Current and future targeted alpha particle therapies for osteosarcoma: Radium-223, actinium-225, and thorium-227

Osteosarcoma is a high-grade sarcoma characterized by osteoid formation, nearly universal expression of IGF1R and with a subset expressing HER-2. These qualities provide opportunities for the use of the alpha particle-emitting isotopes to provide targeted radiation therapy via alpha particles precisely to bone-forming tumors in addition to IFG1R or Her-2 expressing metastases. This review will detail experience using the alpha emitter radium-223 (Ra-223, tradename Xofigo), that targets bone formation, in osteosarcoma, specifically related to patient selection, use of gemcitabine for radio-sensitization, and using denosumab to increasing the osteoblastic phenotype of these cancers. A case of an inoperable left upper lobe vertebral-paraspinal-mediastinal osteoblastic lesion treated successfully with Ra-223 combined with gemcitabine is described. Because not all areas of osteosarcoma lesions are osteoblastic, but nearly all osteosarcoma cells overexpress IGF1R, and some subsets expressing Her-2, the anti-IGF1R antibody FPI-1434 linked to actinium-225 (Ac-225) or the Her-2 antibody linked to thorium-227 (Th-227) may become other means to provide targeted alpha particle therapy against osteosarcoma (NCT03746431 and NCT04147819).