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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1489-1495 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.1126 Improved Staging of Patients With Carcinoid and Islet Cell Tumors With 18F-Dihydroxy-Phenyl-Alanine and 11C-5-Hydroxy-Tryptophan Positron Emission Tomography
From the Departments of Nuclear Medicine and Molecular Imaging, Medical Oncology, Pathology and Laboratory Medicine, and Endocrinology, University Medical Center Groningen, University of Groningen; Department of Radiology, Martini Hospital Groningen, the Netherlands Corresponding author: Elisabeth G.E. de Vries, MD, PhD, Department of Medical Oncology, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, the Netherlands, e-mail: e.g.e.de.vries{at}int.umcg.nl
Purpose To evaluate and compare diagnostic sensitivity of positron emission tomography (PET) scanning in carcinoid and islet cell tumor patients with a serotonin and a catecholamine precursor as tracers. Patients and Methods Carcinoid (n = 24) or pancreatic islet cell tumor (n = 23) patients with at least one lesion on conventional imaging including somatostatin receptor scintigraphy (SRS) and computed tomography (CT) scan underwent 11C-5-hydroxytryptophan (11C-5-HTP) PET and 6-[F-18]fluoro-L-dihydroxy-phenylalanin (18F-DOPA) PET. PET findings were compared with a composite reference standard derived from all available imaging along with clinical and cytologic/histologic information. Results In carcinoid tumor patients, per-patient analysis showed sensitivities for 11C-5-HTP PET, 18F-DOPA PET, SRS, and CT of 100%, 96%, 86%, 96%, respectively, and in islet cell tumors of 100%, 89%, 78%, 87%, respectively. In carcinoid patients, per-lesion analysis revealed sensitivities for 11C-5-HTP PET, 11C-5-HTP PET/CT, 18F-DOPA PET, 18F-DOPA PET/CT, SRS, SRS/CT, and CT alone of, respectively, 78%, 89%, 87%, 98%, 49%, 73%, and 63% and in islet cell tumors of 67%, 96%, 41%, 80%, 46%, 77%, and 68%, respectively. In all carcinoid patients 18F-DOPA PET and 11C-5-HTP PET detected more lesions than SRS (P < .001). 11C-5-HTP PET was superior to 18F-DOPA PET in islet cell tumors (P < .0001). In all cases, CT improved the sensitivity of the nuclear scans. Conclusion 18F-DOPA PET/CT is the optimal imaging modality for staging in carcinoid patients and 11C-5-HTP PET/CT in islet cell tumor patients.
Carcinoid tumors and pancreatic islet cell tumors are relatively indolent tumors. They belong to the group of neuroendocrine tumors that arise from neuroendocrine cells. These tumors can produce and secrete a large variety of products because of their intrinsic ability to take up, accumulate, and decarboxylate amine precursors.1 Treatment options for these tumors include curative or debulking surgery, systemic treatment with somatostatin analogs, interferon, and chemotherapy.2 To assess individual treatment options, accurate knowledge of tumor localization, biochemical activity, and rate of progression is essential. The initial work-up for patients with carcinoid and islet cell tumors consists of morphologic imaging methods such as computed tomography (CT), combined with functional whole-body imaging using somatostatin receptor scintigraphy (SRS).3,4 However, on CT scan and magnetic resonance imaging (MRI) of the abdomen, it can be difficult to correctly distinguish tumors and mesenterial metastases from intestinal structures. In addition, CT and MRI lesions cannot always be perfectly characterized as being malignant, especially in the pancreas, because frequently benign lesions or cysts may have rather similar or a mixed appearance.5-7 Apart from the advantage of covering the whole body in a single investigation, functional imaging methods also allow characterization of lesions on CT or MRI. SRS is often used for this purpose. However, it may produce false-negative findings as a result of variable affinity and expression levels of somatostatin receptors or small size of lesions because of the limited resolution of the gammacamera and single photon-emission tomography (SPECT) methods.8,9 Recently, two positron emission tomography (PET) tracers have emerged as potential functional imaging modalities in neuroendocrine tumors. In combination with the high resolution of PET, this may lead to a clinically relevant improvement in detection, characterization and staging of these tumors. The first new tracer method employs the catecholamine precursor 18F-dihydroxy-phenyl-alanine (18F-DOPA),5,6,10 whose uptake is based on the property of neuroendocrine tumors to take up amine precursors.1,11 For the detection of carcinoid disease, its superiority over presently used modalities has been shown, but this advantage is less clear for islet cell tumors.5,6 The second metabolic PET tracer, 11C-5-hydroxytryptophan (11C-5-HTP), is a direct precursor for the serotonin pathway and therefore a potentially sensitive universal method for neuroendocrine tumor detection. However, availability and experience with 11C-5-HTP is limited because of its complex production.12-14 Currently, there are no head-to-head studies available in which 18F-DOPA is compared with 11C-5-HTP PET in ability to detect neuroendocrine tumors. Therefore, the aim of this study was to evaluate the diagnostic sensitivity of 11C-5-HTP in comparison with 18F-DOPA PET in a large population of patients with a carcinoid or islet cell tumor.
Patients Patients eligible for this prospective single-center diagnostic accuracy study were new patients referred to our center with a carcinoid or pancreatic islet cell tumor, on the basis of clinical, histologic, and/or biochemical findings and at least one abnormal lesion detected on CT, MRI, sonography, or SRS; and patients known to have a histopathologically proven neuroendocrine tumor who had a clinical indication for (re)staging and who had at least one abnormal lesion on conventional imaging studies. We excluded patients younger than 18 years, pregnant patients, and those with an additional non-neuroendocrine tumor. Each consecutive patient underwent 11C-5-HTP PET, 18F-DOPA PET, SRS, and CT of the abdomen and also the chest, when indicated, within a short interval, and in random order. Biochemical analysis for relevant tumor markers in blood and urine was performed. All patients were allowed to continue their medication. The local medical ethics committee approved the study, and all patients gave written informed consent.
Procedures 18F-DOPA was produced as described earlier.17 Patients fasted for 6 hours before the examination. Whole-body 2D PET images were acquired as described for 11C-5-HTP PET 60 minutes after the IV administration of 18F-DOPA (180 [SD, 50] MBq, with a mean radiation dose of 4 mSv18). Two nuclear medicine physicians (K.P.K., P.L.J.) blinded for the results of other imaging examinations and clinical information interpreted the sets of 11C-HTP and 18F-DOPA PET images independently. Discrepant cases were reviewed in a multidisciplinary team and a consensus was reached. Only lesions with an unequivocal visibility clearly greater than normal activity in that body region were considered abnormal. SRS. According to Dutch standards, 24 hours after IV administration of 200 MBq 111In-octreotide (Octreoscan; Mallinckrodt, Petten, the Netherlands; estimated mean radiation dose of 10 mSv19), planar total-body and SPECT images were obtained using standard methods (Siemens Multispect 2 gammacamera, medium energy collimator, 10-minute spotviews, 64 projections of 30 seconds). If interfering bowel activity was observed, 48-hour images were recorded.20 SRS scans were interpreted by dedicated specialists as part of routine patient care, and subsequently independently reread by a nuclear medicine physician (P.L.J.) blinded for the results of other imaging examinations and clinical information. CT. CT (four to 16 slices; Siemens Somatom Sensation, Siemens Medical Systems, Erlangen, Germany; estimated mean radiation dose of 8 to 20 mSv21) was performed using oral contrast and IV contrast (Visipaque 270 [Amersham Biosciences, Piscataway, NJ], 120 mL, 2.5 mL/sec) enhancement. The reconstruction interval was 0.75 to 5 mm. All patients underwent an abdominal CT, and 42 patients also a chest CT. CT scans were interpreted as part of routine patient care and were reread by an experienced radiologist (K.V.) blinded for the clinical information. In discrepant cases, consensus was reached after multidisciplinary discussion.
Composite Reference Standard
Biochemical Analysis
Data and Statistical Analysis PET and SRS are whole-body modalities, whereas CT covers only the most relevant parts of the body. To eliminate bias towards total-body imaging methods, only body areas for which all four imaging modalities were available have been evaluated. Sensitivities were calculated using the composite reference standard, and were compared using paired observations and McNemar's test. Patient-based sensitivity was calculated as number of patients with a positive test (at least one lesion detected) by total number of patients. Per lesion sensitivity of a modality was calculated by dividing the number of positive lesions detected with that modality by the total number of positive lesions. Significance level was 0.05, two-sided. The statistical tests were carried out using the SPSS package version 12.0 (SPSS Inc, Chicago, IL).
Patients Between February 2005 and February 2007, 50 consecutive patients were recruited, of whom three patients declined one or more of the imaging procedures, leaving full data of 24 patients with a carcinoid tumor and 23 patients with an islet cell tumor for analysis, as presented in the flow diagram (Fig 1). Patient characteristics are presented in Table 1. All carcinoid patients and 39% of islet cell tumor patients had biochemical proof of increased serotonin metabolism. CT, SRS, 11C-5-HTP PET, 18F-DOPA PET were carried out within a median of 55 days. In 29 patients, both PET scans were performed on the same day. The mean interval between both PET scans was 18 days. Newly detected lesions were confirmed with MRI (n = 2), bone scintigraphy (n = 2), planar x-ray (n = 3), and sonography (n = 3), surgery (n = 3), or biopsy (n = 1). Results in a representative patient are shown in Figure 2.
Patient-Based Analysis On the basis of our selection criteria, all patients were considered positive for tumor. In a per-patient analysis in carcinoid tumor patients, 11C-5-HTP PET detected one or more tumor lesions in all 24 patients (sensitivity, 100%; Table 2), whereas 18F-DOPA PET and CT detected one or more tumor lesions in 23 of 24 patients (sensitivity, 96%) and SRS detected one or more tumor lesions in 18 of 21 patients (sensitivity, 86%).
In a per-patient analysis in patients with islet cell tumors, 11C-5-HTP detected one or more tumor lesions in 23 of a total of 23 patients (sensitivity, 100%) CT detected one or more tumor lesions in 20 of 23 patients (sensitivity, 87%), SRS in 14 of 19 patients (sensitivity, 78%) and 18F-DOPA PET in 16 of 23 patients (sensitivity, 89%). However, there were no statistically significant differences.
Lesion-Based Analysis
In patients with islet cell tumors, a total of 294 tumor lesions were detected. Most lesions (71%) were found in the liver and abdomen. In these patients, 11C-5-HTP PET and CT performed equally well, and were both better than the other imaging modalities, although not statistically significant. Both SRS and 18F-DOPA PET had a relatively poor performance for islet cell tumor detection. Again, combining SRS and PET with CT led to an increased number of detected islet cell tumor lesions and therefore increased sensitivity (Table 3). The combination of 11C-5-HTP PET with CT had the highest sensitivity. When SRS was left out of comparisons, only 8% of all lesions were missed. These PET-negative lesions were found in two patients. There was no statistical relationship between elevation of biochemical parameters and imaging results of 18F-DOPA PET, 11C-5-HTP PET, SRS, or CT.
This study demonstrates that both 11C-5-HTP PET and 18F-DOPA PET have excellent sensitivity to detect carcinoid and islet cell tumors lesions. 11C-5-HTP PET was the only imaging method able to detect tumor lesions in all carcinoid and islet cell tumor patients. In carcinoid patients, 18F-DOPA PET was the best modality because it detected more lesions compared with all other modalities including 11C-5-HTP PET, CT, and SRS. In islet cells tumors 11C-5-HTP PET detected more tumor-positive patients and lesions than 18F-DOPA PET and SRS (Fig 3). Adding CT to both PET techniques resulted in a slight further improvement in sensitivity (Table 3). Therefore, 18F-DOPA PET/CT is considered the optimal technique for staging of patients with carcinoid tumors, and 11C-5-HTP PET/CT for islet cell tumor patients. In patients with carcinoid tumors, SRS scanning can be omitted without missing any lesions.
For islet cell tumors, SRS usefulness is less clear cut. 11C-5-HTP PET combined with CT gives the best tumor detection for most patients. However, in a minority, namely 8% of patients, SRS performs equal or better then metabolic PET imaging methods. Therefore, in patients with islet cell tumors, SRS remains of additional value. Overactivity of the serotonin, and most likely also the catecholamine pathways, appears to be the key factor that determines the intracellular tracer concentration. Increased activity of transmembrane amino acid transporters results in high entry of both tracers in cells. In the tumoral cytoplasm, 11C-5-HTP and 18F-DOPA PET are metabolized via the abundantly present enzyme aromatic amino acid decarboxylase to hormonal products that can be stored in pathway-specific secretory vesicles. In contrast to islet cell tumors, in most patients with carcinoid tumors, the serotonin pathway is highly active. In these cells, the storage capability for the 11C-5-HTP metabolites is relatively saturated by endogenous serotonin. The 11C-5-HTP metabolites are therefore rapidly degraded via monoamino-oxidase activity and subsequently excreted from the cell. This may explain the superior diagnostic performance for 18F-DOPA PET in carcinoid and 11C-5-HTP in islet cell tumors.27 The intracellular tracer concentration is directly related to the probability of visualization using the PET scanner. These high tracer concentrations allow the detection of smaller lesions, up to 5 mm in diameter. In both patient groups, CT detected additional lesions and was therefore complementary to the PET techniques. The combination of 11C-5-HTP PET with CT proved to be the best method to detect islet cell tumor lesions, whereas the combination of 18F-DOPA PET with CT detected most tumor lesions in patients with carcinoid disease. Both PET combinations performed better then the combination of SRS with CT in both tumor types. Although difficult to quantify, another advantage of combining CT with 11C-5-HTP or 18F-DOPA PET is the ability to characterize neuroendocrine origin of lesions of lesions found on CT. Both PET methods allow better staging and estimation of the total body tumor load. The addition of 11C-5-HTP PET to CT in islet cell tumor patients clearly helps to provide a better understanding of the number of lesions and their distribution, which will support treatment decisions. In addition, better estimation of the total body tumor load and the detection of metastases in unknown regions may refine clinical management. Finally, the recent development of combined PET-CT scanning gives superior diagnostic information in a single session, largely obviates the need for SRS, and reduces the burden of multiple diagnostic tests. All other published data regarding 11C-5-HTP are from Mohnike et al.28 They studied 42 patients with a mixture of neuroendocrine and nonendocrine tumor patients, and concluded that 11C-5-HTP PET was superior to SRS and CT for neuroendocrine tumor lesions and could be regarded as a universal imaging agent for these tumors.13 No head-to-head comparison of 18F-DOPA and 11C-5-HTP versus CT and SRS was performed. Recent data also point to the utility of 18F-DOPA PET in assessing pancreatic lesions in infants and adults with hyperinsulinism.28 In our study in both patient groups 11C-5-HTP PET was far superior to SRS, and in islet cell tumor patients, 11C-5-HTP PET performed even better than 18F-DOPA PET. Therefore, 11C-5-HTP PET could indeed be seen as a universal imaging agent for carcinoid and islet cell tumors. However, the synthesis of 11C-5-HTP PET is complex. For efficient use of available resources and time, it seems logical to use 18F-DOPA PET for all patients with non–islet cell tumors and 11C-5-HTP PET only for those with a proven or a suspected islet cell tumor. Because PET is now generally performed in combination with CT, this further improves the lesion detection and characterization properties of both PET scans explored herein and provides anatomic information all in a single and rapid session.
The author(s) indicated no potential conflicts of interest.
Conception and design: Klaas P. Koopmans, Oliver C. Neels, Ido P. Kema, Philip H. Elsinga, Willem J. Sluiter, Pieter L. Jager, Elisabeth G.E. de Vries Financial support: Ido P. Kema, Philip H. Elsinga, Pieter L. Jager, Elisabeth G.E. de Vries Administrative support: Klaas P. Koopmans, Philip H. Elsinga, Adrienne H. Brouwers, Pieter L. Jager, Elisabeth G.E. de Vries Provision of study materials or patients: Klaas P. Koopmans, Oliver C. Neels, Ido P. Kema, Koen Vanghillewe, Pieter L. Jager, Elisabeth G.E. de Vries Collection and assembly of data: Klaas P. Koopmans, Willem J. Sluiter, Koen Vanghillewe, Adrienne H. Brouwers, Pieter L. Jager, Elisabeth G.E. de Vries Data analysis and interpretation: Klaas P. Koopmans, Oliver C. Neels, Ido P. Kema, Philip H. Elsinga, Willem J. Sluiter, Koen Vanghillewe, Adrienne H. Brouwers, Pieter L. Jager, Elisabeth G.E. de Vries Manuscript writing: Klaas P. Koopmans, Oliver C. Neels, Ido P. Kema, Philip H. Elsinga, Adrienne H. Brouwers, Pieter L. Jager, Elisabeth G.E. de Vries Final approval of manuscript: Klaas P. Koopmans, Oliver C. Neels, Ido P. Kema, Philip H. Elsinga, Willem J. Sluiter, Koen Vanghillewe, Adrienne H. Brouwers, Pieter L. Jager, Elisabeth G.E. de Vries
Supported by Grant No. 2003-2936 from the Dutch Cancer Society. Presented in part at the 54th Annual Meeting of the Society of Nuclear Medicine June 2-6, 2007, Washington, DC. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Orlefors H, Sundin A, Lu L, et al: Carbidopa pretreatment improves image interpretation and visualisation of carcinoid tumours with (11)C-5-hydroxytryptophan positron emission tomography. Eur J Nucl Med Mol Imaging 33:60-65, 2006[CrossRef][Medline] 17. Vries EFJ, Luurtsema G, Brussermann M, et al: Fully automated synthesis module for the high yield one-pot preparation of 6-[18F]-fluoro-L-DOPA. Appl Radiat Isot 51:389-419, 1999[CrossRef] 18. Brown WD, Oakes TR, DeJesus OT, et al: Fluorine-18-fluoro-L-DOPA dosimetry with carbidopa pretreatment. J Nucl Med 39:1884-1891, 1998 19. International Commission on Radiological Protection: ICRP publication 80: radiation dose to patients from radiopharmaceuticals. Oxford, United Kingdom, Elsevier, 2000 20. Balon HR, Goldsmith SJ, Siegel BA, et al: Procedure guideline for somatostatin receptor scintigraphy with (111)In-pentetreotide. J Nucl Med 42:1134-1138, 2001 21. 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Willemsen JJ, Ross HA, Wolthers BG, et al: Evaluation of specific high-performance liquid-chromatographic determinations of urinary metanephrine and normetanephrine by comparison with isotope dilution mass spectrometry. Ann Clin Biochem 38:722-730, 2001[CrossRef][Medline] 26. Bossuyt PM, Reitsma JB, Bruns DE, et al: Towards complete and accurate reporting of studies of diagnostic accuracy: The STARD initiative. Standards for reporting of diagnostic accuracy. Clin Chem 49:1-6, 2003 27. Smith CC: Evidence for separate serotonin and catecholamine compartments in human platelets. Biochim Biophys Acta 1291:1-4, 1996[Medline] 28. Mohnike K, Blankenstein O, Christesen HT, et al: Proposal for a standardized protocol for 18F-DOPA-PET (PET/CT) in congenital hyperinsulinism. Horm Res 66:40-42, 2006[CrossRef][Medline] Submitted October 28, 2007; accepted December 3, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
