ESMO 2011 Report – Radium-223 chloride in bone metastasis

by Dr Sunil Upadhyay – Despite encouraging progress in the early diagnosis and better management outcome of common cancers, a high proportion of patients still present with advanced stage disease or develop relapse. Bone metastasis is common in tumours of breast, prostate, lung and colorectal origin. Over 90% of the metastatic castration resistance prostate cancer (CRPC) patients have radiological evidence of bone metastases. Skeletal related events (SREs) such as bone pain, pathological fractures and spinal cord compression require surgery and/or external radiotherapy, sometimes multiple courses of radiotherapy. Bone metastases are a major cause of death, disability, decreased quality of life and increased drain on resources. Unfortunately, the currently available bone-targeted therapies have not been shown to improve survival in these groups of patients.

Radium-223 chloride is a radioactive agent which targets bone and emits alpha particles with a short penetration range (<100μm) of 2-10 cell diameters and large biological effect. Alpha particles can induce highly localised tumour cell killing due to double strand DNA lethal damage in the adjacent tumour cells with minimal damage to surrounding normal tissue. A Phase II placebo-controlled study¹ on the use of Radium-223 in CRPC was shown to improve overall survival.

Marie Curie discovered radium together with her husband Pierre Curie in 1898 for which she was presented the 1911 Noble Prize in chemistry awarded by the Royal Swedish Academy of Sciences. It was a fitting tribute to her that the phase III ALSYMPCA trial results were presented in Stockholm at the presidential symposium by Chris Parker from Royal Marsden Hospital, at EMCC 2011. Moreover, the Scandinavian location could not have been better given that Radium-223 chloride was developed by a Norwegian company.

ALSYMPCA trial design

The patients received 6 injections of Radium-223 chloride 50kBq/kg IV every 4 weeks or matching placebo (saline). The results presented showed that 922 patients were randomised (radium-223 n=615 and placebo n=307) and the patients characteristics were well balanced in the two arms with mean age of 70 years. Only 50% of the patients in the radium-223 arm received all 6 injections. The results of the interim analysis showed that radium-223 significantly improved OS in patients with CRPC with bone metastasis (p=0.00185, HR=0.695). The median overall survival was 14.0 months for radium-223 compared to 11.2 months for the placebo group.

Similarly, the mean time to first skeletal related events was 13.6 months for the radium-223 and 8.4 months (p=0.00046, HR=0.61) for the placebo group. All the secondary end points were also met. The subgroup analysis showed that the overall survival benefit in favour of radium-223 was maintained across all treatment subgroups. The safety and tolerability were also very favourable with a low incidence of myelosuppression.

Prior to the above results, Stronsium-89, Samarium-153 and Rhenium-186/188 have been used in the treatment of bone metastases. However, they emit light β-particles with a relatively long range and limited biological effect. They have been successfully used for the treatment of pain due to bone secondaries but patients frequently develop reversible myelosuppression and no survival advantage. However, treatment with Radium-223 resulted in survival benefit and very limited toxicity when given as a single agent. These results are practice changing and once approved, it has the potential of becoming the standard of treatment in CRPC patients with bone metastases.  As a consequence of the short range of α-particles and high biological effect, there is a theoretical advantage of their use for microscopic disease with other therapies thus giving a new opportunity for improving patient outcomes in an adjuvant setting. (1LBA, EMCC 2011)

 

Reference:

1. Nilsson S, Franzén L, Parker C, Tyrell C et al. Lancet Oncology 2007; 8: 585-94