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Dosimetry of bone metastases in targeted radionuclide therapy with alpha-emitting 223Ra-dichloride

  • Massimiliano Pacilio
  • Guido Ventroni
  • Giuseppe De Vincentis
  • Bartolomeo Cassano
  • Rosanna Pellegrini
  • Elisabetta Di Castro
  • Viviana Frantellizzi
  • Giulia Anna Follacchio
  • Tatiana Garkavaya
  • Leda Lorenzon
  • Pasquale Ialongo
  • Roberto Pani
  • Lucio Mango
Original Article

Abstract

Purpose

Ra-dichloride is an alpha-emitting radiopharmaceutical used in the treatment of bone metastases from castration-resistant prostate cancer. Image-based dosimetric studies remain challenging because the emitted photons are few. The aim of this study was to implement a methodology for in-vivo quantitative planar imaging, and to assess the absorbed dose to lesions using the MIRD approach.

Methods

The study included nine Caucasian patients with 24 lesions (6 humeral head lesions, 4 iliac wing lesions, 2 scapular lesions, 5 trochanter lesions, 3 vertebral lesions, 3 glenoid lesions, 1 coxofemoral lesion). The treatment consisted of six injections (one every 4 weeks) of 50 kBq per kg body weight. Gamma-camera calibrations for 223Ra included measurements of sensitivity and transmission curves. Patients were statically imaged for 30 min, using an MEGP collimator, double-peak acquisition, and filtering to improve the image quality. Lesions were delineated on 99mTc-MDP whole-body images, and the ROIs superimposed on the 223Ra images after image coregistration. The activity was quantified with background, attenuation, and scatter correction. Absorbed doses were assessed deriving the S values from the S factors for soft-tissue spheres of OLINDA/EXM, evaluating the lesion volumes by delineation on the CT images.

Results

In 12 lesions with a wash-in phase the biokinetics were assumed to be biexponential, and to be monoexponential in the remainder. The optimal timing for serial acquisitions was between 1 and 5 h, between 18 and 24 h, between 48 and 60 h, and between 7 and 15 days. The error in cumulated activity neglecting the wash-in phase was between 2 % and 12 %. The mean effective half-life (T 1/2eff) of 223Ra was 8.2 days (range 5.5–11.4 days). The absorbed dose (D) after the first injection was 0.7 Gy (range 0.2–1.9 Gy. Considering the relative biological effectiveness (RBE) of alpha particles (RBE = 5), D RBE = 899 mGy/MBq (range 340–2,450 mGy/MBq). The percent uptake of 99mTc and 223Ra (activity extrapolated to t = 0) were significantly correlated.

Conclusion

The feasibility of in vivo quantitative imaging in 223Ra therapy was confirmed. The lesion uptake of 223Ra-dichloride was significantly correlated with that of 99mTc-MDP. The D RBE to lesions per unit administered activity was much higher than that of other bone-seeking radiopharmaceuticals, but considering a standard administration of 21 MBq (six injections of 50 kBq/kg to a 70-kg patient), the mean cumulative value of D RBE was about 19 Gy, and was therefore in the range of those of other radiopharmaceuticals. The macrodosimetry of bone metastases in treatments with 223Ra-dichloride is feasible, but more work is needed to demonstrate its helpfulness in predicting clinical outcomes.

Keywords

Bone metastases 223Ra-dichloride Radionuclide therapy Dosimetry 

Notes

Acknowledgments

All patients enrolled in this research were participating to a multicentre study (protocol 88-8223/16216) sponsored by Bayer HealthCare Pharmaceuticals, entitled “Radium-223 chloride in treatment of CRPC/HRPC patients with bone metastasis”.

Compliance with ethical standards

Conflicts of interest

None.

Ethical approval

The authors declare that this study complied with the current laws of the country (Italy) where it was performed, and that the clinical ethics committee at each participating centre approved the study.

References

  1. 1.
    Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12:6243s–9s.CrossRefPubMedGoogle Scholar
  2. 2.
    Sgouros G, Roeske JC, McDevitt MR, Palm S, Allen BJ, Fisher DR, et al. MIRD pamphlet no. 22 (abridged): radiobiology and dosimetry of α-particle emitters for targeted radionuclide therapy. J Nucl Med. 2010;51:311–28.CrossRefPubMedGoogle Scholar
  3. 3.
    Hobbs RF, Song H, Watchman CJ, Bolch WE, Aksnes AK, Ramdahl T, et al. A bone marrow toxicity model for Ra-223 α-emitter radiopharmaceutical therapy. Phys Med Biol. 2012;57:3207–22.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    CTEP. Common terminology criteria for adverse events (CTCAE) v4.0. Bethesda, MD: Cancer Therapy Evaluation Program, National Cancer Institute; 2015. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed 1 Aug 2015.
  5. 5.
    Nilsson S, Larsen RH, Fossa SD, Balteskard L, Borch KW, Westlin JE, et al. First clinical experience with α-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. 2005;11:4451–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Nilsson S, Franzen L, Parker C, Tyrrell C, Blom R, Tennvall J, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8:587–94.CrossRefPubMedGoogle Scholar
  7. 7.
    Parker CC, Pascoe S, Chodacki A, O'Sullivan JM, Germá JR, O'Bryan-Tear CG, et al. A randomized, double-blind, dose-finding, multicenter, phase 2 study of radium chloride (Ra 223) in patients with bone metastases and castration-resistant prostate cancer. Eur Urol. 2013;63:189–97.CrossRefPubMedGoogle Scholar
  8. 8.
    Pandit-Taskar N, Larson SM, Carrasquillo JA. Bone-seeking radiopharmaceuticals for treatment of osseous metastases, Part 1: α therapy with 223Ra-Dichloride. J Nucl Med. 2014;55:268–74.CrossRefPubMedGoogle Scholar
  9. 9.
    Nilsson S, Strang P, Aksnes AK, Franzèn L, Olivier P, Pecking A, et al. A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. Eur J Cancer. 2012;48:678–86.CrossRefPubMedGoogle Scholar
  10. 10.
    Larsen RH, Saxtorph H, Skydsgaard M, Borrebaek J, Jonasdottir TJ, Bruland OS, et al. Radiotoxicity of the α-emitting bone-seeker Ra-223 injected intravenously into mice: histology, clinical chemistry and hematology. In Vivo. 2006;20:325–31.PubMedGoogle Scholar
  11. 11.
    Jadvar H, Quinn DI. Targeted α-particle therapy of bone metastases in prostate cancer. Clin Nucl Med. 2013;38:966–71.PubMedGoogle Scholar
  12. 12.
    Henriksen G, Breistol K, Bruland OS, Fodstad O, Larsen RH. Significant antitumor effect from bone-seeking, α-particle-emitting Ra-223 demonstrated in an experimental skeletal metastases model. Cancer Res. 2002;62:3120–5.PubMedGoogle Scholar
  13. 13.
    Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–23.CrossRefPubMedGoogle Scholar
  14. 14.
    Lassmann M, Nosske D. Dosimetry of 223Ra-chloride: dose to normal organs and tissues. Eur J Nucl Med Mol Imaging. 2013;40:207–12.CrossRefPubMedGoogle Scholar
  15. 15.
    Carrasquillo JA, O’Donoghue JA, Pandit-Taskar N, Humm JL, Rathkopf DE, Slovin SF, et al. Phase I pharmacokinetic and biodistribution study with escalating doses of Ra-dichloride in men with castration-resistant metastatic prostate cancer. Eur J Nucl Med Mol Imaging. 2013;40:1384–93.CrossRefPubMedGoogle Scholar
  16. 16.
    Hindorf C, Chittenden S, Aksnes AK, Parker C, Flux GD. Quantitative imaging of 223Ra-chloride (Alpharadin) for targeted alpha-emitting radionuclide therapy of bone metastases. Nucl Med Commun. 2012;33:726–32.CrossRefPubMedGoogle Scholar
  17. 17.
    Loevinger R, Berman M. A revised schema for calculating the absorbed dose from biologically distributed radionuclides. MIRD Pamphlet no. 1. New York: Society of Nuclear Medicine; 1975.Google Scholar
  18. 18.
    Siegel JA, Thomas SR, Stubbs JB. MIRD Pamphlet No. 16: Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med. 1999;40:37s–61s.PubMedGoogle Scholar
  19. 19.
    Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55.CrossRefPubMedGoogle Scholar
  20. 20.
    Khan FM, The physics of radiation therapy. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.Google Scholar
  21. 21.
    Buijs WC, Siegel JA, Boerman OC, Corstens FH. Absolute organ activity estimated by five different methods of background correction. J Nucl Med. 1998;39:2167–72.PubMedGoogle Scholar
  22. 22.
    Ljungberg M, Strand SE. A Monte Carlo program for the simulation of scintillation camera characteristics. Comput Methods Programs Biomed. 1989;29:257–72.CrossRefPubMedGoogle Scholar
  23. 23.
    Hindorf C, Flux GD, Ibisch C, Bodéré Kraeber F. Clinical dosimetry in the treatment of bone tumours: old and new agents. Q J Nucl Med Mol Imaging. 2011;55:198–204.PubMedGoogle Scholar
  24. 24.
    Blake GM, Zivanovic MA, Blaquiere RM, Fine DR, McEwan AJ, Ackery DM. Strontium-89 therapy: measurement of absorbed dose to skeletal metastases. J Nucl Med. 1988;29:549–57.PubMedGoogle Scholar
  25. 25.
    Cristy M, Eckerman KF. Specific absorbed fractions of energy at various ages from internal photon sources. Technical Report ORNL/TM-8381/V1. Oak Ridge, TN: Oak Ridge National Laboratory; 1987.Google Scholar
  26. 26.
    Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 2005;46:1023–7.PubMedGoogle Scholar
  27. 27.
    Pacilio M, Ventroni G, Basile C, Ialongo P, Becci D, Mango L. Improving the dose-myelotoxicity correlation in radiometabolic therapy of bone metastases with 153Sm-EDTMP. Eur J Nucl Med Mol Imaging. 2014;41:238–52.CrossRefPubMedGoogle Scholar
  28. 28.
    Strigari L, Sciuto R, D’Andrea M, Pasqualoni R, Benassi M, Maini CL. Radiopharmaceutical therapy of bone metastases with 89SrCl2, 186Re-HEDP and 153Sm-EDTMP: a dosimetric study using Monte Carlo simulation. Eur J Nucl Med Mol Imaging. 2007;34:1031–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Liepe K, Kotzerke J. A comparative study of 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr in the treatment of painful skeletal metastases. Nucl Med Commun. 2007;28:623–30.CrossRefPubMedGoogle Scholar
  30. 30.
    Breen SL, Powe JE, Porter AT. Dose estimation in strontium-89 radiotherapy of metastatic prostatic carcinoma. J Nucl Med. 1992;33:1316–23.PubMedGoogle Scholar
  31. 31.
    van Rensburg AJ, Alberts AS, Louw WKA. Quantifying the radiation dosage to individual skeletal lesions treated with samarium-153-EDTMP. J Nucl Med. 1998;39:2110–5.PubMedGoogle Scholar
  32. 32.
    Maxon HR, Schroder LE, Thomas SR, Hertzberg VS, Deutsch EA, Scher HI, et al. Re-186(Sn) HEDP for treatment of painful osseous metastases: initial clinical experience in 20 patients with hormone-resistant prostate cancer. Radiology. 1990;176:155–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Maxon HR, Schroder LE, Hertzberg VS, Thomas SR, Englaro EE, Samaratunga R, et al. Rhenium-186(Sn)HEDP for treatment of painful osseous metastases: results of a double-blind crossover comparison with placebo. J Nucl Med. 1991;32:1877–81.PubMedGoogle Scholar
  34. 34.
    Liepe K, Hliscs R, Kropp J, Runge R, Knapp Jr FF, Franke WG. Dosimetry of 188Re-hydroxyethylidene diphosphonate in human prostate cancer skeletal metastases. J Nucl Med. 2003;44:953–60.PubMedGoogle Scholar
  35. 35.
    Silberstein EB, Williams C. Strontium-89 therapy for the pain of osseous metastases. J Nucl Med. 1985;26:345–8.PubMedGoogle Scholar
  36. 36.
    Silberstein EB. Systemic radiopharmaceutical therapy of painful osteoblastic metastases. Semin Radiat Oncol. 2000;10:240–9.CrossRefPubMedGoogle Scholar
  37. 37.
    McEwan AJ. Use of radionuclides for the palliation of bone metastases. Semin Radiat Oncol. 2000;10:103–14.CrossRefPubMedGoogle Scholar
  38. 38.
    Li WB, Höllriegl V, Roth P, Oeh U. Influence of human biokinetics of strontium on internal ingestion dose of 90Sr and absorbed dose of 89Sr to organs and metastases. Radiat Environ Biophys. 2008;47:225–39.CrossRefPubMedGoogle Scholar
  39. 39.
    Lewington VJ. Bone-seeking radionuclides for therapy. J Nucl Med. 2005;46:38S–47S.PubMedGoogle Scholar
  40. 40.
    Dant JT, Richardson RB, Nie LH. Monte Carlo simulation of age-dependent radiation dose from alpha- and beta-emitting radionuclides to critical trabecular bone and bone marrow targets. Phys Med Biol. 2013;58:3301–19.CrossRefPubMedGoogle Scholar
  41. 41.
    Bruland ØS, Nilsson S, Fisher DR, Larsen RH. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res. 2006;12:6250s–7s.CrossRefPubMedGoogle Scholar
  42. 42.
    Chouin N, Bardies M. Alpha-particle microdosimetry. Curr Radiopharm. 2011;4:266–80.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Massimiliano Pacilio
    • 1
  • Guido Ventroni
    • 2
  • Giuseppe De Vincentis
    • 3
  • Bartolomeo Cassano
    • 4
  • Rosanna Pellegrini
    • 5
  • Elisabetta Di Castro
    • 3
  • Viviana Frantellizzi
    • 3
  • Giulia Anna Follacchio
    • 3
  • Tatiana Garkavaya
    • 3
  • Leda Lorenzon
    • 4
  • Pasquale Ialongo
    • 6
  • Roberto Pani
    • 5
  • Lucio Mango
    • 2
  1. 1.Department of Medical PhysicsAzienda Ospedaliera San Camillo ForlaniniRomeItaly
  2. 2.Department of Nuclear MedicineAzienda Ospedaliera San Camillo ForlaniniRomeItaly
  3. 3.Department of Radiological, Oncological and Anatomo Pathological Sciences“Sapienza” University of RomeRomeItaly
  4. 4.Postgraduate School of Medical Physics“Sapienza” University of RomeRomeItaly
  5. 5.Department of Molecular Medicine“Sapienza” University of RomeRomeItaly
  6. 6.Department of RadiologyAzienda Ospedaliera San Camillo ForlaniniRomeItaly

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