Experimental facts supporting a red marrow uptake due to radiometal transchelation in 90Y-DOTATOC therapy and relationship to the decrease of platelet counts

  • Stephan Walrand
  • Raffaella Barone
  • Stanislas Pauwels
  • François Jamar
Original Article



The aim of this study was to retrospectively evaluate whether the red marrow (RM) takes up 111In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide and 86Y-DOTATOC and to assess the correlation between the RM absorbed doses and platelet count reduction as a biological dose estimate.


Data from 12 patients who underwent at 24 h p.i. high statistics 111In single photon emission computed tomography (SPECT) and 86Y positron emission tomography (PET) acquisitions of the chest were analysed. Uptake was measured on >7 cm spine length and converted to total RM uptake using standard RM distribution in man. RM absorbed doses were calculated assuming specific RM uptake and using the plasma and remainder of the body models. RM doses were correlated with the platelet count reduction at 4 weeks. In vitro experiments explored the metabolism of 111In-DTPA-D-Phe1-octreotide and 90Y-DOTATOC in plasma.


The correlation between the uptake of both tracers was excellent (R = 0.80), indicating that RM uptake of 86Y-DOTATOC reflects a real physiological process and not reconstruction artefacts. The kinetics of 86Y-DOTATOC RM activity was different than that in blood and tumours, with no activity at 4 h p.i. indicating that the uptake is not somatostatin receptor dependent. In vitro experiments showed a transchelation of both radiometals to free transferrin that could explain the RM uptake. In patients without chemotherapy and with a normal platelet count recovery, a good correlation (R = 0.96) was found between the RM doses and the platelet count reduction at the nadir.


These experimental facts support the existence of a true RM uptake likely related to transchelation of the radiometal to transferrin. RM uptake correlates well with the observed acute RM toxicity.


Red marrow uptake Radiometal transchelation Absorbed dose Platelet count 

Supplementary material

259_2011_1744_MOESM1_ESM.ppt (118 kb)
Supplementary material 1(PPT 117 kb)
259_2011_1744_MOESM2_ESM.doc (88 kb)
Supplementary material 2(DOC 88 kb)


  1. 1.
    Brans B, Linden O, Giammarile F, Tennvall J, Punt C. Clinical applications of newer radionuclide therapies. Eur J Cancer 2006;42:994–1003.PubMedCrossRefGoogle Scholar
  2. 2.
    Flux G, Bardies M, Monsieurs M, Savolainen S, Strand SE, Lassmann M, et al. The impact of PET and SPECT on dosimetry for targeted radionuclide therapy. Z Med Phys 2006;16:47–59.PubMedGoogle Scholar
  3. 3.
    Flux G, Bardies M, Chiesa C, Monsieurs M, Savolainen S, Strand SE, et al. Clinical radionuclide therapy dosimetry: the quest for the “Holy Gray”. Eur J Nucl Med Mol Imaging 2007;34:1699–700.PubMedCrossRefGoogle Scholar
  4. 4.
    Brans B, Bodei L, Giammarile F, Linden O, Luster M, Oyen WJ, et al. Clinical radionuclide therapy dosimetry: the quest for the “Holy Gray”. Eur J Nucl Med Mol Imaging 2007;34:772–86.PubMedCrossRefGoogle Scholar
  5. 5.
    Sgouros G, Frey E, Wahl R, He B, Prideaux A, Hobbs R. Three-dimensional imaging-based radiobiological dosimetry. Semin Nucl Med 2008;38:321–34.PubMedCrossRefGoogle Scholar
  6. 6.
    Stabin MG, Brill AB. State of the art in nuclear medicine dose assessment. Semin Nucl Med 2008;38:308–20.PubMedCrossRefGoogle Scholar
  7. 7.
    Barone R, Borson-Chazot F, Valkema R, Walrand S, Chauvin F, Gogou L, et al. Patient-specific dosimetry in predicting renal toxicity with (90)Y-DOTATOC: relevance of kidney volume and dose rate in finding a dose-effect relationship. J Nucl Med 2005;46:99S–106S.PubMedGoogle Scholar
  8. 8.
    Wessels BW, Konijnenberg MW, Dale RG, Breitz HB, Cremonesi M, Meredith RF, et al. MIRD pamphlet No. 20: the effect of model assumptions on kidney dosimetry and response—implications for radionuclide therapy. J Nucl Med 2008;49:1884–99.PubMedCrossRefGoogle Scholar
  9. 9.
    Pauwels S, Barone R, Walrand S, Borson-Chazot F, Valkema R, Kvols LK, et al. Practical dosimetry of peptide receptor radionuclide therapy with (90)Y-labeled somatostatin analogs. J Nucl Med 2005;46:92S–8S.PubMedGoogle Scholar
  10. 10.
    Cremonesi M, Ferrari M, Bodei L, Tosi G, Paganelli G. Dosimetry in peptide radionuclide receptor therapy: a review. J Nucl Med 2006;47:1467–75.PubMedGoogle Scholar
  11. 11.
    Forrer F, Krenning EP, Kooij PP, Bernard BF, Konijnenberg M, Bakker WH, et al. Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA(0), Tyr(3)]octreotate. Eur J Nucl Med Mol Imaging 2009;36:1138–46.PubMedCrossRefGoogle Scholar
  12. 12.
    Hnatowich DJ, Griffin TW, Kosciuczyk C, Rusckowski M, Childs RL, Mattis JA, et al. Pharmacokinetics of an indium-111-labeled monoclonal antibody in cancer patients. J Nucl Med 1985;26:849–58.PubMedGoogle Scholar
  13. 13.
    Cremonesi M, Ferrari M, Chinol M, Stabin MG, Grana C, Prisco G, et al. Three-step radioimmunotherapy with yttrium-90 biotin: dosimetry and pharmacokinetics in cancer patients. Eur J Nucl Med 1999;26:110–20.PubMedCrossRefGoogle Scholar
  14. 14.
    Meares CF, Moi MK, Diril H, Kukis DL, McCall MJ, Deshpande SV, et al. Macrocyclic chelates of radiometals for diagnosis and therapy. Br J Cancer Suppl 1990;10:21–6.PubMedGoogle Scholar
  15. 15.
    Wu C, Virzi F, Hnatowich DJ. Investigations of N-linked macrocycles for 111In and 90Y labeling of proteins. Int J Rad Appl Instrum B 1992;19:239–44.PubMedGoogle Scholar
  16. 16.
    Hnatowich DJ, Virzi F, Doherty PW. DTPA-coupled antibodies labeled with yttrium-90. J Nucl Med 1985;26:503–9.PubMedGoogle Scholar
  17. 17.
    de Klerk JMH, van Dieren EB, van het Schip AD, Hoekstra A, Zonnenberg BA, van Dijk A, et al. Bone marrow absorbed dose of rhenium-186-HEDP and the relationship with decreased platelet counts. J Nucl Med 1996;37:38–41.PubMedGoogle Scholar
  18. 18.
    Turner JH, Claringbold PG. A phase II study of treatment of painful multifocal skeletal metastases with single and repeated dose samarium-153 ethylenediaminetetramethylene phosphonate. Eur J Cancer 1991;27:1084–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Langham WH. Radiobiological factors in manned space flight. Washington DC: National Academy Press; 1967.Google Scholar
  20. 20.
    Hindorf C, Glatting G, Chiesa C, Lindén O, Flux G, EANM Dosimetry Committee, et al. EANM Dosimetry Committee guidelines for bone marrow and whole-body dosimetry. Eur J Nucl Med Mol Imaging 2010;37:1238–50.PubMedCrossRefGoogle Scholar
  21. 21.
    Lassmann M, Chiesa C, Flux G, Bardiès M, EANM Dosimetry Committee, et al. EANM Dosimetry Committee guidance document: good practice of clinical dosimetry reporting. Eur J Nucl Med Mol Imaging 2011;38:192–200. doi:10.1007/s00259-010-1549-3 Google Scholar
  22. 22.
    Walrand S, Jamar F, Mathieu I, De Camps J, Lonneux M, Sibomana M, et al. Quantitation in PET using isotopes emitting prompt single gammas: application to yttrium-86. Eur J Nucl Med Mol Imaging 2003;30:354–61.PubMedCrossRefGoogle Scholar
  23. 23.
    Walrand SH, van Elmbt LR, Pauwels S. A non-negative fast multiplicative algorithm in 3D scatter-compensated SPET reconstruction. Eur J Nucl Med 1996;23:1521–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Cristy M. Active bone marrow distribution as a function of age in humans. Phys Med Biol 1981;26:389–400.PubMedCrossRefGoogle Scholar
  25. 25.
    Stabin MG, Eckerman KF, Bolch WE, Bouchet LG, Patton PW. Evolution and status of bone and marrow dose models. Cancer Biother Radiopharm 2002;17:427–33.PubMedCrossRefGoogle Scholar
  26. 26.
    Shih WJ, Van Wyk C. Tc-99m depreotide SPECT demonstrates photon-deficiency in the thoracic vertebrae after adjunct radiation therapy of lung cancer: correlation with MRI and bone scintigraphy. Ann Nucl Med 2003;17:245–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Barone R, Walrand S, Leveque P, Pauwels S, Jamar F. Red marrow toxicity after therapy with radiolabelled somatostatin analogues: a possible role of plasma protein binding. Eur J Nucl Med 2003;30:S232.CrossRefGoogle Scholar
  28. 28.
    Hauser W, Atkins HL, Nelson KG, Richards P. Technetium-99m DTPA: a new radiopharmaceutical for brain and kidney scanning. Radiology 1970;94:679–84.PubMedGoogle Scholar
  29. 29.
    Moerlein SM, Welch MJ. The chemistry of gallium and indium as related to radiopharmaceutical production. Int J Nucl Med Biol 1981;8:277–87.PubMedCrossRefGoogle Scholar
  30. 30.
    Stern HS, Goodwin DA, Scheffel D, Wagner HN, Kramer HH. In 113m for blood-pool and brain scanning. Nucleonics 1967;25:62–8.Google Scholar
  31. 31.
    Kroll H, Korman S, Siegel E, Hart HE, Rosoff B, Spencer H, et al. Excretion of yttrium and lanthanum chelates of cyclohexane 1,2-trans diamine tetraacetic acid and diethylenetriamine pentaacetic acid in man. Nature 1957;180:919–20.PubMedCrossRefGoogle Scholar
  32. 32.
    Jeffcoat MK, McNeil BJ, Davis MA. Indium and iron as tracers for erythroid precursors. J Nucl Med 1978;19:496–500.PubMedGoogle Scholar
  33. 33.
    Goodwin DA, Sundeberg MW, Diamanti C et al. 111In-labeled radiopharmaceuticals and their clinical use. In: Subramanian G, Rhodes BA, Cooper JF, Sood VJ, editors. Radiopharmaceuticals. New York: The Society of Nuclear Medicine; 1975. p. 80.Google Scholar
  34. 34.
    Welch MJ, Welch TJ. Solution chemistry of carrier-free indium. In: Subramanian G, Rhodes BA, Cooper JF, Sood VJ, editors. Radiopharmaceuticals. New York: The Society of Nuclear Medicine; 1975. p. 73.Google Scholar
  35. 35.
    Breeman WP, van der Wansem K, Bernard BF, van Gameren A, Erion JL, Visser TJ, et al. The addition of DTPA to [(177)Lu-DOTA(0),Tyr(3)]octreotate prior to administration reduces rat skeleton uptake of radioactivity. Eur J Nucl Med Mol Imaging 2003;30:312–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Oomen SP, van Hennik PB, Antonissen C, Lichtenauer-Kaligis EG, Hofland LJ, Lamberts SW, et al. Somatostatin is a selective chemoattractant for primitive (CD34+) hematopoietic progenitor cells. Exp Hematol 2002;30:116–25.PubMedCrossRefGoogle Scholar
  37. 37.
    Skikne BS. Serum transferrin receptor. Am J Hematol 2008;83:872–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Stephan Walrand
    • 1
  • Raffaella Barone
    • 1
  • Stanislas Pauwels
    • 1
  • François Jamar
    • 1
  1. 1.Centre de Médecine nucléaireUniversité Catholique de LouvainBrusselsBelgium

Personalised recommendations