösch (eds.), Theranostics, Gallium-68, and Other Radionuclides, Recent Results in Cancer Research 194, DOI: 10.1007/978-3-642-27994-2_21, Ó Springer-Verlag Berlin Heidelberg 2013

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Keywords



Positron emission tomography Medullary thyroid carcinoma Diagnosis Neuroendocrine tumors





PET/CT



Contents 1 Introduction.......................................................................................................................... 386 2 Our Experience.................................................................................................................... 387 2.1 Patients........................................................................................................................ 387 2.2 PET/CT Protocol and Data Analysis......................................................................... 387 2.3 Statistical Analysis ..................................................................................................... 388 2.4 Results......................................................................................................................... 388 3 Literature Review ................................................................................................................ 389 4 Discussion ............................................................................................................................ 389 5 Conclusion ........................................................................................................................... 391 References.................................................................................................................................. 392

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Introduction

Medullary thyroid carcinoma (MTC) derives from neuroendocrine parafollicular C thyroid cells, accounting for only 5–8% of all thyroid malignancies. It mostly occurs sporadically (70–80% of cases), but familial forms (occurring alone or as part of MEN 2A and MEN 2B syndromes) have also been described (20–30% of cases) (Pacini et al. 2010). First-line treatment is radical thyroidectomy with associated cervical lymphadenectomy. Surgery is curative in the vast majority of patients with MTC; however, disease can persist or recur, and early detection of malignant lesions is a crucial step in the therapeutic management of these patients. Tumor recurrence after surgery, either locally or with metastatic spread (typically to lungs, liver, bone), is associated with rising levels of blood calcitonin and/or CEA (Kebebew et al. 2000; Pellegriti et al. 2003). Several morphological and functional imaging techniques have been used to detect recurrent MTC with variable results (Rufini et al. 2006; Rufini et al. 2008a, b). Among nuclear medicine techniques, currently there is growing interest in positron emission tomography (PET) methodology, which offers higher image quality and higher spatial resolution, and in PET tracers such as 18F-fluorodeoxyglucose (18F-FDG), which is the most used PET tracer in oncology and reflects tumor glucose metabolism and proliferative activity; 18F-fluorodihydroxyphenylalanine (18F-DOPA), which reflects a typical metabolic pathway (amine decarboxylation) of neuroendocrine tumors; and 68Ga-somatostatin analogs, which reflect the expression of somatostatin receptors (Rufini et al. 2008a, b; Ambrosini et al. 2010).

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We report our experience of the comparison of different PET tracers in patients with residual/recurrent MTC suspected on the basis of increased serum calcitonin levels. We also report the results of other authors who performed PET/CT with different tracers in patients with residual/recurrent MTC.

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Our Experience

2.1

Patients

Inclusion criteria for our study were: early surgery for MTC, availability of serum calcitonin and carcinoembryonic antigen (CEA) levels, increased serum calcitonin levels, availability of conventional imaging studies and functional imaging modalities (18F-DOPA PET/CT, 18F-FDG PET/CT, and 68Ga-somatostatin analogs PET/CT performed within a 6-month interval), and availability of a cytohistological diagnosis or clinical information on follow-up (at least 12 months). Eighteen patients (6 men, 12 women, mean age 53 years, range 24–86 years) with residual/recurrent MTC were included. All patients had undergone total thyroidectomy with prophylactic central compartment neck dissection 12–192 months (median 90 months) before imaging; in 11 cases also lateral compartment neck dissection had been performed. In 5 cases (28%) the reason for the imaging study was to functionally assess known lesions detected at conventional imaging; in 13 cases (72%) the reason was to detect and localize recurrent disease suggested by biochemical data. In all cases neck ultrasonography (US) was performed. Additional imaging studies were available: whole-body contrast-enhanced CT in 16 cases, magnetic resonance imaging (MRI) of the abdomen in 2 cases, and bone scintigraphy in 2 cases. The use of 68Ga-somatostatin analogs was approved by the local medical ethics committees. All patients gave written informed consent for the three PET/CT studies and for treatment of personal data.

2.2

PET/CT Protocol and Data Analysis

PET/CT studies were performed in three Italian centers: the PET/CT center of the Policlinico A. Gemelli, Università Cattolica del Sacro Cuore in Rome (center A), the PET/CT center of the Sant’Orsola-Malpighi Hospital in Bologna (center B), and the PET/CT center of Santa Maria Nuova Hospital in Reggio Emilia (center C). All 18F-DOPA and 18F-FDG PET/CT studies were performed in center A according to a previously described protocol (Rufini et al. 2011; Treglia et al. 2011). 68 Ga-somatostatin analogs PET/CT studies were performed in the three centers according to a previously described protocol (Castellucci et al. 2011; Versari et al. 2010). Any focal accumulation of each tracer outside the normal distribution or higher than the surrounding physiological uptake was considered an abnormal finding.

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Studies were classified as positive if at least one abnormal focus was found. Since increased calcitonin levels are related to residual and/or recurrent disease, any negative PET/CT result was interpreted as a false negative. The number and site of abnormal foci detected by all methods were also recorded. Comparison of the results of the three functional imaging modalities was made on a per-patient basis and on a per-lesion basis. At the end of the observational study, cytohistology was available in 8 of the 18 cases (44%). When a cytological or histological examination was not available, a combination of all morphologic and functional imaging modalities and clinical information at follow-up (at least 12 months) was used as a reference standard for the presence of tumoral lesions.

2.3

Statistical Analysis

For statistical analysis we used the Kruskal–Wallis test to compare the results of PET/CT methods. p-Value \0.05 was considered statistically significant. The statistical tests were performed using StatistixÒ software for Windows.

2.4

Results

2.4.1 Laboratory and Radiological Findings Calcitonin levels were increased in all patients with a mean value of 2,580 pg/mL (range 66.7–14,186 pg/mL). CEA levels were increased in 14/18 patients (78%) with a mean value of 67.6 ng/mL (range 0.5–322 ng/mL). According to cytohistology and the combination of all imaging studies and clinical information at follow-up, locoregional disease was detected in 8 of 18 patients (44%), locoregional disease and distant metastases in 3 patients (17%), and distant disease alone in 2 (11%). In five patients (28%) the disease site was undetected at all imaging studies. 2.4.2 PET/CT Findings: Patient-Based Analysis At least one focus of abnormal uptake was observed in 13/18 patients at 18F-DOPA PET/CT [72.2% sensitivity, 95% confidence interval (CI) 48.8–87.8%], in 3/18 at 18F-FDG PET/CT (16.7% sensitivity, CI 5.0–40.0%), and in 6/18 at 68 Ga-somatostatin analogs PET/CT (33.3% sensitivity, CI 16.1–56.4%) (p = 0.001). Seven patients were positive at 18F-DOPA PET/CT alone. No patient was positive at 68Ga-somatostatin analogs or 18F-FDG PET/CT alone. In 5 of 18 patients (28%) there were known lesions at conventional imaging; 18F-DOPA PET/CT was positive in all five and showed new sites of involvement in three cases; both 18F-FDG PET/CT and 68Ga-somatostatin analogs PET/CT were positive in three cases and showed new sites of involvement in two of them. In 13 of 18 patients (72%) conventional imaging was negative or inconclusive: 18 F-DOPA PET/CT was positive in 8, 68Ga-somatostatin analogs PET/CT in 3,

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whereas 18F-FDG PET/CT was negative in all 13 patients. In five patients the three PET/CT studies gave negative results. The statistical analysis showed a significant difference between 18F-DOPA PET/CT and 18F-FDG PET/CT results (p = 0.005) and between 18F-DOPA PET/CT and 68Ga-somatostatin analogs PET/CT results (p = 0.02). No significant differences between 68Ga-somatostatin analogs PET/CT and 18F-FDG PET/CT were found.

2.4.3 PET/CT Findings: Lesion-Based Analysis Overall, 72 lesions were identified with the three PET/CT studies. 18F-DOPA PET/CT detected 85% of lesions (61/72), 68Ga-somatostatin analogs PET/CT 20% of lesions (14/72), and 18F-FDG PET/CT 28% of lesions (20/72) (p = 0.002). In 10 cases 18 F-DOPA PET/CT identified more lesions than 68Ga-somatostatin analogs and 18 F-FDG PET/CT, whereas in 1 case 18F-FDG PET/CT revealed multiple liver lesions missed by the other two methods, as well as two additional locoregional lymph nodes. No additional lesions were identified by 68Ga-somatostatin analogs PET/CT. According to the site of involvement, there were 12 bone lesions, 32 liver lesions, 26 locoregional lymph nodes, and 1 local recurrence. The statistical analysis showed a significant difference between the number of lymph nodes detected by 18F-DOPA PET/CT and 18F-FDG PET/CT (p = 0.02) and between 18F-DOPA PET/CT and 68 Ga-somatostatin analogs PET/CT (p = 0.009), while there was no difference between 68Ga-somatostatin analogs PET/CT and 18F-FDG PET/CT results (p: ns). Even though 18F-DOPA PET/CT detected more liver and bone lesions than the other two PET/CT studies, the difference was not statistically significant.

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Literature Review

A search for articles comparing PET or PET/CT findings with different tracers in patients with residual/recurrent MTC was also performed; Pubmed and Embase databases were investigated, and the literature search was updated until August 2011. Some articles compared 18F-DOPA with 18F-FDG PET or PET/CT (Hoegerle et al. 2001; Beuthien-Baumann et al. 2007; Koopmans et al. 2008; Beheshti et al. 2009; Marzola et al. 2010) and 68Ga-somatostatin analogs with 18 F-FDG PET/CT (Conry et al. 2010; Pałyga et al. 2010) in patients with residual/ recurrent MTC. Nevertheless, comparison between 18F-DOPA and 68Ga-somatostatin analogs PET/CT in patients with residual/recurrent MTC was lacking. Only one article compared 11C-methionine and 18F-FDG (Jang et al. 2010).

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Discussion

In our experience, we compared 18F-DOPA, 18F-FDG, and 68Ga-somatostatin analogs PET/CT findings in a group of patients with residual/recurrent MTC on the basis of increased serum calcitonin levels. Both patients with known lesions and

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patients with negative or inconclusive conventional imaging results were included, the latter representing the greatest number. Early detection of residual/recurrent MTC is a crucial step in the selection of patients who may benefit from curative surgery. Our study confirmed that 18F-DOPA PET/CT is a valuable tool in the evaluation of patients with residual/recurrent MTC, providing better results than the other functional imaging methods, on both a per-patient and a per-lesion basis. The different behavior of 18F-DOPA, 18F-FDG, and 68Ga-somatostatin analogs can be explained by their different uptake mechanisms that reflect the different metabolic pathways of neuroendocrine cells, including MTC cells. L-DOPA is an amino acid that enters the cell by the larger amino acid transporter (LAT) and is converted to dopamine by aromatic amino-acid decarboxylase; labeled with 18 F, L-DOPA is retained in the cells owing to intracellular decarboxylation, which is a feature of the neuroendocrine origin of MTC. So, it is assumed that higher 18 F-DOPA uptake is related to a higher degree of cell differentiation, and this might explain the high sensitivity of 18F-DOPA PET/CT in the detection of small lymph node lesions, so-called minimal or occult disease (Hoegerle et al. 2001; Beuthien-Baumann et al. 2007; Koopmans et al. 2008; Beheshti et al. 2009; Marzola et al. 2010). 18 F-FDG, the glucose analog most used in oncology, accumulates in neoplastic cells, allowing scintigraphic visualization of those tumors that use glucose as an energy source according to their proliferative activity. Neuroendocrine tumors usually show an indolent course, and consequently low 18F-FDG uptake. These tumors, however, when undergoing dedifferentiation, become more aggressive and may show increased 18F-FDG uptake (Adams et al. 1998). Due to their neuroendocrine origin, MTC cells express somatostatin receptors on their surface; however, immunohistochemical studies have produced generally low estimates for somatostatin receptor density in MTC cells (Reubi et al. 1991; Papotti et al. 2001). In vivo detection of expression of somatostatin receptors has been the molecular basis for tumor imaging with radiolabeled somatostatin analogs in PET imaging (Conry et al. 2010; Pałyga et al. 2010). Previous studies comparing 18F-DOPA and 18F-FDG in the assessment of residual/recurrent MTC patients showed either better results of 18F-DOPA (Beheshti et al. 2009; Koopmans et al. 2008) or a complementary role of the two tracers (Marzola et al. 2010; Beuthien-Baumann et al. 2007). First of all, in 2001, Hoegerle et al. reported 11 MTC patients who underwent both PET modalities, reporting a per-lesion sensitivity of 63% for 18F-DOPA PET versus 44% for 18 F-FDG PET (Hoegerle et al. 2001). Our findings are in line with those reported by Hoegerle et al. who obtained the best results with 18F-DOPA PET for detection of lymph node involvement and locoregional relapse. Beheshti et al. found superiority of 18F-DOPA PET/CT with respect to the other imaging modalities in 26 patients with residual/recurrent MTC, and proposed this technique as a one-stop procedure to provide both functional and morphological information in order to select those patients who may benefit from reoperation with curative intent. These authors reported per-patient sensitivity of 81% for 18F-DOPA PET/CT versus 58% for 18F-FDG PET/CT, and per-lesion sensitivity of 94% for 18F-DOPA PET/CT

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versus 62% for 18F-FDG PET/CT (Beheshti et al. 2009). Koopmans et al. in their study reported per-patient sensitivity of 62% for 18F-DOPA PET versus 23% for 18 F-FDG PET, and per-lesion sensitivity of 71% for 18F-DOPA PET versus 30% for 18F-FDG PET (Koopmans et al. 2008). In 18 patients with aggressive MTC and rapidly increasing calcitonin levels, Marzola et al. found slightly higher sensitivity of 18F-DOPA than 18F-FDG PET/CT on per-patient analysis (83 versus 61% respectively); nevertheless, in some cases the 18F-FDG scan was superior to the 18F-DOPA PET/CT results, thus suggesting a complementary role of the two modalities, in order to gain the maximum benefit from their combined sensitivity (Marzola et al. 2010). The complementary role of these two PET modalities in patients with recurrent MTC has been also suggested by Beuthien-Baumann et al. who reported the same per-patient sensitivity with both methods (47%), which, however, detected different metastatic lesions (Beuthien-Baumann et al. 2007). The experience with 68Ga-somatostatin analogs in MTC is very limited (Conry et al. 2010; Pałyga et al. 2010). In particular, Conry et al. compared 68 Ga-DOTATATE PET/CT versus 18F-FDG PET/CT in 18 MTC patients; these authors found similar per-patient sensitivity of these methods (78 and 72% respectively); nevertheless, 18F-FDG PET/CT showed more lesions than 68 Ga-somatostatin analogs PET/CT, mainly in the liver (Conry et al. 2010). In a similar way, in our series 68Ga-somatostatin analogs PET/CT missed all liver lesions detected by 18F-FDG PET/CT and 18F-DOPA PET/CT, a finding that may be explained by the low lesion-to-background ratio due to the low expression of the somatostatin receptors and the physiological uptake of the tracer in the liver. Up to now, there are no published data comparing 18F-DOPA and 68 Ga-somatostatin analogs in patients with residual/recurrent MTC. In our study, PET/CT with 68Ga-somatostatin analogs showed lower sensitivity than 18F-DOPA PET/CT (33.3 versus 72.2% respectively), providing no additional information on any patient, except for the feasibility of 90Y/177Lu-radioreceptor therapy to treat metastatic lesions showing high uptake (Bodei et al. 2004). Preliminary data about 11C-methionine PET/CT in residual/recurrent MTC showed that, despite its similar sensitivity to 18F-FDG PET/CT for detecting residual or metastatic MTC lesions, 11C-methionine PET/CT provided minimal additional information compared with combined 18F-FDG PET/CT and neck US (Jang et al. 2010).

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Conclusion

F-DOPA PET/CT, whose distinctive characteristic is the specific uptake mechanism reflecting the metabolic pathways of neuroendocrine cells, seems to be the most useful imaging method to detect persistent or recurrent lesions in patients with MTC. 18F-FDG positivity is a sign of aggressive tumor behavior and may complement 18F-DOPA PET/CT. 68Ga-somatostatin analogs PET/CT does not provide any additional information except for the feasibility of radioreceptor

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therapy to treat metastatic lesions showing high uptake. In any case, the different uptake patterns observed with the various PET tracers reflect different metabolic pathways such as the uptake of hormone precursors, glucose metabolism, and receptor expression; this information may help to broaden the knowledge of MTC and potentially to select the most appropriate treatment. Acknowledgments This manuscript was awarded as ‘‘Best Oral Presentation’’ at the 1st World Congress on Gallium-68 and Peptide Receptor Radionuclide Therapy, Bad Berka (Germany), June 23–26, 2011

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