![]() Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016. Global Burden of Disease Cancer Collaboration. Understanding the mode of action of 223Ra and its interactions with those of other anticancer agents offers potential for new treatment combinations for bone-metastatic cancers.Ĭlinical trials are investigating 223Ra in combination with agents targeting the androgen receptor signalling axis, cell microtubules, the immune response and the DNA damage response.Ĭurrent combination studies are preliminary and further clinical testing will be required to demonstrate safety, efficacy and clinical benefit.Ģ23Ra treatment in patients with metastatic castration-resistant prostate cancer has led to the development of other targeted alpha therapies for the treatment of patients with different cancers that also have bone-predominant metastases.Īmerican Institute for Cancer Research. Radium-223 ( 223Ra) deposited in the intralesional bone matrix emits high-energy alpha-particles that induce potentially cytotoxic DNA double-strand breaks in cells within a 100-µm distance while sparing surrounding normal tissue.Ģ23Ra acts via a multi-modal mechanism, killing both tumour cells and the effector cells of pathological bone metabolism, osteoblasts and osteoclasts 223Ra might also promote local antitumour immune responses. On the basis of the current mechanistic knowledge and potential clinical benefits, combination therapies of 223Ra with microtubule-stabilizing cytotoxic drugs and agents targeting the androgen receptor axis, immune checkpoint receptors or DNA damage response proteins are being explored in patients with CRPC and metastatic bone disease. A thorough understanding of the mechanism of action could inform the design of new combinatorial treatment strategies that might be more efficacious than monotherapy. The clinical utility of 223Ra has encouraged the development of other anticancer targeted alpha therapies. 223Ra might also modulate immune responses within the bone. Consequently, tumour growth and abnormal bone formation are inhibited by these direct effects and by the disruption of positive-feedback loops between tumour cells and the bone microenvironment. ![]() The emitted high-energy alpha particles induce DNA double-strand breaks that might be irreparable and lead to cell death in nearby exposed tumour cells, osteoblasts and osteoclasts. Preclinical studies demonstrate that 223Ra preferentially incorporates into newly formed bone matrix within osteoblastic metastatic lesions. The targeted alpha therapy radium-223 ( 223Ra) can prolong survival in men with castration-resistant prostate cancer (CRPC) who have symptomatic bone metastases and no known visceral metastases.
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