Dose estimation after a mixed field exposure: Radium-223 and intensity modulated radiotherapy

Radium-223 dichloride ([²²³Ra]RaCl₂), a radiopharmaceutical that delivers α-particles to regions of bone metastatic disease, has been proven to improve overall survival of men with metastatic castration resistant prostate cancer (mCRPC). mCRPC patients enrolled on the ADRRAD clinical trial are treated with a mixed field exposure comprising radium-223 (²²³Ra) and intensity modulated radiotherapy (IMRT). While absorbed dose estimation is an important step in the characterisation of wider systemic radiation risks in nuclear medicine, uncertainties remain for novel radiopharmaceuticals such as ²²³Ra.

24-Colour karyotyping was used to quantify the spectrum of chromosome aberrations in peripheral blood lymphocytes of ADRRAD patients at incremental times during their treatment. Dicentric equivalent frequencies were used in standard models for estimation of absorbed blood dose. To account for the mixed field nature of the treatment, existing models were used to determine the ratio of the component radiation types. Additionally, a new approach (M-FISH_LET), based on the ratio of cells containing damage consistent with high-LET exposure (complex chromosomal exchanges) and low-LET exposure (simple exchanges), was used as a pseudo ratio for ²²³Ra:IMRT dose.

Total IMRT estimated doses delivered to the blood after completion of mixed radiotherapy (after 37 IMRT fractions and two [²²³Ra]RaCl₂ injections) were in the range of 1.167 ± 0.092 and 2.148 ± 0.096 Gy (dose range across all models applied). By the last treatment cycle analysed in this study (four [²²³Ra]RaCl₂ injections), the total absorbed ²²³Ra dose to the blood was estimated to be between 0.024 ± 0.027 and 0.665 ± 0.080 Gy, depending on the model used. Differences between the models were observed, with the observed dose variance coming from inter-model as opposed to inter-patient differences. The M-FISH_LET model potentially overestimates the ²²³Ra absorbed blood dose by accounting for further PBL exposure in the vicinity of metastatic sites.

The models presented provide initial estimations of cumulative dose received during incremental IMRT fractions and [²²³Ra]RaCl₂ injections, which will enable improved understanding of the doses received by individual patients. While the M-FISH_LET method builds on a well-established technique for external exposures, further consideration is needed to evaluate this method and its use in assessing non-targeted exposure by ²²³Ra after its localization at bone metastatic sites.