Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8,Met(O2)11]-substance P: a pilot trial

  • D. Cordier
  • F. Forrer
  • F. Bruchertseifer
  • A. Morgenstern
  • C. Apostolidis
  • S. Good
  • J. Müller-Brand
  • H. Mäcke
  • J. C. Reubi
  • A. Merlo
Original Article



Functionally critically located gliomas represent a challenging subgroup of intrinsic brain neoplasms. Standard therapeutic recommendations often cannot be applied, because radical treatment and preservation of neurological function are contrary goals. The successful targeting of gliomas with locally injected beta radiation-emitting 90Y-DOTAGA-substance P has been shown previously. However, in critically located tumours, the mean tissue range of 5 mm of 90Y may seriously damage adjacent brain areas. In contrast, the alpha radiation-emitting radionuclide 213Bi with a mean tissue range of 81 µm may have a more favourable toxicity profile. Therefore, we evaluated locally injected 213Bi-DOTA-substance P in patients with critically located gliomas as the primary therapeutic modality.


In a pilot study, we included five patients with critically located gliomas (WHO grades II–IV). After diagnosis by biopsy, 213Bi-DOTA-substance P was locally injected, followed by serial SPECT/CT and MR imaging and blood sampling. Besides feasibility and toxicity, the functional outcome was evaluated.


Targeted radiopeptide therapy using 213Bi-DOTA-substance P was feasible and tolerated without additional neurological deficit. No local or systemic toxicity was observed. 213Bi-DOTA-substance P showed high retention at the target site. MR imaging was suggestive of radiation-induced necrosis and demarcation of the tumours, which was validated by subsequent resection.


This study provides proof of concept that targeted local radiotherapy using 213Bi-DOTA-substance P is feasible and may represent an innovative and effective treatment for critically located gliomas. Primarily non-operable gliomas may become resectable with this treatment, thereby possibly improving the prognosis.


Glioma Substance P Targeted therapy 213Bi 



This work was supported by the European Commission FP7, contract TARCC No.HEALTH-F2-2007-201962.


  1. 1.
    Lacroix M, Abi-Said D, Fourney DR, Gikaslan ZL, Shi W, DeMonte F, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 2001;95(2):190–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987–96.CrossRefPubMedGoogle Scholar
  3. 3.
    Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC, et al. Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 2008;62(3):564–76. discussion 564–576.CrossRefPubMedGoogle Scholar
  4. 4.
    Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery 2008;62(4):753–64. discussion 264–756.CrossRefPubMedGoogle Scholar
  5. 5.
    Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 2006;7(5):392–401.CrossRefPubMedGoogle Scholar
  6. 6.
    Fahlbusch R, Nimsky C. Intraoperative MRI developments. Neurosurg Clin N Am 2005;16(1):xi–xiii.CrossRefPubMedGoogle Scholar
  7. 7.
    Nimsky C, Ganslandt O, Fahlbusch R. Functional neuronavigation and intraoperative MRI. Adv Tech Stand Neurosurg 2004;29:229–63.PubMedGoogle Scholar
  8. 8.
    Kaloshi G, Benouaich-Amiel A, Diakite F, Tallibert S, Lejeune J, Laigle-Donadey F, et al. Temozolomide for low-grade gliomas: predictive impact of 1p/19q loss on response and outcome. Neurology 2007;68(21):1831–6.CrossRefPubMedGoogle Scholar
  9. 9.
    van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 2005;366(9490):985–90.CrossRefPubMedGoogle Scholar
  10. 10.
    Pignatti F, van den Bent M, Curran D, Debruyne C, Sylvester R, Therasse P, et al. Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 2002;20(8):2076–84.CrossRefPubMedGoogle Scholar
  11. 11.
    Stieber VW. Low-grade gliomas. Curr Treat Options Oncol 2001;2(6):495–506.CrossRefPubMedGoogle Scholar
  12. 12.
    Hoang-Xuan K, Capelle L, Kujas M, Tallibert S, Duffau H, Lejeune J, et al. Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions. J Clin Oncol 2004;22(15):3133–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology 1980;30(9):907–11.PubMedGoogle Scholar
  14. 14.
    Hennig IM, Laissue JA, Horisberger U, Reubi JC. Substance-P receptors in human primary neoplasms: tumoral and vascular localization. Int J Cancer 1995;61(6):786–92.CrossRefPubMedGoogle Scholar
  15. 15.
    Kneifel S, Cordier D, Good S, Ionescu MC, Ghaffari A, Hofer S, et al. Local targeting of malignant gliomas by the diffusible peptidic vector 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-substance p. Clin Cancer Res 2006;12(12):3843–50.CrossRefPubMedGoogle Scholar
  16. 16.
    Boyd M, Ross SC, Dorrens J, Fullerton NE, Tan KW, Zalutsky MR, et al. Radiation-induced biologic bystander effect elicited in vitro by targeted radiopharmaceuticals labeled with alpha-, beta-, and auger electron-emitting radionuclides. J Nucl Med 2006;47(6):1007–15.PubMedGoogle Scholar
  17. 17.
    Raja C, Graham P, Abbas Rizvi SM, Song E, Goldsmith H, Thompson J, et al. Interim analysis of toxicity and response in phase 1 trial of systemic targeted alpha therapy for metastatic melanoma. Cancer Biol Ther 2007;6(6):846–52.CrossRefPubMedGoogle Scholar
  18. 18.
    Allen BJ, Raja C, Rizvi S, Tsui W, Graham P, Thompson JF, et al. Intralesional targeted alpha therapy for metastatic melanoma. Cancer Biol Ther 2005;4(12):1318–24.PubMedCrossRefGoogle Scholar
  19. 19.
    Jurcic JG, Larson SM, Sgouros G, McDevitt MR, Finn RD, Divgi CR, et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood 2002;100(4):1233–9.PubMedGoogle Scholar
  20. 20.
    Apostolidis C, Molinet R, Rasmussen G, Morgenstern A. Production of Ac-225 from Th-229 for targeted alpha therapy. Anal Chem 2005;77(19):6288–91.CrossRefPubMedGoogle Scholar
  21. 21.
    Apostolidis C, Molinet R, McGinley J, Abbas K, Mollenbeck J, Morgenstern A. Cyclotron production of Ac-225 for targeted alpha therapy. Appl Radiat Isot 2005;62(3):383–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Sangha H, Lipson D, Foley N, Salter K, Bhogal S, Pohani G, et al. A comparison of the Barthel Index and the Functional Independence Measure as outcome measures in stroke rehabilitation: patterns of disability scale usage in clinical trials. Int J Rehabil Res 2005;28(2):135–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Zielinska B, Apostolidis C, Bruchertseifer F, Morgenstern A. An improved method for the production of Ac-225/Bi-213 from Th-229 for targeted alpha therapy. Solv Extr Ion Exch 2007;25(3):339–49.CrossRefGoogle Scholar
  24. 24.
    Bruchertseifer FGS, Apostolidis C, Mäcke H, Morgenstern A. An improved method for Bi-213 labelling of DOTA-/DOTAGA-chelated peptides. Eur J Nucl Med Mol Imaging 2006;33(S2):S161.Google Scholar
  25. 25.
    Merlo A, Hausmann O, Wasner M, Steiner P, Otte A, Jermann E, et al. Locoregional regulatory peptide receptor targeting with the diffusible somatostatin analogue 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC): a pilot study in human gliomas. Clin Cancer Res 1999;5(5):1025–33.PubMedGoogle Scholar
  26. 26.
    Merlo A, Jermann E, Hausmann O, Chiquet-Ehrismann R, Probst A, Landolt H, et al. Biodistribution of 111In-labelled SCN-bz-DTPA-BC-2 MAb following loco-regional injection into glioblastomas. Int J Cancer 1997;71(5):810–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Schumacher T, Hofer S, Eichhorn K, Wasner M, Zimmerer S, Freitag P, et al. Local injection of the 90Y-labelled peptidic vector DOTATOC to control gliomas of WHO grades II and III: an extended pilot study. Eur J Nucl Med Mol Imaging 2002;29(4):486–93.CrossRefPubMedGoogle Scholar
  28. 28.
    Nimsky C, von Keller B, Schlaffer S, Kuhnt D, Weigel D, Ganslandt O, et al. Updating navigation with intraoperative image data. Top Magn Reson Imaging 2009;19(4):197–204.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • D. Cordier
    • 1
  • F. Forrer
    • 2
  • F. Bruchertseifer
    • 3
  • A. Morgenstern
    • 3
  • C. Apostolidis
    • 3
  • S. Good
    • 2
  • J. Müller-Brand
    • 2
  • H. Mäcke
    • 2
    • 4
  • J. C. Reubi
    • 5
  • A. Merlo
    • 1
  1. 1.Division of NeurosurgeryUniversity HospitalsBaselSwitzerland
  2. 2.Institute of Nuclear MedicineUniversity HospitalsBaselSwitzerland
  3. 3.European Commission, Joint Research CentreInstitute for Transuranium ElementsKarlsruheGermany
  4. 4.Nuclear Medicine and Radiological ChemistryUniversity Hospital BaselBaselSwitzerland
  5. 5.Institute of PathologyUniversity of BerneBerneSwitzerland

Personalised recommendations