Oral sodium clodronate improves overall survival in men with advanced prostate cancer, but does not reduce the risk of death in men with localised disease, according to the final results of the MRC PR05 and MRC PR04 trials, published online and in the September edition of The Lancet Oncology.
Prostate cancer most commonly spreads to the bone. Thus, it has been suggested that bisphosphonates, such as sodium clodronate, a group of drugs that prevent the loss of bone mass, might improve the outcomes of patients with advanced prostate cancer.
In 1994, two UK-led trials commenced to examine the effect of sodium clodronate in men with advanced or localised prostate cancer. In the first trial, 311 consenting men with advanced prostate cancer who were starting or responding to hormone therapy (standard care) for bone metastases were randomly allocated to take oral sodium clodronate or placebo for up to 3 years. In the second trial, 508 consenting men with localised prostate cancer who were receiving standard care (usually treatment with radiotherapy, hormone therapy, or both) were randomly allocated to take oral sodium clodronate or placebo for up to 5 years. The primary results of the original trials, published 6 and 3 years previously, showed that men with advanced disease had a reduction in the development of symptomatic bone metastases and some improvement in overall survival, and that men with localised disease showed no improvement in overall survival or delay in the spread of cancer.
In this study, Matthew Sydes from the Medical Research Council Clinical Trials Unit, David Dearnaley at The Institute of Cancer Research and colleagues report the long-term survival outcomes of patients involved in both the original trials.
Findings showed a 23% relative decrease of death in the group allocated to clodronate (with a 95% confidence interval ranging between relative improvements of 2% and 40%). At five years, overall survival was 30% in the clodronate treated group and 21% in the placebo group and after 10 years, 17% vs 9% respectively. These were mature results: 93% of these men had now died.
In men with localised disease, clodronate showed no benefit in overall survival—at five years, overall survival was 78% in patients given clodronate and 80% in patients given placebo, and after 10 years 48% vs 51% (this was a 12% relative worsening of risk, although a 95% confidence interval cannot rule out a true value that is an 11% relative improvement or a 42% relative worsening).
Professor David Dearnaley, of The Institute of Cancer Research, who was the Chief Investigator for the metastatic trial, said: “PR05 is the first trial, to our knowledge, to show an overall survival benefit conferred by an oral bisphosphonate when given in addition to standard hormone therapy to men with bone metastases who are starting or responding to hormone therapy. However, there is no evidence that clodronate is of any benefit when given as an adjuvant to treatment in men with non-metastatic prostate cancer.”
Professor Malcolm Mason, Cancer Research Wales Professor of Clinical Oncology at Cardiff University’s School of Medicine, who was the Chief Investigator for the non-metastatic trial, said: “Most men diagnosed with localised prostate cancer today have an extremely good outlook, but prostate cancer still claims the lives of 10,000 men each year in the UK. We badly need better treatments for these men, and bisphosphonates may be an important weapon against prostate cancer spreading to bone. Sodium clodronate, as used in these studies, is not as potent as newer bisphosphonates, and our results encourage further research with such treatments. Our next trial, STAMPEDE, follows in this direction.”