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© 2000 American Society for Clinical Oncology Value of Peptide Receptor Scintigraphy Using 123I-Vasoactive Intestinal Peptide and 111In-DTPA-D-Phe1-Octreotide in 194 Carcinoid Patients: Vienna University Experience, 1993 to 1998From the Departments of Internal Medicine I, Nuclear Medicine, Internal Medicine III, Internal Medicine IV, Surgery, and Radiology, University of Vienna, and Research Center Seibersdorf, Vienna, Austria. Address reprint requests to Irene Virgolini, MD, Department of Nuclear Medicine, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; email irene.virgolini{at}akh-wien.ac.at
PURPOSE: To report our experience with both 123I-vasoactive intestinal peptide (VIP) and 111In-DTPA-D-Phe1-octreotide for imaging to identify primary and metastatic tumor sites in carcinoid patients. PATIENTS AND METHODS: One hundred ninety-four patients with a verified or clinically suspected diagnosis of a carcinoid tumor were injected with 111In-DTPA-D-Phe1-OCT for imaging purposes, while 133 patients underwent scanning with both 123I-VIP and 111In-DTPA-D-Phe1-OCT in random order. Imaging results were compared with computed tomography scans, results of conventional ultrasound, endosonography, and endoscopy, and results of surgical exploration in case of inconclusive conventional imaging. RESULTS: Primary or recurrent carcinoid tumors could be visualized with 111In-DTPA-D-Phe1-OCT in 95 (91%) of 104 patients; metastatic sites were identified in 110 (95%) of 116 patients. In 11 (51%) of 21 patients with suggestive symptoms but without identified lesions by conventional imaging, focal tracer uptake located the carcinoid tumor. In addition, metastatic disease was demonstrated in three patients after resection. In a direct comparison in the 133 patients who underwent both imaging modalities, 111In-DTPA-D-Phe1-OCT was found to be superior to 123I-VIP, with 35 (93%) of 38 versus 32 (82%) of 38 scans being positive in primary or recurrent tumors, 58 (90%) of 65 versus 53 (82%) of 65 being positive in patients with metastatic sites, and seven (44%) of 16 versus four (25%) of 16 being positive in patients with symptoms but otherwise negative work-ups. Overall, additional lesions not seen on conventional imaging were imaged in 43 (41%) of 158 versus 25 (25%) of 103 scans with 111In-DTPA-D-Phe1-OCT and 123I-VIP, respectively. CONCLUSION: Both peptide tracers have a high sensitivity for localizing tumor sites in patients with ascertained or suspected carcinoid tumors, with 111In-DTPA-D-Phe1-OCT scintigraphy being more sensitive than 123I-VIP receptor scanning. Both, however, had a higher diagnostic yield than conventional imaging, as verified by surgical intervention or long-term follow-up. The combination of both peptide receptor scans does not seem to further enhance diagnostic information.
NEUROENDOCRINE TUMORS are rare disease entities, often presenting as bizarre diagnostic puzzles.1 The fact that such malignancies arise from hormonally active cells explains the wide variety of symptoms encountered in patients with neuroendocrine cancers of various origin. The different manifestations are related to the release of hormones or other biologically active substances produced in excessive amounts by the tumor, including insulin, gastrin, vasoactive intestinal peptide (VIP), glucagon, and serotonin.2-4 Such cancers constitute a group of relatively slow-growing malignancies, which are sometimes diagnosed only after years of symptoms. This is due to the fact that the amount of hormones secreted does not necessarily correlate with tumor size, whereas small cancers tend to escape clinical detection by means of conventional radiologic imaging.5-7 Thus, the initiation of successful therapy or symptomatic palliation is often delayed in such patients. Carcinoid tumors constitute the group with the highest incidence among all cases of neuroendocrine malignancies, predominantly arising in the gastrointestinal (GI) tract but also in various other anatomic sites.8 According to epidemiologic data, carcinoids of the GI tract occur at a rate of 1.5 cases per 100,000 people per year.9 As has been stated, the onset of symptoms related to excessive serotonin production, summarized under the term carcinoid syndrome, may precede the correct diagnosis and localization of the tumor by years. While long-term symptomatic control of tumor-related symptoms can be achieved in some patients by noninvasive means, the treatment of choice, at least in localized disease, remains surgical resection because it is the only measure to offer potential cure. On the other hand, the removal of the primary cancer in the absence of symptoms such as bowel obstruction does not significantly alter the prognosis in patients with disseminated disease. In vitro data have demonstrated a high amount of receptors for various hormones and peptides on malignant cells of neuroendocrine origin, including carcinoid tumors.10 Among the latter, binding sites for members of the somatostatin (SST) family (SST receptors/1 through 5) are frequently found, and their expression has led to therapeutic and diagnostic attempts to specifically target these receptors. According to findings in patients with tumors arising from endocrine-active cells,11-14 the use of radiolabeled octreotide (OCT) for imaging purposes has been incorporated into the clinical work-up of patients suspected of having neuroendocrine tumors. VIP is a peptide consisting of 28 amino acids displaying a broad range of biologic activities.15 Apart from its vasodilatory properties, it has been implicated in the promotion of growth and proliferation of normal as well as malignant tissues.16,17 These effects are also mediated via cell-surface receptors (VIPR). Large numbers of VIPR are expressed on a variety of tumors, including adenocarcinomas,18 breast cancer tumors,19 and endocrine tumors.20,21 In addition, our own data suggest a significant cross-competition between SST and VIP on the cellular level,20 which might be the result of binding to SSTR3.22 Based on these findings, a peptide receptor scan using radioiodinated VIP as a tumor-seeking agent has been developed and successfully applied at the University of Vienna in patients with various types of cancer.21,23-27 In this article, we report our experience with both 111In-DTPA-D-Phe1-OCT and 123I-VIP in 194 consecutive patients with histologically verified or clinically suspected carcinoid tumors admitted to our institution between January 1993 and December 1998.
Patients A total of 194 patients with a median age of 63 years (range, 43 to 79 years) with verified carcinoid tumors or clinically suspected malignancy were admitted to our institution between 1993 and 1998 (Table 1). In 158 patients, a histologic diagnosis had been established before application of radiotracers, while 21 patients were believed to have a carcinoid tumor on the basis of symptoms (diarrhea alone in 13 patients, diarrhea accompanied by flushing in five patients, and flushing alone in three patients), an elevated level of urinary 5-hydroxyindoleacetic acid (5-HIAA), and no lesions indicating the site of malignancy on conventional computed tomography (CT) scans or different staging methods, including sonography, endoscopy, and endosonography. In addition, 15 patients were admitted to our institution after resection of a carcinoid tumor that was found during appendectomy or rectoscopy; they were thought to be free of tumor at the time of imaging. In total, 42 patients had primary tumors alone, whereas 62 had metastases along with their primary tumor. Histologic verification of at least one of these lesions was performed before surgery, and additional biopsies were attempted only in cases of lesions with uncharacteristic radiologic features or the absence of clear progression on consecutive CT scans performed at an interval of at least 3 months. In 54 cases, metastases were diagnosed after resection of the primary tumor, and histologic verification of biopsy specimens was performed in 26 patients, whereas in 15 patients, the appearance of new lesions on CT scans along with the development of clinical symptoms (accompanied by a rise in 5-HIAA in 11 cases) was rated diagnostic for relapse. In the additional 13 cases, only the appearance of new lesions progressing on a second CT investigation performed between 3 to 6 months later was present, and five of these patients also had elevated 5-HIAA levels without symptoms.
All 194 patients were injected with 111In-DTPA-D-Phe1-OCT for imaging purposes, while 133 patients received both 123I-VIP and 111In-DTPA-D-Phe1-OCT in random order to allow for a direct comparison. In total, 361 scans were performed and evaluated during this study. Scans were interpreted independently by two nuclear medicine physicians in a single blinded way, ie, without knowledge of the results of conventional staging. After consensus had been achieved between the two physicians, the results were compared with conventional radiologic imaging results and evaluated on a per-patient and per-lesion basis. In cases of more than five lesions involving the liver, lungs, or bone, no effort was made to analyze all neoplastic sites present on a per-lesion basis, but both the largest and smallest lesions as seen on CT scans in every segment of the liver or lobe of the lung were used as target lesions for comparison. Conventional CT imaging served as the gold standard, but sonographic, endosonographic, and endoscopic results were also taken into account. For lesions detected by scintigraphic but not conventional imaging, follow-up examinations were performed 3 to 6 months later to check for the appearance of corresponding lesions on conventional imaging. In cases of negative work-ups and ongoing symptoms, surgical exploration was performed with consecutive histologic analysis. When results of scintigraphic imaging corresponded with those of conventional imaging or surgery, or when a corresponding lesion appeared on conventional imaging during the follow-up period, lesions were rated as true-positive. Lesions not detected on scintigraphy but seen on conventional imaging (and showing progression during the follow-up period) and surgically detected tumors verified by histologic examination without a corresponding "hot spot" were rated as false-negative. False-positive results were defined as hot spots on gamma-camera imaging rated suggestive for a malignant process without a corresponding result on conventional imaging within the follow-up period or on surgical exploration.
Preparation of Radioiodinated VIP
Preparation of Radiolabeled OCT
Gamma-Camera Imaging and Analysis 111In-DTPA-D-Phe1-OCT scintigraphy. For planar and SPET studies, a large field-of-view gamma-camera (Toshiba America Medical Systems, Inc, Tustin, CA) equipped with a medium-energy general-purpose collimator was used. At the time of injection, the field of view covered the abdomen and some of the thorax. For recording and visualization, standard techniques were used. Sequential images were recorded every minute, starting immediately after the injection for 30 minutes (matrix, 128 x 128 pixels). Planar images in anterior, posterior, and lateral views were acquired at 30 minutes, between 3 and 6 hours, between 18 and 24 hours, and at approximately 72 hours after intravenous injection covering the brain and neck, thorax, and abdomen (matrix, 128 x 128 pixels; 150 to 300 kcounts; scanning time, 10 to 20 minutes). SPET acquisition was performed in all patients between 18 and 24 hours and at 48 hours after injection. Both energy peaks were used for scanning (set at 173 keV and 247 keV) with a 20% window. SPET imaging was done in a 360° circle, using 6° steps, 30 seconds per step. After being processed by a dedicated computer (prefiltering with a Wiener filter, postfiltering with a ramp filter), the data were reconstructed in three planes (slice thickness of 7 mm). All scans were viewed by at least two nuclear medicine physicians with no knowledge of the extent of tumor spread. A yes-or-no system was used to evaluate the presence of primary tumors and metastases as judged both by planar and SPET reconstructions.
111In-DTPA-D-Phe1-OCT Scintigraphy Overall, a high sensitivity for both primary and metastatic tumors was obtained in our series with application of 111In-DTPA-D-Phe1-OCT, irrespective of organ site and lesion size. In total, primary or recurrent carcinoid tumors could be visualized by means of 111In-DTPA-D-Phe1-OCT in 95 (91%) of 104 patients. Metastatic sites were identified in 110 (95%) of 116 patients, corresponding to 325 (88%) of 374 lesions. Overall, lesions not seen on initial conventional staging were encountered in 79 (41%) of 194 patients. In 11 (51%) of 21 patients with suggestive symptoms and elevated 5-HIAA levels exceeding 20 mg/mL but without identified lesions by conventional imaging, focal tracer uptake identified the location of the carcinoid tumor. This was confirmed in all cases by histologic evaluation after surgery. However, of the 10 remaining patients scheduled for a repeat imaging, six were lost to follow-up and four patients did not return for another 111In-DTPA-D-Phe1-OCT scan but underwent surgery for increasing symptoms of bowel obstruction. In all four patients, a carcinoid tumor could be pathologically demonstrated after surgery. In addition, the presence of metastatic disease was demonstrated in three patients thought to be free of tumor after resection, which was also confirmed during second-look surgical intervention. Concerning the time of imaging, the highest diagnostic accuracy was observed with SPET reconstructions performed 24 hours after injection of the tracer. SPET studies performed 48 hours after injection did not result in a higher diagnostic yield (Fig 1).
123I-VIPR Scanning and Direct Comparison With 111In-DTPA-D-Phe1-OCT One hundred thirty-three patients were given 123I-VIP and 111In-DTPA-D-Phe1-OCT in random order. In total, 74 patients were injected with radiolabeled VIP as the first imaging modality, and in 59 patients, 111In-DTPA-D-Phe1-OCT was applied as the initial tracer (Table 2).
In patients with documented primary/recurrent carcinoids, 38 (84%) of 45 had positive VIPR scintigraphy results. Thirty-three of 35 primary tumors located in the GI tract were identified correctly, whereas only five of 10 located in the lung were seen on VIPR scanning. In patients with disseminated disease, 123I-VIP was able to visualize metastatic spread in 53 (82%) of 65 patients. In total, 48 (83%) of 56 patients with liver metastases had a positive scan identifying 124 (85%) of 146 lesions, whereas VIPR imaging depicted lymph node metastases in six of 11 patients (22/42 lesions, 52%), lung metastases in one in five patients (one of 19 lesions, 5%), and bone lesions in one of nine patients (two of 26 lesions, 7%). However, VIPR scintigraphy visualized additional lesions not indicated by conventional means in 25 (25%) of 103 patients. In four (25%) of 16 patients who had elevated 5-HIAA levels along with symptoms suggestive of carcinoid tumor, focal tracer uptake indicated the site of malignancy in the absence of positive CT results. In addition, one of 12 patients thought to be free of disease after resection had a positive VIP scan. Direct comparison showed superior results with 111In-DTPA-D-Phe1-OCT: 42 (93%) of 45 v 38 (84%) of 45 scans were positive for primary or recurrent tumors, 83 (90%) of 92 v 76 (82%) of 92 scans were positive in patients with metastatic sites, and seven (43%) of 16 v four (25%) of 16 scans were positive in patients with symptoms and elevated 5-HIAA levels but otherwise negative work-ups. Identification of additional and as yet unknown lesions was possible in 38 (37%) of 104 patients. On a per-lesion basis, 111In-DTPA-D-Phe1-OCT visualized 134 (92%) of 146 known liver metastases, 37 (89%) of 42 lymph node lesions, 19 (100%) of 19 lung lesions, and 23 (88%) of 26 bone lesions.
The finding that neuroendocrine tumors express high amounts of SSTR had led to the development of radiolabeled OCT, which has demonstrated its ability to localize such tumors in large cohorts of patients.11-14 As has been published, this agent interacts preferentially with SSTR subtypes 2 and 5, which are expressed in relatively high amounts in most neuroendocrine tumors. In addition, a high density of binding sites for VIP could be found in vitro in cell lines and human tumor samples, and our first in vivo series have underscored the potential of 123I-VIP for visualizing neuroendocrine tumors and metastases.21,23-27 On the basis of these initial data, we performed a study to compare directly the diagnostic capability of both labeled peptides. Our data confirm that peptide receptor scintigraphy plays an important role in the detection and staging of carcinoid tumors. Both tracers applied in our study displayed the potential to localize primary as well as metastatic lesions, even in cases with no evidence of disease on conventional work-up. As could be expected from our initial series,18,19 VIPR scintigraphy had a high sensitivity for primary tumors (84%) and metastases (82%). In addition, four of 16 patients with symptomatic disease but otherwise negative conventional work-ups had their tumors located by the novel peptide tracer. However, superior diagnostic results were obtained with the application of 111In-DTPA-D-Phe1-OCT. A more than 90% sensitivity both for primary and metastatic lesions was found in our patients, and six of 21 patients without lesions documented with conventional staging methods had positive scans in the presence of symptoms and elevated 5-HIAA levels. A direct comparison of both tracers in 133 patients showed a sensitivity of 93% versus 83% in patients with primary and recurrent lesions, respectively, while metastases could be imaged in 90% of patients as compared with 82% with VIP. As could be expected from pharmacokinetic data,18,19 one of the major shortcomings of 123I-VIP is its inability to visualize small pulmonary lesions. In fact, about 40% of the tracer is trapped in the lung a few minutes after application,19 providing a high rate of physiologic background. Thus, small tumors or lesions with a low receptor density cannot be distinguished from normal lung uptake. In fact, 111In-DTPA-D-Phe1-OCT, which is not trapped in the lungs, demonstrated a striking superiority for imaging of lung lesions, whereas less than 50% of pulmonary deposits could be seen on VIPR scintigraphy. Both imaging methods, however, showed comparable performance for target lesions located in the liver, irrespective of lesion size. Given the overall results, 111In-DTPA-D-Phe1-OCT is the tracer of choice to date for diagnosis in patients with suspected carcinoids or for staging in patients with verified carcinoid tumors. Our data are also in line with the findings published by Krenning et al,28,29 who found a high sensitivity for various types of neuroendocrine tumors, including carcinoids. These findings as well as our results nevertheless seem to be superior to other series published in the literature.30,31 As has already been pointed out,28,29 this might be related to differences in scanning procedures as well as to the routine performance of SPET studies of both the thorax and abdomen in all patients, as performed by Krenning et al as well as in this study. Nevertheless, evaluation of new compounds to further improve diagnostic accuracy is still warranted, since 10% to 15% of lesions are apparently missed with the application of radiolabeled OCT, even with state-of-the-art SPET studies as routinely performed in our series in all patients. We conclude that both tracers are able to visualize carcinoid tumors with a higher sensitivity compared with conventional imaging. However, our results indicate that 111In-DTPA-D-Phe1-OCT is superior to 123I-VIPR scintigraphy for imaging of carcinoid tumors.
1. Moertel CG: Karnovsky Memorial Lecture: An odyssey in the land of small tumors. J Clin Oncol 5:1503-1522, 1987 2. Kvols L: Medical oncology considerations in patients with metastastic neuroendocrine tumors. Semin Oncol 21:56-60, 1994 (suppl 13)[Medline] 3. Farndon JR: Gastrin and gastrinomas. Br J Surg 77:1-2, 1990[Medline] 4. Averbuch SD: Endocrine tumors, in Pinedo HM, Longo DL, Chabner BA (eds): Cancer Chemotherapy and Biologic Response Modifiers: Annual 13. New York, NY,Elsevier Science, 1992, pp 493-507 5. Snow ND, Liddle RA: Neuroendocrine tumors, in Rustgi AK (ed): Gastrointestinal Cancers: Biology, Diagnosis and Therapy. Philadelphia, PA,Lippincott-Raven Publishers, 1995, pp 585-607 6. Ahlman H, Wängberg B, Nisson O, et al: Aspects on diagnosis and treatment of the foregut carcinoid syndrome. Gastroenterol 27:459-471, 1992 7. Macgillivray DC, Snyder DA, Drucker W, et al: Carcinoid tumors: The relationship between clinical presentation and the extent of disease. Surgery 110:68-72, 1991[Medline] 8. Vinik AI, McLeod MK, Fig LM, et al: Clinical features, diagnosis, and localization of carcinoid tumors and their management. Gastroenterol Clin North Am 18:865-896, 1989[Medline] 9. Godwin JD: Carcinoid tumors: An analysis of 2837 cases. Cancer 36:560-569, 1975[Medline] 10. Jonas S, John M, Boese-Landgraf J, et al: Somatostatin receptor subtypes in neuroendocrine tumor cell lines and tumor tissues. Langenbecks Arch Chir 380:90-95, 1995[Medline] 11. Krenning EP, Bakker WH, Breeman WA, et al: Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet 1:242-244, 1989[Medline] 12. Krenning EP, Kwekkeboom DJ, Bakker WH, et al: Somatostatin receptor scintigraphy with (111In-DTPA-D-Phe1)- and (123I-Thyr3)-octreotide: The Rotterdam experience with more than 1000 patients. Eur J Nucl Med 18:1-16, 1993
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Krenning EP, Bakker WH, Kooij PP, et al: Somatostatin receptor scintigraphy with indium 111-DTPA-D-Phe1-octreotide in man: Metabolism, dosimetry and comparison with iodine123 Tyr3-octreotide. J Nucl Med 33:652-658, 1992 14. Virgolini I, Angelberger P, Li S, et al: In vitro and in vivo studies of three radiolabeled somatostatin analogues: 123I-Octreotide (OCT), 123I-Tyr-3-OCT and 111In-DTPA-D-Phe-1-OCT. Eur J Nucl Med 23:1388-1399, 1996[Medline]
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
