Selective hepatic arterial infusion of In-111-DTPA-Phe1-octreotide in neuroendocrine liver metastases

  • Georgios S. Limouris
  • Achilles Chatziioannou
  • Dimitrios Kontogeorgakos
  • Dimitrios Mourikis
  • Maria Lyra
  • Panagiotis Dimitriou
  • Anastasia Stavraka
  • Athanassios Gouliamos
  • Lambros Vlahos
Original Article

Abstract

Purpose

The aim of this study is to evaluate the effectiveness of 111In-DTPA-Phe1-octreotide infusions after selective catheterization of the hepatic artery in inoperable metastasised liver, sst2 receptor-positive neuroendocrine tumours due to the effect of 111In Auger electron emission, minimising in parallel the toxicity of non-target tissue.

Methods

The average dose per session administered monthly to each patient (17 cases in total) was 6.3 ± 2.3 GBq. Repetitions did not exceed 12-fold, except in one case (15 sessions). Response assessment was classified according to the Response Evaluating Criteria in Solid Tumours. CT/MRI scans were performed as baseline before, during and after the end of treatment, and monthly ultrasound images for follow-up measurements. Toxicity (World Health Organization criteria) was measured using blood and urine tests of renal, hepatic and bone marrow function.

Results

Complete response was achieved in one (5.9%) patient and partial in eight (47.0%), and disease stabilization in 3 (17.7%) patients; five (29.4%) did not respond. A 32-month median survival time was estimated in 12 (70.5%). Nine of these 12 surviving had a mean target diameter shrinkage from 144 ± 81 to 60 ± 59 mm. Grade 1 erythro-, leuko- and thrombo-cytopenia occurred in three (17.6%) cases.

Conclusion

In unresectable metastatic liver lesions positive for somatostatin receptors repeated, transhepatic high doses of 111In-DTPA-Phe1-octreotide show an effective therapeutic outcome. Given the locoregional modality character of the administration technique plus the extremely short range of 111In Auger and internal conversion electrons emission, no nephro-, liver- or myelo-toxicity has so far been observed.

Keywords

111In-DTPA-d-Phe1-octreotide Therapeutic infusions Hepatic artery catheterization 

Notes

Acknowledgement

This project was co-financed within Op. Education by the ESF (European Social Fund) and National Resources (Irakleitos program grants 70/3/7166 and 70/3/7231). We are thankful to Maria Paphiti, radiation physicist, for her valuable assistance.

References

  1. 1.
    Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol. 1999;20:157–98.PubMedCrossRefGoogle Scholar
  2. 2.
    Janson ET, Westlin J-E, Öhrvall U, Öberg K, Lukinius A. Nuclear localization of 111In after intravenous injections of [111In-DTPA-d-Phe1]-octreotide in patients with neuroendocrine tumors. J Nucl Med. 2000;41:1514–8.PubMedGoogle Scholar
  3. 3.
    Krenning EP, Kwekkeboom DJ, Bakker WH, Breeman WA, Kooij PP, Oei HY, et al. Somatostatin receptor scintigraphy with [111In-DTPA-d-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med. 1993;20:716–31.PubMedCrossRefGoogle Scholar
  4. 4.
    De Jong M, Bernard BF, De Bruin E, Van Gameren A, Bakker WH, Visser TJ, et al. Internalization of radiolabelled [DTPA°]octreotide and [DOTA°, Tyr3]octreotide: peptides for somatostatin receptor-targeted scintigraphy and radionuclide therapy. Nucl Med Commun. 1998;19:283–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Anderson P, Forssel-Aronsson E, Johanson V, Wängberg B, Nilsson O, Fjälling M, et al. Internalization of indium-111 into human neuroendocrine tumor cell after incubation with indium-11-DTPA-d-Phe1-octreotide. J Nucl Med. 1996;37:2002–6.Google Scholar
  6. 6.
    Bass LA, Lanahan MV, Duncan JR, Erion JL, Srinivasan A, Schmidt MA, et al. Identification of the soluble in vivo metabolites of indium-111-diethylenetriaminepentaacetic acid-d-Phe1-octreotide. Bioconjug Chem. 1998;9:192–200.PubMedCrossRefGoogle Scholar
  7. 7.
    Krenning EP, Kooij PPM, Bakker WH, Breeman WA, Postema PT, Kwekkeboom DJ, et al. Radiotherapy with a radiolabeled somatostatin analogue, [111In-DTPA-D.Phe1]-octreotide; a case history. Ann NY Acad Sci 1994;733:496–506.PubMedCrossRefGoogle Scholar
  8. 8.
    Kaltsas GA, Stefanidou Z, Papadogias D, Grossmann A. Treatment of advanced neuroendocrine tumours with radiolabelled somatostatin analogue octreotide. Hormones. 2002;1(3):149–56.PubMedGoogle Scholar
  9. 9.
    Adelstein SJ. The Auger process: a therapeutic promise? AJR. 1993;160:707–13.PubMedGoogle Scholar
  10. 10.
    Breeman WA, De Jong M, Kwekkeboom DK, Valkema R, Bakker WH, Kooij PPM, et al. Somatostatin receptor-mediated imaging and therapy: basic science, current knowledge, limitations and future perspectives. Eur J Nucl Med. 2001;28:1421–9.PubMedCrossRefGoogle Scholar
  11. 11.
    McLean JR, Wilkinson D. The radiation dose to cells in vitro from intracellular indium-111. Biochem Cell Biol. 1989;67:661–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Mariani G, Bodei L, Adelstein SJ, Kassis AI, et al. Emerging roles for radiometabolic therapy of tumours based on auger electron emission. J Nucl Med. 2000;41:1519–21.PubMedGoogle Scholar
  13. 13.
    Kassis AI, Adelstein SJ. Radiobiologic principles in radionuclide. therapy. J Nucl Med. 2005;46:4S–12S.PubMedGoogle Scholar
  14. 14.
    Wiseman GA, Kvols LK. The radiolabelled MIBG and Somatostatin analogues. Semin Nucl Med 1995;XXV(3):272–8.CrossRefGoogle Scholar
  15. 15.
    De Jong M, Bakker WH, Krenning EP, Breeman WAP, Van der Pluijm ME, Bernard BF, et al. Yttrium-90 and indium-111 labelling, receptor binding and biodistribution of [DOTA, D-Phe1, Tyr3]-octreotide; a promising somatostatin analogue for radionuclide therapy. Eur J Nucl Med. 1997;24:368–71.PubMedCrossRefGoogle Scholar
  16. 16.
    Limouris GS, Lyra M, Skarlos D, Hatziioannou A, Gouliamos A, Moulopoulou A, et al. Auger and conversion electron therapy with In-111 pentetreotide in hepatocellular carcinoma. In: Bergmann H, Koehn H, Sinzinger H, editors. Radioactive isotopes in clinical medicine and research. Boston: Birkhäuser; 1999. p. 551–4.Google Scholar
  17. 17.
    Valkema R, De Jong M, Bakker WH, Breeman WAP, Kooij PPM, Lugtenburg PJ, et al. Phase I study of peptide receptor radionuclide therapy with [111In-DTPA°]octreotide: the Rotterdam experience. Semin Nucl Med. 2002;32(2):110–22.PubMedCrossRefGoogle Scholar
  18. 18.
    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-DOTA°, Tyr3]octreotate. Eur J Nucl Med. 2003;30:417–22.Google Scholar
  19. 19.
    Caplin ME, Mielcarek W, Buscombe JR, Jones AL, Croasdale PL, Cooper MS, et al. Toxicity of high-activity in-111 octreotide therapy in patients with disseminated neuroendocrine tumours. Nucl Med Commun. 2000;21:97–102.PubMedCrossRefGoogle Scholar
  20. 20.
    Lafortune M, Madore F, Patriquin H, Breton G. Segmental anatomy of the liver; a US approach to the Couinaud nomenclature. Radiology. 1991;181:443–8.PubMedGoogle Scholar
  21. 21.
    Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays MT, Koral KF, et al. MIRD pamphlet no. 16: techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med. 1999;40:37–61.Google Scholar
  22. 22.
    Kontogeorgakos D, Dimitriou P, Limouris GS, Vlachos LJ. Patient specific dosimetry calculations during therapy with in-111-DTPA-d-Phe1-octreotide infusions after catheterization of the hepatic artery using mathematical models of different anatomical sizes. J Nucl Med. 2006;47(9):1476–82.PubMedGoogle Scholar
  23. 23.
    Therasse P, Arbuck SG, Eienhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumours. J Natl Cancer Inst. 2000;92(30):205–16.PubMedCrossRefGoogle Scholar
  24. 24.
    Stabin M. MIRDOSE: the personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 1996;37:538–46.PubMedGoogle Scholar
  25. 25.
    Hellman P, Lundström T, Öhrvall V, Eriksson B, Skogseid B, Öberg K, et al. Effect of surgery on the outcome of midgut carcinoid disease with lymph node and liver metastases. World J Surg. 2002;26:991–97.PubMedCrossRefGoogle Scholar
  26. 26.
    Öberg K. Therapeutic alternative in metastasizing neuroendocrine tumours; in carefully selected cases liver transplantation is possible? Laekartidningen. 1999;96:3745–7.Google Scholar
  27. 27.
    Kress O, Wagner HJ, Wied M, Klose KJ, Arnold R, Alfke H. Transarterial chemoembolization of advanced liver metastases of neuroendocrine tumours; a retrospective single-center analysis. Digestion. 2003;68:94–101.PubMedCrossRefGoogle Scholar
  28. 28.
    Dodd GD, Soulen MC, Kane RA, Livraghi T, Lees WR, Yamashita Y, et al. Minimally invasive treatment of malignant hepatic tumours; at the threshold of major breakthrough. Radiographics. 2000;20:9–27.PubMedGoogle Scholar
  29. 29.
    Öberg K. Carcinoid tumours: molecular genetics, tumour biology and update of diagnosis and treatment. Curr Opin Oncol. 2002;14:38–45.PubMedCrossRefGoogle Scholar
  30. 30.
    Öberg K. Interferon in the management of neuroendocrine GEP-tumours: a review. Digestion 2000;62(Suppl 1):92–7.PubMedGoogle Scholar
  31. 31.
    Kaltsas GA, Besser MG, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev. 2004;25(3):458–511.PubMedCrossRefGoogle Scholar
  32. 32.
    Kaltsas GA, Mucherjee JJ, Plowman PN, Grassman AB. The role of chemotherapy in the nonsurgical management of malignant neuroendocrine tumours. Clin Endocrinol. 2001;55:575–87.CrossRefGoogle Scholar
  33. 33.
    Wang DG. Apoptosis in neuroendocrine tumours. Clin Endocrinol. 1999;51:1–9.CrossRefGoogle Scholar
  34. 34.
    Virgolini I, Britton K, Buscome JR, Moncay R, Paganelli G, Riva P. In- and Y-DOTA lanreotide: results and implications of the Mauritius trial. Semin Nucl Med. 2000;32:148–55.CrossRefGoogle Scholar
  35. 35.
    Paganelli G, Zoboli S, Cremonesi M, Bodei L, Ferrari M, Grana C, et al. Receptor-mediated radiotherapy with Y-90-d-Phe1-Tyr3-octreotide. Eur J Nucl Med. 2001;28:426–34.PubMedCrossRefGoogle Scholar
  36. 36.
    Handkiewicz Junak D, Baum R, Jarzab B. Leukocyte and white blood cell toxicity during long-term peptide receptor radiotherapy using Y-90 and Lu-177 labelled somatostatin analogues. Eur J Nucl Med 2005;32(9):S100.Google Scholar
  37. 37.
    Kwekkeboom DJ, Bakker WH, Kooij PPM, Konijnenberg MW, Srinivasan A, Erion JL, et al. Lu-177-DOTA Tyr octreotate: comparison with In-111-DTPA-octreotide in patients. Eur J Nucl Med. 2001;28:1319–25.PubMedCrossRefGoogle Scholar
  38. 38.
    Anthony LB, Woltering EA, Espanan GD, Cronin MD, Maloney TJ, McCarthy KE, et al. Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies. Semin Nucl Med. 2002;32(2):123–32.PubMedCrossRefGoogle Scholar
  39. 39.
    Buscombe JR, Caplin ME, Hilson JW. Long-term efficacy of high-activity 111In-pentetreotide therapy in patients with disseminated neuroendocrine tumors. J Nucl Med. 2003;44:1–6.PubMedGoogle Scholar
  40. 40.
    Förster GJ, Engelbach M, Brockmann J, Reber H, Buchholz H-G, Mäcke HR, et al. Preliminary data on biodistribution and dosimetry for therapy planning of somatostatin receptor positive tumours: comparison of 86Y-DOTATOC and 111In-DTPA-octreotide. Eur J Nucl Med. 2001;28:1743–50.PubMedCrossRefGoogle Scholar
  41. 41.
    Helisch A, Förster GJ, Reber H, Buchholz H-G, Arnold R, Göke B, et al. Pre-therapeutic dosimetry and biodistribution of 86Y-DOTA-Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advanced neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2004;31(10):1386–92.PubMedCrossRefGoogle Scholar
  42. 42.
    Goddu SM, Budinger TF. MIRD: cellular S values. Reston, VA: SNM; 1997.Google Scholar
  43. 43.
    Buchegger F, Perillo-Adamer F, Dupertuis YM, Bischof Delaloye A. Auger radiation targeted into DNA: a therapy perspective. Eur J Nucl Med Mol Imaging. 2006;33(11):1352–63.PubMedCrossRefGoogle Scholar
  44. 44.
    Health Physics J. RADAR; 2008. http://www.doseinfo-radar.com/RADARSoft.html
  45. 45.
    Limouris GS, Dimitropoulos N, Kontogeorgakos D, Papanikolos G, Koutoulidis V, Hatzioannou A, et al. Evaluation of the therapeutic response to In-111-DTPA octreotide-based targeted therapy in liver metastatic neuroendocrine tumours according to CT/MRI/US findings. Cancer Biother Radiopharm. 2005;20(2):215–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Kwekkeboom DJ, Mueller-Brand J, Paganelli G, Anthony LB, Pauwels S, Kvols LK, et al. Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs. J Nuclear Med. 2005;46(Suppl 1):62–6.Google Scholar
  47. 47.
    Bodei L, Cremonesi M, Zoboli S, Grana C, Bartolomei M, Rocca P, et al. Receptor-mediated radionuclide therapy with 90Y-DOTATOC in association with amino acid infusion: a phase I study. Eur J Nucl Med. 2003;30:207–16.Google Scholar
  48. 48.
    Waldherr C, Pless M, Maecke HR, Schumacher T, Crazzolara A, Nitzsche EU, et al. Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq 90Y-DOTATOC. J Nucl Med. 2002;43(5):610–6.PubMedGoogle Scholar
  49. 49.
    Cremonesi M, Ferrari M, Bodei L, Tosi G, Paganelli G. Dosimetry in peptide radionuclide receptor therapy: a review. J Nucl Med. 2006;47(9):1467–75.PubMedGoogle Scholar
  50. 50.
    De Jong M, Valkema R, Van Gameren A, Van Boven H, Bex A, Van de Weyer EP, et al. Inhomogenous localization of radioactivity in the human kidney after injection of [111In-DTPA]octreotide. J Nucl Med. 2004;45(7):1168–71.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Georgios S. Limouris
    • 1
  • Achilles Chatziioannou
    • 2
  • Dimitrios Kontogeorgakos
    • 1
  • Dimitrios Mourikis
    • 2
  • Maria Lyra
    • 1
  • Panagiotis Dimitriou
    • 1
  • Anastasia Stavraka
    • 1
  • Athanassios Gouliamos
    • 2
  • Lambros Vlahos
    • 2
  1. 1.Divisions of Nuclear Medicine, Radiology I DepartmentAretaieion University Hospital, Athens Medical SchoolAthensGreece
  2. 2.Divisions of Angiography, Radiology I DepartmentAretaieion University Hospital, Athens Medical SchoolAthensGreece

Personalised recommendations