Alpha Particle Radiobiology for Radium-223 (“Alpharadin”): The Fortuitous “Goldilocks” Effect Observed for Hormone-resistant Metastatic Prostate Cancer

Abstract

Purpose/Objectives: The ALSYMPCA Trial of 223 Ra (“Alpharadin”) for men with metastatic castrate-resistant prostate cancer was a Phase III randomized trial comparing 223 Ra plus SOC vs best SOC. This trial was stopped early after 921 patients enrolled at over 100 centers achieved highly significant improvements in primary (overall survival) and all secondary endpoints.These extremely positive results prompted us to review some of the unique aspects of alpha particle radiobiology and ultra-short range molecular targeting capabilities resulting from endosteal surface new bone localization. The anatomic relationships between endosteal surfaces where isotope localization occurs and the positions of metastatic target cells and nearby marrow reserves were especially considered. Materials and Methods: Literature analysis and review of published radium autoradiographs Results: Highly energetic alpha particles such as those released during decay of 223 Ra (T 1/2 = 11.4 days) display unique radiobiologic and dosimetric aspects which may make them ideal for treating bony metastatic disease. The nuclear dose required in vitro for approximately 90% target cell kill by alpha particles is estimated to be less than 1 Gy and electron micrographs of various cell types obtained shortly after exposure confirm bizarre blebbing and condensation of chromosomal material characteristic of apoptosis. These radiobiologic effects may depend heavily on cell culture condition with more nonuniform DNA strand break damage observed in isolated detached cells. The 20-100 micron alpha particle path length (2-10 cells) appears to allow specific target cell populations to be killed within bony stroma without excessive damage to nearby sensitive hematopoietic cells. There may also be advantageous secondary cytokine signals produced as bystander effects. Calculated dosimetry models suggest bone surface to nearby marrow dose ratios of >10:1. 223 Ra treatment in rodent models showed that this family of Ca ++ analogs delivers extremely high doses to stromal elements such as bone-resorbing osteoclasts and this selectivity may aid in decreasing SREs and in pain relief. Conclusions: We highlight the fact that some basic radiobiologic and cell compartment-specific stromal localization principles known to be important in alpha particle radiopharmaceutical therapy may contribute to the very positive clinical outcomes observed while allowing minimal damage accumulation to nontarget cell groups. The highly localized cytotoxicity and fortuitous endosteal uptake patterns oberved (close enough to target cells and destructive osteoclasts for treatment efficacy but far enough away from marrow reserves to limit hemotoxicity) may serve to produce a salubrious Goldilocks effect and thereby aid in the observed treatment success. #3304