Alpha-Particle Emitter Dosimetry MIRD Pamphlet No. 22 - Radiobiology and Dosimetry of Alpha- Particle Emitters for Targeted Radionuclide Therapy George Sgouros1, John C. Roeske2, Michael R. McDevitt3, Stig Palm4, Barry J. Allen5, Darrell R. Fisher6, A. Bertrand Brill7, Hong Song1, Roger W. Howell8, Gamal Akabani9 1Radiology and Radiological Science, Johns Hopkins University, Baltimore MD 2Radiation Oncology, Loyola University Medical Center, Maywood IL 3Medicine and Radiology, Memorial Sloan-Kettering Cancer Center, New York NY 4International Atomic Energy Agency, Vienna, Austria 5Centre for Experimental Radiation Oncology, St. George Cancer Centre, Kagarah, Australia 6Radioisotopes Program, Pacific Northwest National Laboratory, Richland WA 7Department of Radiology, Vanderbilt University, Nashville TN 8Division of Radiation Research, Department of Radiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark NJ 9Food and Drug Administration, Rockville MD In collaboration with the SNM MIRD Committee: Wesley E. Bolch, A Bertrand Brill, Darrell R. Fisher, Roger W. Howell, Ruby F. Meredith, George Sgouros (Chairman), Barry W. Wessels, Pat B. Zanzonico Correspondence and reprint requests to: George Sgouros, Ph.D. Department of Radiology and Radiological Science CRB II 4M61 / 1550 Orleans St Johns Hopkins University, School of Medicine Baltimore MD 21231 410 614 0116 (voice); 413 487-3753 (FAX) [email protected] (e-mail) - 1 - Alpha-Particle Emitter Dosimetry INDEX A B S T R A C T.......................................................................................................................... 4 A. Introduction................................................................................................................................ 4 B. Historical Review....................................................................................................................... 5 C. Alpha-Particle Radiobiology...................................................................................................... 6 Introduction................................................................................................................................. 6 Traversals required for cell kill................................................................................................... 7 Cell survival curve ...................................................................................................................... 8 Double strand break (DSB) yield and repair............................................................................... 9 Oxygen effect............................................................................................................................ 10 Dose-rate................................................................................................................................... 11 Oncogenesis .............................................................................................................................. 11 Bystander effect ........................................................................................................................ 12 Bystander effect, in vivo ........................................................................................................... 13 Fractionation ............................................................................................................................. 14 Radiomodulation....................................................................................................................... 14 D. Relative Biological Effectiveness (RBE)................................................................................. 15 Introduction............................................................................................................................... 15 RBE defined.............................................................................................................................. 15 RBE vs LET.............................................................................................................................. 16 RBE, in vivo.............................................................................................................................. 17 RBE, Q, and wR......................................................................................................................... 19 E. Alpha-Particle Dosimetry......................................................................................................... 19 Introduction............................................................................................................................... 19 Case for microdosimetry........................................................................................................... 20 Microdosimetric techniques...................................................................................................... 20 Criterion for adopting microdosimetry ..................................................................................... 21 Microdosimetry implementation techniques............................................................................. 21 Applications of microdosimetry ............................................................................................... 21 Application to cellular clusters ................................................................................................. 23 Application to the bone marrow ............................................................................................... 23 F. Alpha-Particle Emitters of Interest for Human Use ................................................................. 24 Astatine-211 (211At) .................................................................................................................. 24 Radionuclide properties ........................................................................................................ 24 Pre-clinical studies................................................................................................................ 25 Clinical studies...................................................................................................................... 30 Bismuth-212 (212Bi) .................................................................................................................. 31 Radionuclide properties ........................................................................................................ 31 Pre-clinical studies................................................................................................................ 31 Bismuth-213 (213Bi) .................................................................................................................. 33 Radionuclide properties ........................................................................................................ 33 Pre-clinical studies................................................................................................................ 34 Clinical studies...................................................................................................................... 37 Actimium-225 (225Ac)............................................................................................................... 37 Radionuclide properties ........................................................................................................ 37 - 2 - Alpha-Particle Emitter Dosimetry Pre-clinical studies................................................................................................................ 38 Clinical studies...................................................................................................................... 42 Radium-223 (223Ra) .................................................................................................................. 42 Radionuclide properties ........................................................................................................ 42 Pre-clinical studies................................................................................................................ 43 Clinical studies...................................................................................................................... 44 Terbium-149 (149Tb) ................................................................................................................. 45 Radionuclide properties ........................................................................................................ 45 Pre-clinical studies................................................................................................................ 46 Thorium-227 (227Th) ................................................................................................................. 47 Radionuclide properties ........................................................................................................ 47 Pre-clinical studies................................................................................................................ 47 G. Recommendations for Dosimetry of Deterministic Effects..................................................... 49 Introduction............................................................................................................................... 49 Recommendations..................................................................................................................... 50 Efficacy Modeling ...................................................................................................................