Radiation risks from high-let alpha particle emitters using radium-223 as a model

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University London[223Ra]RaCl2 was recently approved for the treatment of bone metastatic disease in prostate cancer patients. Once intravenously administered 223Ra localises to areas of increased calcium turnover. During its decay, 223Ra will emit high linear energy transfer (LET) α-particles that are effective in targeting metastatic sites. α-particles have a range of ≤ 100 μm suggesting normal tissue sparing; however, there is uncertainty regarding the heterogeneous distribution of dose at the cellular/tissue levels. It remains unclear if 223Ra may also result in unwanted exposure of neighbouring bone marrow (BM) cells. To date, the potential risk of BM exposure as a consequence of this treatment remains unquantified. The aim of this project was to resolve these uncertainties by assessing changes in the genomic structure of peripheral blood lymphocyte (PBLs) potentially in contact with 223Ra. To do so, blood samples from patients enrolled on to the ADRRAD clinical trial were collected. The treatment included 6 intravenous injections of [223Ra]RaCl2 each administered 4 weeks apart (55 kbq/kg) and 2 Gy fractionated IMRT (daily for 5 days a week over 7.5 weeks). Blood samples were collected prior to each 223Ra administration and PBL cultured to 1st in vitro division. The PBLs were assayed by Multiplex-fluorescent-in-situ-hybridization (M-FISH) and Giemsa solid stain for cytogenetic analysis. In this study we demonstrated that chromosomal aberration complexity reflects the treatment regime. This indicates PBLs were exposed to α-particle by 223Ra. The change in chromosomal spectrum was used to create a novel method for absorbed blood dose estimation and this was compared to existing physical models. The persistence and transmissibility of aberrations was evaluated with chromatid aberrations consistent with delayed effects observed in follow up samples. A lower administered activity of 223Ra was suggested to be as effective as larger administer activities, this indicates that the dosing strategy may need re-evaluating