Nuclear Medicine Review 2/2016-Evaluation of neuroendocrine tumors with 99mTc-EDDA/HYNIC TOC

Evaluation of neuroendocrine tumors with 99mTc-EDDA/HYNIC TOC

Vera Artiko1, Aida Afgan2, Jelena Petrović3, Branislava Radović2, Nebojša Petrović1, Marina Vlajković4, Dragana Šobić-Šaranović1, Vladimir Obradović1

1Center for Nuclear Medicine Clinical Center of Serbia, Faculty of Medicine University of Belgrade

2Center for Nuclear Medicine Clinical Center of Serbia

3Clinical Center of Serbia

4Center for Nuclear Medicine Clinical Center Nis, Faculty of Medicine University of Nis

 

[Received 23 VII 2016; Accepted 27 VII 2016]

Abstract

BACKGROUND: This paper is the short review of our preliminary results obtained with 99mTc-EDDA/HYNIC-TOC.

MATERIAL AND METHODS: The total of 495 patients with different neuroendocrine tumors were investigated during last few years.

RESULTS: There have been 334 true positive (TP), 73 true negative (TN), 6 false positive (FP) and 82 false negative findings (FN). Diagnosis was made according to SPECT findings in 122 patients (25%). The mean T/NT ratio for TP cases was significantly higher (p < 0.01) on SPECT (3.12 ± 1.13) than on whole body scan (2.2 ± 0.75). According to our results, overall sensitivity of the method is 80%, specificity 92%, positive predictive value 98%, negative predictive value 47% and accuracy 82%. Fifteen TP patients underwent therapy with 90Y-DOTATATE.

CONCLUSION: Scintigraphy of neuroendocrine tumors with 99mTc-Tektrotyd is a useful method for diagnosis, staging and follow up of the patients suspected to have neuroendocrine tumors. SPECT had important role in diagnosis. It is also helpful in the appropriate choice of the therapy, including the peptide receptor radionuclide therapy. In the absence of 68Ga-labeled peptides and PET/CT, the special emphasize should be given to application of SPECT/CT as well as to the radioguided surgery.

 

KEY words: scintigraphy, 99mTc-EDDA/HYNIC-TOC, NET, SPECT

 

Nucl Med Rev 2016; 19, 2: 99-103

Introduction

Neuroendocrine tumors (NETs) are rare tumors originating from neural crest, and can be localized in different organs. They are slowly growing and therefore not easy to detect. The first line diagnosis is made by laboratory analysis and radiological (anatomic) imaging modalities such as ultrasonography (US), computerized tomography (CT), magnetic resonance imaging (MRI) and angiography. The presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane of these tumors allow clinical use of specific radiopharmaceuticals for imaging and therapy (theranostics) [1]. Thus, radiolabeled metaiodobenzylguanidine (131 l-MIBG, 123I-MIBG) have been used to detect catecholamine-secreting tumors, while technetium (99mTc)-labeled pentavalent dimercaptosuccinicacid (DMSA-V), sestamibi (MlBl) or tetrofosmin are used only for diagnosis of medullary thyroid cancer. The fact that the majority of NETs express somatostatin receptors provided a possibility for development of various radiolabeled somatostatin analogs for their diagnosis and therapy.

The first in vivo studies were performed with the radioiodinated (123I) derivative of octreotide [2] but had drawbacks such as the high price, unavailability of 123I, time consuming and demanding preparation and predominantly biliary excretion obscuring intra-abdominal tumors. In order to overcome these disadvantages, 111In-DTPA-D-Phe1 -octreotide was developed [3] with a high affinity for somatostatin receptors, easy labeling and predominant elimination by the kidneys. Although 111In pentetreotide was proved to be reliable for the detection of NETs, the potential clinical advantage of 99mTc labeling in comparison to labeling with 111In, led to development of 99mTc-labeled somatostain analogs. 99mTc is not expensive and easily available on site. Physical characteristiscs of 99mTc are more suitable for imaging with gamma camera, leading to the lower radiation burden to the patient allowing the better image quality with lower radiation doses. 99mTc-EDDA/HYNIC-TOC (Tektrotyd) is a radiopharmaceutical indicated for diagnosis of tumors with overexpression of somatostatin receptors (especially subtype 2, sstr2). This paper is a short review of our preliminary results obtained with this radiopharmaceutical.

Material and methods

During last few years, in our Center, somatostatin receptor scintigraphy was performed in 495 patients (281 women and 214 men, mean age 52.3 ± 16.5 years).Indications were: detection and localization of NETs, staging, determination of the sstr status of tumor lesions and follow-up. NET diagnosis were different: medullary thyroid carcinomas (48), lung (50), mediastinal (12), ovarian (6), kidney (4), hypophysis (10), brain (5), breast (7), paraganglioma (12), parathyroid (1), pheochromocytoma (7), NET of unknown origin (95), pancreatic (97), gastric (32), colorectal (21), small bowel (71), carcinoid of appendix (10), liver (7).

Scintigraphy of the whole body was performed 2h and 24h after i.v. administration of 740 MBq 99mTc-Tektrotyd, Polatom. Investigation was followed by SPECT of particular region. It was performed using 360° orbit, step and shoot mode, at 30 sec per view. The acquired data were collected in a 128 x 128 computer matrix and reconstructed using filtered back-projections with a Butterworth filter (cut-off 0.6 cycles/pixel, order 5) and iterative reconstruction. If necessary, the study was supplemented with liver/spleen radiocolloid and/or bone diphosphonate scintigraphy. Before study therapy with somatostatin analogs was withdrawn, mild laxatives were introduced, patients were fasting and were well hydrated. The study was performed with ECAM gamma camera and computer (ESOFT), using high resolution collimator and one photopeak activity (140keV ± 20%).

Whole body and SPECT images were first evaluated visually by two experienced nuclear medicine physicians. Visual appearance of an increased focal uptake of tracer in the suspected tumor site was considered a positive finding. Subsequent semiquantitative analysis was limited to cases with positive findings to compare the tumor uptake of radiopharmaceutical to non tumor tissue in NETs on SPECT and whole body imaging. For that purpose, tumor to non/tumor (T/NT) ratio was calculated after drawing the region of interest around the lesion and at the corresponding contralateral area on both whole body and SPECT images.

Other imaging techniques were also applied and analysed in individual cases (US, MRI, CT, scintigraphy with 99mTc(V)-DMSA, 131I-MIBG, 99mTc-MDP 111In-DTPA-octreotide, 99mTc-Sn colloid) as well as laboratory analysis.

Results

There have been 334 true positive (TP), 73 true negative (TN), 6 false positive (FP) and 82 false negative findings (FN) (Table 1). Diagnosis was made according to SPECT findings in 122 patients (25%). The mean T/NT ratio for TP cases was significantly higher (p < 0.01) on SPECT (3.12 ± 1.13) than on whole body scan (2.2 ± 0.75). According to our results, overall sensitivity of the method is 80%, specificity 92%, positive predictive value 98%, negative predictive value 47% and accuracy 82%. Some of the typical results are presented on Figures 1-4. Fifteen TP patients underwent therapy with 90Y-DOTATATE (Figure 5).

Table 1. Findings of somatostatin receptor scintigraphy in various NETs

Diagnosis Medullary thyroid carcinoma Lung NET Mediastinal NET Ovarian NET Kidney NET Hypophysis NET
TP 38 37 11 1 3 6
TN 3 6 1 1 1 1
FP 0 1 0 0 0 1
FN 7 6 0 4 0 2
SUM 48 50 12 6 4 10

Table 1. cont. Findings of somatostatin receptor scintigraphy in various NETs

Diagnosis Brain NET Breast NET Paraganglioma Parathyroid NET Pheochromocytoma NET of unknown origin
TP 4 5 7 1 5 80
TN 1 1 4 0 1 2
FP 0 0 0 0 0 0
FN 0 1 1 0 1 13
SUM 5 7 12 1 7 95

Table 1. cont. Findings of somatostatin receptor scintigraphy in various NETs

Diagnosis Pancreatic NET Gastric NET Colorectal NET Small bowel NET Carcinoid of appendix Liver NET SUM
TP 61 6 12 45 5 7 334
TN 15 8 5 18 5 0 73
FP 0 1 2 1 0 0 6
FN 21 17 2 7 0 0 82
SUM 97 32 21 71 10 7 495

Figure 1. Lung carcinoid. Scintigraphy with 99mTc-Tektrotyd

Figure 2. Bone, liver and lung metastases of NET of unknown origin. Scintigraphy with 99mTc-Tektrotyd

Figure 3. Ileal carcinoid with liver metastases. Scintigraphy with 99mTc-Tektrotyd

Figure 4. Pancreatic NET with liver metastases. Scintigraphy with 99mTc-Tektrotyd

Figure 5. Multiple metastases in bones, lung, liver. A. scintigraphy with 99mTc-Tektrotyd; B. therapy with 90Y-DOTATATE

Discussion

Our results proved high sensitivity, specificity, accuracy, as well as positive predictive value. The additional value of SPECT is confirmed in 25% of patients as well as estimation of T/NT ratio. In FP patients, mainly inflammation was confirmed, as well as physiological uptake of radiopharmaceutical increased on particular foci because of previous surgery. In patients with FN findings, the cause were particular hystological tumor characteristics (mainly low differentiated tumors, dedifferentiated tumors...) or very small lesions. They were mainly confirmed with other nuclear medicine and other (morphological) methods. Correllation of results of 99mTc-EDDA/HYNIC-TOC scintigraphy with results of other imaging methods, as well as with laboratory analysis and clinical parameters will be evaluated further.

Our previous results [4] mainly in patients with NET of unknown origin or digestive NETs showed sensitivity 87%, specificity 86%, positive predictive value 95% negative predictive value 67% and accuracy 87%. Our previous results in lung lesions [5, 6] showed 87-88% sensitivity, 84-85% specificity, and 86-88% accuracy. This investigation has been reported to be usefull method for the detection of NET of different origin and localization, the results were similar to those obtained with 111In-pentetreotide as well as reliable for the appropriate choice of therapy [7-15].

Results of other authors are similar. Thus, Gabriel et al. [16] in GEP tumors obtained sensitivity of 80%, specificity of 94.4% and accuracy of 82.9%, and recommended it as an accurate procedure. They [17] revealed a higher sensitivity of this pharmaceutical compared with 111In-Octreotide.

The recent investigations evaluated the potential of using this radiopharmaceutical for the imaging of a wide range of primary and metastatic tumors like hepatocellular carcinomas [20], pituitary adenomas, meningiomas [18] liposarcoma, carcinoids, breast carcinoma, and lung cancer, as well as the metastases of malignant melanomas, pheochromocytoma, prostate cancer, leiomyosarcoma, pancreatic carcinoma ectopically secreting adrenocorticotropic hormone, carcinoid of the thymus, mesenchymal tumors, parathyroid hyperplasia etc. [19-22].

Some other somatostatin analogs, very similar to 99mTc-EDDA/HYNIC TOC have been recently investigated and recommended for clinical use [23-30]. Some of them are: 99mTc-EDDA-tricine-HYNIC-NATE, 99mTc-EDDA/HYNIC-octreotate, 99mTc (HYNIC-OC, HYNIC-TOC and HYNIC-TATE) and 111In (DTPA-OC and DOTA-TATE), 99mTc-demotate, 99mTc-P829. Introduction of hybrid systems (SPECT/CT, SPECT/MRI), additionally contributed to the accuracy and clinical validity of this method [31, 32]. A step forward was also made with [33, 34] the potential use of radio-guided surgery.

18F-FDG PET/CT can be used for detecting of low differentiated or heterogenous tumors [35]. However, other positron emiting radionuclides are recommended such as 18F-fluorodopamine, and, the most widely used, 68Ga-labeled peptides. In spite of superior resolution, short imaging time and imaging whole body in three dimensions, the price and availability of use of this pharmaceuticals still do not allow wide application [36, 37].

Conclusion

Our results show that scintigraphy of neuroendocrine tumors with 99mTc-Tektrotyd is a useful method for diagnosis, staging and follow up of the patients suspected to have neuroendocrine tumors. SPECT had important role in diagnosis. It is also helpful in the appropriate choice and monitoring of the therapy, including the radionuclide one. In the absence of 68Ga-labeled peptides and PET/CT, the special emphasize should be given to application of SPECT/CT as well as to the radioguided surgery. Correllation of results 99mTc-EDDA/HYNIC-TOC scintigraphy with results of other imaging methods, as well as with laboratory analysis and clinical parameters will be evaluated further.

Acknowledgements

The study was performed owing to grant Ministry of Science of Serbia number 175018; The majority patients were investigated in cooperation with Clinic for Endocrinology and Metabolism, Clinical Center of Serbia

References

  1. Rufini V, Calcagni ML, Baum RR imaging of neuroendocrine tumors. Semin Nucl Med 2006; 36: 228-247.
  2. Lamberts SWJ, Reubi J-C, krenning ER Validation of somatostatin receptor scintigraphy in the localization of neuroendocrine tumors. Acta Oncologica 1993; 32: 167-170.
  3. Bakker WH, Albert R, Bruns C et al. [111In-DTPA-D-Phe1]-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation. Life Sci 1991; 49: 1583-1591.
  4. Artiko V, Sobic-Saranovic D, Pavlovic S et al. The clinical value of scintigraphy of neuroendocrine tumors using (99m)Tc-HYNIC-TOC. J BUON 2012; 17: 537-542.
  5. Pavlovic S, Artiko V, Sobic-Saranovic D et al. The utility of 99mTc-EDDA/HYNIC-TOC scintigraphy for assessment of lung lesions in patients with neuroendocrine tumors. Neoplasma 2010; 57: 68-73.
  6. Sobic-Saranovic DP, Pavlovic SV, Artiko VM et al. The utility of two somatostatin analog radiopharmaceuticals in assessment of radiologically indeterminate pulmonary lesions. Clin Nucl Med 2012; 37: 14-20.
  7. Vlajkovic MZ, Rajic MP, Stevie ML et al. The role of Tc-99m-Tektrotyd somatostatin receptor scintigraphy in carcinoid tumor patients management. Eur J Nucl Med Mol imaging 2010; 37: S440-S440.
  8. Artiko V, Novosel S, Petrovic N et al. Detection of Neuroendocrine Tumors with Tc-99m-Tektrotyd. Eur J Nucl Med Mol Imaging 2009; 36: S299-S299.
  9. Sobic-Saranovic D, Bojic Lj, Pavlovic S et al. 99mTc-EDDA/HYNIC-TOC and 99mTc-Depreotid in assessment of solitary lung lesions. Eur J Nucl Med Mol Imaging 2009; 36: S461-S461.
  10. Obradovic V, Artiko V, Novosel S et al. Therapy of Neuroendocrine Tumors with Y-90-DOTA-TATE. Eur J Nucl Med Mol imaging 2009; 36: S417-S418.
  11. Artiko V, Novosel S, Petrovic N et al. Imaging of Neuroendocrine Tumors using ln-111 Pentetreotide (Meeting Abstract). Eur J Nucl Med Mol imaging 2009; 36: S445-S446.
  12. Pavlovic S, Sobic-Saranovic D, Artiko Vet al. Usefulness of 99mTc-Tektrotyd in evaluation of lung lesions. Eur J Nucl Med Mol imaging 2008; 35: S283-S283.
  13. Artiko V, Obradovic V, Petrovic N et al. Detection of Neuroendocrine Tumors in the Lungs Using Tc-99m Tektrotyd (Meeting Abstract). Eur J Nucl Med Mol imaging 2008; 35: S361-S362.
  14. Obradovic V, Artiko V, Petrovic N et al. Radionuclide Detection of Neuroendocrine Tumors Using In-111 Pentetreotide. Anticancer Res 2008; 28: 495.
  15. Artiko V, Obradovic V, Petrovic N et al. Scintigraphy with Tc-99m-Tektrotyd in The Detection of Neuroendocrine Tumors. Anticancer Res 2008; 28: 30.
  16. Gabriel M, Muehllechner P, Decristoforo C et al.99mTc-EDDA/HYNIC-Tyr(3)-octreotide for staging and follow-up of patients with neuroendocrine gastro-entero-pancreatic tumors. Q J Nucl Med Mol imaging 2005; 49: 237-244.
  17. Gabriel M, Decristoforo C, Donnemiller E et al. An intrapatient comparison of 99mTc-EDDA/HYNIC-TOC with 111In-DTPA-octreotide for diagnosis of somatostatin receptor-expressing tumors. J Nucl Med 2003; 44: 708-716.
  18. Li Y, Si JM, Zhang J et al. Somatostatin receptor subtype 2-mediated scintigraphy and localization using (99m)Tc-HYNIC-Tyr(3)-octreotide in human hepatocellular carcinoma-bearing nude mice. World J Gastroenterol 2005; 11: 3953-3957.
  19. Wang S, Yang W, Deng J, Zhang J, Ma F, Wang J. Correlation between 99mTc-HYNIC-octreotide SPECT/CT somatostatin receptor scintigraphy and pathological grading of meningioma. J Neurooncol 2013; 113: 519-526.
  20. Plachcinska A, Mikołajczak R, Maecke H et al. Clinical usefulness of Tc-EDDA/HYNIC-TOC scintigraphy in oncological diagnostics: a pilot study. Cancer Biother Radiopharm 2004; 19: 261-270.
  21. Płachcińska A, Mikołajczak R, Maecke HR et al. Clinical usefulness of 99mTc-EDDA/HYNIC-TOC scintigraphy in oncological diagnostics: a preliminary communication. Eur J Nucl Med Mol imaging 2003; 30: 1402-1406.
  22. Jing H, Li F, Zhong D, Zhuang H. 99mTc-HYNIC-TOC (99mTc-hydrazinonicotinyl-Tyr3-octreotide) scintigraphy identifying two separate causative tumors in a patient with tumor-induced osteomalacia (TIO). Clin Nucl Med 2013; 38: 664-667.
  23. Niu N, Mao X, Jing H, Li F Parathyroid hyperplasia shown on (99m) Tc-HYNIC-TOC scan. Clin Nucl Med 2013; 38: 294-296.
  24. Gabriel M, Hausler F, Bale R et al. Image fusion analysis of (99m)Tc-HYNIC-Tyr(3)-octreotide SPECT and diagnostic CT using an immobilisation device with external markers in patients with endocrine tumours. Eur J Nucl Med Mol imaging 2005; 32: 1440-1451.
  25. Li F, Chen LB, Jing HL, Du YR, Chen F Preliminary clinical application of 99Tcm-HYNIC-TOC imaging in somatostatin receptor-positive tumors. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2003; 25: 563-566.
  26. Gandomkar M, Najafi R, Shafiei M, Mazidi M, Ebrahimi SE. Preclinical evaluation of [99mTc/EDDA/tricine/HYNIC0, 1-Nal3, Thr8]-octreotide as a new analogue in the detection of somatostatin-receptor-positive tumors. Nucl Med. Biol 2007; 34: 651-657.
  27. Hubalewska-Dydejczyk A, Fröss-Baron K, Gołkowski F, Sowa-Staszczak A, Mikołajczak R, Huszno B. 99mTc-EDDA/HYNIC-octreotate in Detection of Atypical Bronchial Carcinoid. Exp Clin Endocrinol Diabetes 2007; 115: 47-49.
  28. Hubalewska-Dydejczyk A, Fross-Baron K, Mikołajczak R et al. 99mTc-EDDA/HYNIC-octreotate scintigraphy, an efficient method for the detection and staging of carcinoid tumours: results of 3 years’ experience. Eur J Nucl Med Mol imaging 2006; 33: 1123-1133.
  29. Storch D, Behe M, Walter MA et al. Evaluation of [99mTc/E D DA/HYNIC0] octreotide derivatives compared with [111In-DOTA0,Tyr3, Thr8]octreotide and [111In-DTPA0]octreotide: does tumor or pancreas uptake correlate with the rate of internalization? J Nucl Med 2005; 46: 1561-1569.
  30. Gabriel M, Decristoforo C, Maina T et al. 99mTc-N4-[Tyr3]Octreotate Versus 99mTc-EDDA/HYNIC-[Tyr3]Octreotide: an intrapatient comparison of two novel Technetium-99m labeled tracers for somatostatin receptor scintigraphy. Cancer Biother Radiopharm 2004; 19: 73-79.
  31. Zandieh S, Gambini JP, Haller J, Rodrigues M. 99mTc-tektrotyd SPECT/MRI in the diagnosis of a gastroenteropancreatic neuroendocrine tumor. Clin Nucl Med 2012; 37: 684-85.
  32. Yamaga LY Neto GC, da Cunha ML et al. 99mTc-HYNIC-TOC increased uptake can mimic malignancy in the pancreas uncinate process at somatostatin receptor SPECT/CT Radiol Med 2016; 121: 225-228.
  33. Hodolic M, Fettich J, Rubello D. Influence of tumour size and uptake of 99mTc-octreotide on radio-guided surgery for neuroendocrine tumors. Minerva Endocrinol 2009; 34: 89-96.
  34. Hubalewska-Dydejczyk A, Kulig J, Szybinski P et al. Radio-guided surgery with the use of [99mTc-EDDA/HYNIC]octreotate in intra-operative detection of neuroendocrine tumours of the gastrointestinal tract. Eur J Nucl Med Mol imaging 2007; 34: 1545-1555.
  35. Basu S, Abhyankar A. The use of 99mTc-HYNIC-TOC and 18F-FDG PET/CT in the evaluation of duodenal neuroendocrine tumor with atypical and extensive metastasis responding dramatically to a single fraction of PRRT with 177Lu-DOTATATE. J Nucl Med Technol 2014; 42: 296-298.
  36. Nanni C, Fantini L, Nicolini S, Fanti S.Non FDG. PET Clin Radiol 2010; 65: 536-548.
  37. Kratochwil C, Giesel FL, López-Benítez R et al. Intraindividual comparison of selective arterial versus venous 68Ga-DOTATOC PET/CT in patients with gastroenteropancreatic neuroendocrine tumors. Clin Cancer Res 2010; 16: 2899-2905.

Correspondence to: prof. Vera Artiko
Faculty of Medicine University of Belgrade
Center for Nuclear Medicine, Clinical Center of Serbia
Visegradska 26, 11 000 Belgrade
Tel: +381 11 3615641; Fax: +381 11 3615641
e-mail: vera.artiko@gmail.com

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