Clinical utility of indigenously formulated single-vial lyophilized HYNIC-TOC kit in evaluating Gastro-entero Pancreatic neuro endocrine tumours

Document Type : Original Article


1 Nuclear Medicine Department, Kovai Medical Center and Hospital, India

2 Isotope Applications & Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, India


 Objective(s): The objective of this study was to evaluate the performance and utility of 99mTc HYNIC-TOC planar scintigraphy and SPECT/CT in the diagnosis, staging and management of gastroenteropancreatic neuroendocrine tumors (GPNETs).
Methods: 22 patients (median age, 46 years) with histologically proven gastroentero-pancreatic NETs underwent 99mTc HYNIC-TOC whole body scintigraphy and regional SPECT/CT as indicated. Scanning was performed after injection of 370-550 MBq (10-15 mCi) of 99mTc HYNIC-TOC intravenously. Images were evaluated by two experienced nuclear medicine physicians both qualitatively as well as semi quantitatively (tumor to background and tumor to normal liver ratios on SPECT -CT images). Results of SPECT/CT were compared with the results of conventional imaging. Histopathology results and follow-up somatostatin receptor scintigraphy with 99mTc HYNIC TOC or conventional imaging with biochemical markers were considered to be the reference standards.
Results: 99mTc HYNIC TOC showed sensitivity and specificity of 87.5% and 85.7%, respectively, for primary tumor and 100% and 86% for metastases. It was better than conventional imaging modalities for the detection of both primary tumor (P<0.001) and metastases (P<0.0001). It changed the management strategy in 6 patients (31.8%) and supported management decisions in 8 patients (36.3%).
Conclusion: 99mTc HYNIC TOC SPECT/CT appears to be a highly sensitive and specific modality for the detection and staging of GPNETs. It is better than conventional imaging for the evaluation of GPNETs and can have a significant impact on patient management and planning further therapeutic options.


  1. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003; 97:934–59
  2. Sutliff VE, Doppman JL, Gibril F, Venzon D J, Yu F, Serrano J, et al. Growth of newly diagnosed, untreated metastatic gastrinomas and predictors of growth patterns. J Clin Oncol. 1997; 15: 2420-31.
  3. Fraker DL, Jensen RT. Pancreatic endocrine tumors. In: DeVita VT, Hellman S, Rosemberg SA, eds. Cancer: principles and practice of oncology, 5th ed. Philadelphia, PA: Lippincott-Raven; 1997. P. 1678–1704.
  4. Eriksson B, Oberg K, Skogseid B. Neuroendocrine pancreatic endocrine tumors: clinical findings in a prospective study of 84 patients. Acta Oncol. 1989; 28:373–7.
  5. Schillaci O, Spanu A, Scopinaro F, Falchi A, Danieli R,  Marongiu P, et al. Somatostatin receptor scintigraphy in liver metastasis detection from gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2003; 44:359–68.
  6. Madeira I, Terris B, Voss M, Denys A, Suavanet A, Flejou JF, et al. Prognostic factors in patients with endocrine tumours of the duodenopancreatic area. Gut. 1998; 43:422–7.
  7. La Rosa S, Sessa F, Capella C, Riva C , Leone BE, Klersy C, et al. Prognostic criteria in nonfunctioning pancreatic endocrine tumours. Virchows Arch. 1996; 429:323–33.
  8. Malagelada JR, Edis AJ, Adson MA, van Heerden JA, Go VLW. Medical and surgical options in the management of patients with gastrinoma. Gastroenterology. 1983; 84:1524–32.
  9. Andersen DK. Current diagnosis and manage-ment of Zollinger-Ellison syndrome. Ann Surg. 1989; 210:685–703.
  10. Norton JA, Collen MJ, Gardner JD. Prospective study of gastrinoma localization and resection in patients with Zollinger-Ellison syndrome. Ann Surg. 1986; 204:468–79.
  11. Norton JA, Shawker TH, Doppman JL. Localization and surgical treatment of occult insulin-omas. Ann Surg. 1990; 212:615–20.
  12. Howard TJ, Zinner MJ, Stabile BE, Passaro E Jr. Gastrinoma excision for cure: a prospective analysis. Ann Surg. 1990; 211:9–14.
  13. Kwekkeboom DJ, Bakker WH, Kam BL, Teunissen JJM, Kooij PPM, de Herder WW, et al. Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA0,Tyr3] octreotate. Eur J Nucl Med Mol Imaging. 2003; 30:417–22.
  14. Dromain C, de Baere T, Lumbroso J, Caillet H, Laplanche A, Boige V, et al. Detection of liver metastases from endocrine tumors: a prospe-ctive comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging. J Clin Oncol. 2005; 23:70–8.
  15. Kwekkeboom DJ, Krenning EP. Somatostatin receptor imaging. Sem Nucl Med. 2002; 32: 84.
  16. Breeman WAAP, De Jong M, Kwekkeboom DJ, Valkema R, Bakker WH, Kooij PP, et al. Somatostatin receptor-mediated imaging and therapy: Basic science, current knowledge, limitations, and future prospectives. Eur J Nucl Med. 2001; 28: 1421.
  17. Reubi JC, Schaer JC, Laissue JA, Waser B. Somatostatin receptors and their subtypes in human tumors and in peritumoral vessels. 1996; 45(8 suppl. 1):39.
  18. Reubi JC, Shaer JC, Waser B, Mengod G.Expression and localization of somatostatin receptor SSTR1, SSTR2, and SSTR3 messenger RNAs in primary human tumors using in situ Cancer Res. 1994; 54:3455.
  19. Lamberts SW, Reubi JC, Krenning EP. Validation of somatostatin receptor scintigraphy in the localization of neuroendocrine tumors. Acta Oncol. 1993; 32:167.
  20. Warner RRP, O’Dorisio TM. Radiolabeled peptides in diagnosis and tumor imaging: Clinical overview. Semin Nucl Med. 2002; 32:79.
  21. Blum J, Handmaker H, Rinne N. The utility of a somatostatin-type receptor-binding peptide radiopharmaceutical (P829) in the evaluation of solitary pulmonary nodules. 1999; 115:224.
  22. Blum J, Handmaker H, Lister-James J, Rinne N. A multicenter trial with a somatostatin analog 99mTc de-preotide in the evaluation of solitary pulmonary nodules. 2000; 117: 1232.
  23. Menda Y, Kahn D. Somatostatin receptor imaging of non–small cell lung cancer with 99mTc-depreotide.Semin Nucl Med. 2002; 2:92.
  24. Vallabhajosula S, Moyer BR, Lister-James J, McBride BJ,  Lipszyc H,  Lee H, et al. Preclinical evaluation of technetium-99m-labeled somatostatin receptor-binding peptides. J Nucl Med. 1996; 37: 1016.
  25. Pearson DA, Lister-James J, McBride WJ, Wilson DM, Martel LJ, Civitello ER, et al. Somatostatin receptor-binding peptides labeled with technetium-99m: Chemistry and initial biological studies. J Med Chem. 1996; 39:1361.
  26. Maina T, Stolz B, Albert R, Bruns, C, Koch P, Mäcke H, et al. Synthesis, radiochemistry, and biological evaluation of a new somatostatin analog (SDZ 219-387) labeled with technetium-99m. Eur J Nucl Med. 1994; 21:437.
  27. Maecke HR, Béhé M. New octreotide derivatives labeledwith technetium-99m. J Nucl Med. 1996; 37:1144.
  28. Thakur ML, Kolan H, Wiaderkiewicz R, Pallela VR, Duggaraju R, Schally AV, et al. Radiolabeled somatostatin analogs in prostate cancer. Nucl Med Biol. 1997; 24:105.
  29. Liu S, Edwards DS. 99mTc-labeled small peptides as diagnostic radiopharmaceuticals. Chem Rev. 1999; 99:2235.
  30. Bangard M, Behe M, Guhlke S,Otte R, Bender H, Maecke HR, et al. Detection of somatostatin receptor-positive tumors using the new 99mTc-tricine-Hynic-D-Phe1-Tyr3-octreotide: First results in patients and comparison with 111In-DTPA-DPhe1- octreotide. Eur J Nucl Me. 2000; 27:628.
  31. Maina T, Nock B, Nikolopoulou A, Sotiriou P, Loudos G, Maintas D, et al. [99mTc]Demotate, a new 99mTc-based [Tyr3]octreotate analogue for detection of somatostatin receptor-positive tumors: Synthesis and preclinical results. Eur J Nucl Med Mol Imaging. 2002; 29:742.
  32. Decristoforo C, Mather SJ. Technetium-99m somatostatin analogues: Effect of labeling methods and peptide seuqence. Eur J Nucl Med. 1999; 26:869.
  33. Decristoforo C, Mendelez-Alafort L, Sosabowski JK,Mather SJ 99mTc-HYNIC-[Tyr3]-octreotide for imaging of somatostatin- receptor-positive tumors: Preclinical evaluation and comparison with 111In-octreotide. J Nucl Med. 2000; 41:1114.
  34. Decristoforo C, Mather SJ, Cholewinski W, Donnemiller E,Riccabona G, Moncayo R, et al. 99mTc- EDDA/HYNIC-TOC: A new 99mTc-labeled radiopharmaceutical for imaging somatostatin receptor-positive tumors: First clinical results and intrapatient comparison with 111IN-labeled octreotide d rivatives. Eur J Nucl Med. 2000; 27:1318.
  35. Krenning EP, Kwekkeboom DJ, de Jong M, Visser TJ, Reubi JC, Bakker WH, et al. Essentials of peptide receptor scintigraphy with emphasis on somatostatin analog octreotide. Semin Oncol. 1994; 21:6–14.
  36. Lamberts SWJ, Reubi JC, Krenning EP. Somatostatin and the concept of peptide receptor scintigraphy in oncology. Semin Oncol. 1994; 21:1–5.
  37. Prasad V, Ambrosini V, Hommann M, Hoersch D, Fanti S, Baum RP. Detection of unknown primary neuroendocrine tumors (CUP-NET) using 68Ga- DOTA-NOC receptor PET/CT. Eur J Nucl Med Mol Imaging. 2010; 37:67–77.
  38. Campana D, Ambrosini V, Pezzilli R, Fanti S, Morselli Labate AM, Santini D, et al. Standardized uptake values of 68Ga-DOTA-NOC PET: a promising prognostic tool in neuroendocrine tumors. J Nucl Med. 2010; 51:353–9.
  39. Reubi JC, Kvols LK, Waser B, Nagorney DM, Heitz PU, Charboneau JW, et al. Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res. 1990; 50:5969–77.
  40. Reubi JC, Kvols L, Krenning E, Lamberts SWJ. In vitro and in vivo detection of somatostatin receptors in human malignant tissues. Acta Oncol. 1991; 30: 463–8.
  41. Ruf J, Schiefer J, Furth C, Kosiek O, Kropf S, Heuck F, et al. 68Ga-DOTATOC PET/CT of neuroendocrine tumors: spotlight on the CT phases of a triple-phase protocol. J Nucl Med. 2011; 52:697–704.
  42. Moertel CG, Kvols LK, O’Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin: evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer. 1991; 68:227–32.
  43. Ambrosini V, Campana D, Bodei L, Nanni C, Castellucci P, Allegri V, et al.68Ga- DOTA-NOC PET/CT clinical impact in patients with neuroendocrine tumors. J Nucl Med. 2010; 51:669–73.
  44. Guggenberg EV, Mikolajczak R, Janota B, Riccabona G, Decristoforo C. Radiopharmaceutical development of a freezedried kit formulation for the preparation of [99mTc-EDDAHYNIC- D-Phe1,Tyr3]-octreotide, a somatos-tatin analog for tumor diagnosis. J Pharm Sci. 2004; 93(10):2497–506.