Alpha-Emitter Radiopharmaceuticals and External Beam Radiotherapy: A Radiobiological Model for the Combined Treatment

Simple Summary: The linear-quadratic (LQ) model was adapted to Ra-223 therapy using brachytherapy formalism for a mixture of radionuclides, considering the contribution of all daughter isotopes in the decay chain. The LQ model allowed us to predict the two-year overall survival and neutropenia rates with a combination of external beam radiotherapy and Ra-223 treatment. The fitted model could be used to guide future optimization and personalization of combined treatments.Previously published studies combined external beam radiotherapy (EBRT) treatments with different activities of Ra-223. The data of two-year overall survival (2y-OS) and neutropenia (TOX) incidence when combining EBRT and Ra-223 are not homogeneous in literature. We adapted the linear-quadratic model (LQ) to Ra-223 therapy using brachytherapy formalism for a mixture of radionuclides, considering the contribution of all daughter isotopes in the decay chain. A virtual cohort of patients undergoing Ra-223 therapy was derived using data from the literature. The doses delivered using Ra-223 and EBRT were converted into biologically equivalent doses. Fixed-effect logistic regression models were derived for both the 2y-OS and TOX and compared with available literature. Based on the literature search, four studies were identified to have reported the Ra-223 injection activity levels varying from the placebo (0) to 80 kBq/kg, associated or not with EBRT. Logistic regression models revealed a dose-dependent increase in both the 2y-OS (intercept = -1.364; slope = 0.006; p-value & LE; 0.05) and TOX (-5.035; 0.018; & LE;0.05) using the EBRT schedule of 8 Gy in 1 fr. Similar results were obtained for other schedules. Discrepancies between our TOX model and those derived for EBRT combined with chemotherapy are discussed. Radiobiological models allow us to estimate dose-dependent relationships, to predict the OS and TOX following combined Ra-223 + EBRT treatment, which will guide future treatment optimization.