Radiopharmaceuticals for Bone Metastases

As a single organ distributed diffusely throughout the body, bones represent both a unique challenge and unique opportunity for the treatment of symptomatic metastatic disease. While the multifocality of bone metastases often prevents effective complete treatment with focal radiotherapy, the similar pathophysiology of these diffuse sites of disease opens the door to targeted systemic therapy. The relatively rapid dose fall-off from beta- or alpha-emitting particles, if correctly and reliably targeted to osseous metastases, might reduce tumor burden and enhance pain control or improve survival. Radioisotopes have thus been studied keenly with the first generation of primarily beta-emitting radioisotopes, strontium-89 and samarium-153, which reached early FDA approval based on successful endpoints of pain control. More recently, an alpha-emitting therapy, radium-223, has demonstrated a successful endpoint of improved overall survival in patients with a burden of symptomatic, metastatic castrate-resistant prostate cancer (mCRPC) confined to the bones. With this discovery, an additional survival-improving tool beyond systemic and hormonal agents was added to the treatment arsenal for mCRPC for suitable candidates. With an improved understanding of the optimization of hormonal and systemic therapies in the context of mCRPC, there is lingering uncertainty regarding the safety and efficacy of combinatorial use of alpha and beta-emitting therapies with the current generation of systemic agents. In this narrative review, we will highlight the current understanding of the relative utility and clinical paradigms involving alpha- and beta-emitting radioisotopes. We discuss fundamental mechanisms for antineoplastic activity, initial clinical trials validating their use, the use of concurrent antiresorptive therapies to provide bone protection, and ongoing clinical trials targeted at best utilization of these agents in the broader context of mCRPC treatment.