Advertisement

Safety and efficacy of targeted alpha therapy with 213Bi-DOTA-substance P in recurrent glioblastoma

  • Leszek Królicki
  • Frank Bruchertseifer
  • Jolanta KunikowskaEmail author
  • Henryk Koziara
  • Bartosz Królicki
  • Maciej Jakuciński
  • Dariusz Pawlak
  • Christos Apostolidis
  • Saed Mirzadeh
  • Rafał Rola
  • Adrian Merlo
  • Alfred Morgenstern
Original Article

Abstract

Treatment options for recurrent glioblastoma multiforme (GBM) are very limited. GBM cells express high levels of the GPCR neurokinin type 1 receptor (NK-1R), and a modified substance P can be used as its ligand for the tumor cell targeting. Targeted alpha therapy with DOTA-Substance P labeled with the short range alpha emitter 213Bi allows for selective irradiation and killing of tumor cells.

Material and methods

Twenty patients with recurrent GBM were included into the study following a standard therapy. 1–2 intracavitary or intratumoral port-a-cath systems were stereotactically inserted. Patients were treated with 1–7 doses of 213Bi-DOTA-Substance P (213Bi-DOTA-SP) in 2-month intervals. 68Ga-DOTA-Substance P (68Ga-DOTA-SP) was co-injected with 213Bi-DOTA-SP to assess the biodistribution using PET/CT. Therapeutic response was monitored with performance status and MRI imaging.

Results

Treatment with activity up to 11.2 GBq 213Bi-DOTA-SP was well tolerated with only mild and transient adverse reactions. The median progression free survival was 2.7 months. The median overall survival from the first diagnosis was 23.6 months and median survival after recurrence was 10.9 months. The median survival time from the start of 213Bi-DOTA-SP was 7.5 months.

Conclusions

Treatment of recurrent GBM with 213Bi-DOTA-SP is safe and well tolerated. The median overall survival after recurrence of 10.9 months compares favorably to the available alternative treatment options. Once the supply of high activity 225Ac/213Bi radionuclide generators is secured, targeted alpha therapy with 213Bi-DOTA-SP may evolve as a promising novel option to treat recurrent GBM.

Keywords

Glioblastoma multiforme GBM 213Bi-DOTA-SP 68Ga-DOTA-SP Targeted alpha therapy TAT Substance P 

Notes

Acknowledgements

At the EANM Congress in Gothenburg in 2014, this paper was among the 6 selected finalists for the Marie Curie Award.

The authors are indebted for the use of parts of the 225Ac/213Bi to the U.S. Department of Energy’s, Office of Nuclear Physics, Isotope Development and Production for Research and Applications Program.

We thank the Radiochemistry Group in the Department of Nuclear Medicine, the nursing staff and the nuclear medicine technologists of the Medical University of Warsaw for their support.

Compliance with ethical standards

This article does not contain any studies with animals performed by any of the authors.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent was obtained from all individual participants included in the study.

Conflict of interest

All authors declare that they have no conflict of interest in relation to this article.

References

  1. 1.
    Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000;83:588–93.CrossRefGoogle Scholar
  2. 2.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. European Organisation for Research and Treatment of Cancer brain tumor and radiotherapy groups; National Cancer Institute of Canada clinical trials group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;10:987–96.CrossRefGoogle Scholar
  3. 3.
    Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, et al. North American brain tumor consortium. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro-Oncology. 2008;10:162–70.CrossRefGoogle Scholar
  4. 4.
    Tatter SB. Recurrent malignant glioma in adults. Curr Treat Options in Oncol. 2002;3:509–24.CrossRefGoogle Scholar
  5. 5.
    Chang SM, Theodosopoulos P, Lamborn K, Malec M, Rabbitt J, Page M, et al. Temozolomide in the treatment of recurrent malignant glioma. Cancer. 2004;100:605–11.CrossRefGoogle Scholar
  6. 6.
    Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma-are we there yet? Neuro-Oncology. 2013;15:4–27.CrossRefGoogle Scholar
  7. 7.
    Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med. 2000;343:1350–4.CrossRefGoogle Scholar
  8. 8.
    Barbagallo GM, Jenkinson MD, Brodbelt AR. 'Recurrent' glioblastoma multiforme, when should we reoperate? Br J Neurosurg. 2008;22:452–5.CrossRefGoogle Scholar
  9. 9.
    Tully PA, Gogos AJ, Love C, Liew D, Drummond KJ, Morokoff AP. Reoperation for recurrent glioblastoma and its association with survival benefit. Neurosurgery. 2016;79:678–89.CrossRefGoogle Scholar
  10. 10.
    Dhermain F, de Crevoisier R, Parker F, Cioloca C, Kaliski A, Beaudre A, et al. Role of radiotherapy in recurrent gliomas. Bull Cancer. 2004;91:883–9.PubMedGoogle Scholar
  11. 11.
    Wick A, Pascher C, Wick W, Jauch T, Weller M, Bogdahn U, et al. Rechallenge with temozolomide in patients with recurrent gliomas. J Neurol. 2009;256:734–41.CrossRefGoogle Scholar
  12. 12.
    Brandes AA, Tosoni A, Amistà P, Nicolardi L, Grosso D, Berti F, et al. How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial. Neurology. 2004;63:1281–4.CrossRefGoogle Scholar
  13. 13.
    Reithmeier T, Graf E, Piroth T, Trippel M, Pinsker MO, Nikkhah G. BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors. BMC Cancer. 2010;10:30.CrossRefGoogle Scholar
  14. 14.
    Reardon DA, Nabors LB, Mason WP, Perry JR, Shapiro W, Kavan P, et al. Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma. Neuro-Oncology. 2015;17:430–9.PubMedGoogle Scholar
  15. 15.
    Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–40.CrossRefGoogle Scholar
  16. 16.
    Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740–5.CrossRefGoogle Scholar
  17. 17.
    Raizer JJ, Grimm S, Chamberlain MC, Nicholas MK, Chandler JP, Muro K, et al. A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer. 2010;116:5297–305.CrossRefGoogle Scholar
  18. 18.
    Chamberlain MC, Johnston SK. Salvage therapy with single agent bevacizumab for recurrent glioblastoma. J Neuro-Oncol. 2010;96:259–69.CrossRefGoogle Scholar
  19. 19.
    Riva P, Arista A, Franceschi G, Frattarelli M, Sturiale C, Riva N, et al. Local treatment of malignant gliomas by direct infusion of specific monoclonal antibodies labeled with 131I: comparison of the results obtained in recurrent and newly diagnosed tumors. Cancer Res. 1995;55:5952s–6s.PubMedGoogle Scholar
  20. 20.
    Merlo A, Hausmann O, Wasner M, Steiner P, Otte A, Jermann E. 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;5:1025–33.PubMedGoogle Scholar
  21. 21.
    Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The polymer-brain tumor treatment group. Lancet. 1995;345:1008–12.CrossRefGoogle Scholar
  22. 22.
    Buonerba C, Di Lorenzo G, Marinelli A, Federico P, Palmieri G, Imbimbo M, et al. Comprehensive outlook on intracerebral therapy of malignant gliomas. Crit Rev Oncol Hematol. 2011;80:54–68.CrossRefGoogle Scholar
  23. 23.
    Bigner DD, Brown MT, Friedman AH, Coleman RE, Akabani G, Friedman HS, et al. Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results. J Clin Oncol. 1998;16:2202–12.CrossRefGoogle Scholar
  24. 24.
    Zalutsky MR. Targeted radiotherapy of brain tumours. Br J Cancer. 2004;90:1469–73.CrossRefGoogle Scholar
  25. 25.
    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;29:486–93.CrossRefGoogle Scholar
  26. 26.
    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;12:3843–50.CrossRefGoogle Scholar
  27. 27.
    Cordier D, Forrer F, Bruchertseifer F, Morgenstern A, Apostolidis C, Good S, et al. Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8,Met(O2)11]-substance P: a pilot trial. Eur J Nucl Med Mol Imaging. 2010;37:1335–44.CrossRefGoogle Scholar
  28. 28.
    Hennig IM, Laissue JA, Horisberger U, Reubi JC. Substance-P receptors in human primary neoplasms: tumoral and vascular localization. Int J Cancer. 1995;61:786–92.CrossRefGoogle Scholar
  29. 29.
    Kratochwil C, Giesel FL, Bruchertseifer F, Mier W, Apostolidis C, Boll R, et al. 213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience. Eur J Nucl Med Mol Imaging. 2014;41:2106–19.CrossRefGoogle Scholar
  30. 30.
    Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, et al. 225Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med. 2016;57:1941–4.CrossRefGoogle Scholar
  31. 31.
    Kratochwil C, Bruchertseifer F, Rathke H, Bronzel M, Apostolidis C, Weichert W, et al. Targeted α-therapy of metastatic castration-resistant prostate cancer with 225Ac-PSMA-617: dosimetry estimate and empiric dose finding. J Nucl Med. 2017;58:1624–31.CrossRefGoogle Scholar
  32. 32.
    Kratochwil C, Bruchertseifer F, Rathke H, Hohenfellner M, Giesel FL, Haberkorn U, et al. Targeted α-therapy of metastatic castration-resistant prostate cancer with 225Ac-PSMA-617: swimmer-plot analysis suggests efficacy regarding duration of tumor control. J Nucl Med. 2018;59:795–802.CrossRefGoogle Scholar
  33. 33.
    Krolicki L, Bruchertseifer F, Kunikowska J, Koziara H, Królicki B, Jakuciński M, et al. Prolonged survival in secondary glioblastoma following local injection of targeted alpha therapy with 213Bi-substance P analogue. Eur J Nucl Med Mol Imaging. 2018;45:1636–44.CrossRefGoogle Scholar
  34. 34.
    Johnson DR, O'Neill BP. Glioblastoma survival in the United States before and during the temozolomide era. J Neuro-Oncol. 2012;107:359–64.CrossRefGoogle Scholar
  35. 35.
    Lacroix M, Abi-Said D, Fourney DR, Gokaslan 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;95:190–8.CrossRefGoogle Scholar
  36. 36.
    Central Brain Tumor Registry of the United States. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2004–2007. www.cbtrus.org. Accessed 28 June 2012.
  37. 37.
    De Bonis P, Fiorentino A, Anile C, Balducci M, Pompucci A, Chiesa S, et al. The impact of repeated surgery and adjuvant therapy on survival for patients with recurrent glioblastoma. Clin Neurol Neurosurg. 2013;115:883–6.CrossRefGoogle Scholar
  38. 38.
    Perry JR, Bélanger K, Mason WP. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010;2028:2051.CrossRefGoogle Scholar
  39. 39.
    Apostolidis C, Molinet R, Rasmussen G, Morgenstern A. Production of Ac-225 from Th-229 for targeted alpha therapy. Anal Chem. 2005;77:6288–91.CrossRefGoogle Scholar
  40. 40.
    Griswold JR, Medvedev DG, Engle JW, Copping R, Fitzsimmons JM, Radchenko V, et al. Large scale accelerator production of 225Ac: effective cross sections for 78-192MeV protons incident on 232Th targets. Appl Radiat Isot. 2016;118:366–74.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Leszek Królicki
    • 1
  • Frank Bruchertseifer
    • 2
  • Jolanta Kunikowska
    • 1
    Email author
  • Henryk Koziara
    • 3
  • Bartosz Królicki
    • 3
  • Maciej Jakuciński
    • 4
  • Dariusz Pawlak
    • 5
  • Christos Apostolidis
    • 2
  • Saed Mirzadeh
    • 6
  • Rafał Rola
    • 7
  • Adrian Merlo
    • 8
  • Alfred Morgenstern
    • 2
  1. 1.Nuclear Medicine DepartmentMedical University of WarsawWarsawPoland
  2. 2.European Commission, Joint Research Centre, Directorate for Nuclear Safety and SecurityKarlsruheGermany
  3. 3.Department of NeurosurgeryInstitute of Psychiatry and NeurologyWarsawPoland
  4. 4.Department of Nuclear MedicineBrodnowski HospitalWarsawPoland
  5. 5.Radioisotope Centre POLATOMNational Centre for Nuclear ResearchOtwockPoland
  6. 6.Nuclear and Radiochemistry Group, Nuclear Security and Isotope Technology DivisionOak Ridge National LaboratoryOak RidgeUSA
  7. 7.Department of NeurologyMilitary Institute of Aviation MedicineWarsawPoland
  8. 8.NeurosurgeryBern and University of BaselBaselSwitzerland

Personalised recommendations