Abstract
Simple SummaryThe linear–quadratic (LQ) model was adapted to 223Ra 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 223Ra 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 223Ra. The data of two-year overall survival (2y-OS) and neutropenia (TOX) incidence when combining EBRT and 223Ra are not homogeneous in literature. We adapted the linear–quadratic model (LQ) to 223Ra 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 223Ra therapy was derived using data from the literature. The doses delivered using 223Ra 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 223Ra 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 ≤ 0.05) and TOX (−5.035; 0.018; ≤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 223Ra + EBRT treatment, which will guide future treatment optimization.
Highlights
Prostate cancer (PCa) is the most common cancer in men and the second leading cause of cancer death
For the sake of simplicity, we report the results for the external beam radiotherapy (EBRT) schedule of 8 Gy in 1 fraction
We showed that the dose increase is mainly guided by 223Ra treatment, as EQD2TOT does not strongly depend on EBRT when considering a schedule providing EQD2EBRT up to 39 Gy
Summary
Prostate cancer (PCa) is the most common cancer in men and the second leading cause of cancer death. Its clinical benefit is temporary, and most patients develop metastatic castration-resistant PCa (mCRPC) disease [2,3]. This specific pathology is associated with a poor outcome, making metastatic prostate cancer a prime target for bone-targeted therapies using calcium analogs. In 2013, Radium-223 chloride (223RaCl2) was approved by the FDA for bone metastases treatment of mCRPC patients. The radium mimics the behavior of calcium distribution It accumulates in proliferating cells in and around bone metastases, with a high affinity for the bone matrix [4]. The combination of its ultrashort range, high intensity, highly efficient bone localization, and RBE make 223RaCl2 an excellent candidate for targeted molecular radiation therapy
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