On 2014 Feb 03, S Sundar commented:

Radium-223: Radiobiological conundrum and confounding factors.

Radium 223 is an alpha emitter with limited tissue penetration as evidenced by minimal myelosuppression in the study.(1) But this bone targeted radioisotope seems to have a major effect on bone secondaries while having minimal effect on the bone marrow. This radiobiological conundrum means that potential confounding factors on the observed survival benefit need to be excluded.

One significant confounding factor is the liberal use of effective systemic therapies such as anti-androgens, estrogens and steroids in the study. Concurrent use of these effective agents was not controlled in the study and patients were not stratified for use of these agents.

For instance, dexamethasone and diethylstilbesterol, are widely used in Europe. These therapies are active systemic agents with a median overall survival of 19.4 months in a phase 3 study.(2) Since the median overall survival was only 14 months in Radium 223 study arm, the potential imbalances in the use of these concurrently administered therapies could have significantly biased the overall survival results.

Furthermore, a significant usage of these systemic hormonal agents in the study arms would imply that Radium 223 ideally should not be used as mono therapy in clinical practice. Abiraterone and Enzalutamide have recently been approved for castration refractory prostate cancer. Widespread use of Radium 223 along with these newer agents, which is likely to occur in routine clinical practice, is not without any biological rationale. . There is an urgent need for combination therapy trials with Radium 223 and newer hormonal agents

References: 1. Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. 2. Shamash J, Powles T, Sarker SJ, Protheroe A, Mithal N, Mills R, et al. A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol. Br J Cancer. 2011 Feb 15;104(4):620-8.

On 2014 Feb 03, S Sundar commented:

None

On 2014 Feb 03, S Sundar commented:

None

On 2014 Feb 03, S Sundar commented:

Radium-223: Radiobiological conundrum and confounding factors.

Radium 223 is an alpha emitter with limited tissue penetration as evidenced by minimal myelosuppression in the study.(1) But this bone targeted radioisotope seems to have a major effect on bone secondaries while having minimal effect on the bone marrow. This radiobiological conundrum means that potential confounding factors on the observed survival benefit need to be excluded.

One significant confounding factor is the liberal use of effective systemic therapies such as anti-androgens, estrogens and steroids in the study. Concurrent use of these effective agents was not controlled in the study and patients were not stratified for use of these agents.

For instance, dexamethasone and diethylstilbesterol, are widely used in Europe. These therapies are active systemic agents with a median overall survival of 19.4 months in a phase 3 study.(2) Since the median overall survival was only 14 months in Radium 223 study arm, the potential imbalances in the use of these concurrently administered therapies could have significantly biased the overall survival results.

Furthermore, a significant usage of these systemic hormonal agents in the study arms would imply that Radium 223 ideally should not be used as mono therapy in clinical practice. Abiraterone and Enzalutamide have recently been approved for castration refractory prostate cancer. Widespread use of Radium 223 along with these newer agents, which is likely to occur in routine clinical practice, is not without any biological rationale. . There is an urgent need for combination therapy trials with Radium 223 and newer hormonal agents

References: 1. Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. 2. Shamash J, Powles T, Sarker SJ, Protheroe A, Mithal N, Mills R, et al. A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol. Br J Cancer. 2011 Feb 15;104(4):620-8.