Oral sodium clodronate appears to have no effect on the natural history of nonmetastatic prostate cancer, research has found.
According to a study published in the Journal of the National Cancer Institute, adjuvant bisphosphonate therapy improves outcomes of patients with breast cancer that has not metastasised to bone, but it is not known whether it has similar effects in prostate cancer. The researchers therefore sought to investigate whether a first-generation bisphosphonate could improve symptomatic bone metastasis-free survival in men with prostate cancer.
In this double-blind trial (MRC PR04), 458 men with nonmetastatic prostate cancer who were considered to be at high risk of developing bone metastases were randomised to treatment with sodium clodronate 2,080mg/day (n=254) or to placebo (n=254) for up to five years. Randomisation was stratified according to treatment centre, tumour stage (T2 vs T3 vs T4), primary therapy (given vs not given), time from primary therapy to random assignment (0 vs 12 months vs >12 months), and prostate-specific antigen (PSA) value at study entry (<50ng/ml vs 50ng/ml or above).
Primary outcome was symptomatic bone metastasis-free survival, defined as time from randomisation to the development of symptomatic bone metastases or death from prostate cancer. Secondary outcomes included overall survival (OS), toxicity, rate of events affecting bone during the trial, and type of progressive disease (bone vs non-bone).
After a median follow-up of nearly 10 years, clodronate treatment was not associated with any improvement in bone metastasis-free survival, with 80 events in the clodronate group and 68 in the placebo group (hazard ratio = 1.22; 95% CI = 0.88–1.68). Clodronate also demonstrated no benefit in OS (all-cause), with 130 deaths in the clodronate group and 127 in the placebo group (HR = 1.02; 95% CI = 0.80–1.30). Clodronate was generally well tolerated, but gastrointestinal problems and increased lactate dehydrogenase levels were more frequent than in the placebo group.
The authors conclude: “In the MRC PR04 trial, no benefit for adjuvant therapy with oral clodronate was observed in men with nonmetastatic prostate cancer in terms of modification of the natural history of their disease. Sodium clodronate should not be further used in trials in the adjuvant setting, but more potent bisphosphonates should be investigated.”
J Natl Cancer Inst 2007;99:765-76