A recent report from England, about the first-generation oral bisphosphonate sodium clodronate, claims to improve overall survival in men with metastatic but not localized prostate cancer, according to long-term data from two randomized controlled trials.
Among the sample of 278 men all who had metastatic disease starting and who were responding to long-term hormone therapy, the 8-year overall survival was 22% in those who received four tablets per day (2,080 mg) of sodium clodronate for 3 years or less but only 14% in those given a placebo. Median overall survival in the Medical Research Council PRO5 trial was 2.8 years with clodronate versus 2.2 years with placebo.
The survival advantage with clodronate was statistically significant, with a hazard ratio of 0.77
“This is the first study using biphosphonates that has shown a survival advantage in prostate cancer,” principal investigator Dr. David Dearnaley said at a symposium on genitourinary cancers.
Overall, the findings suggest that further investigation of newer biphosphonates is needed, particularly zoledronic acid, a third-generation bisphosphonate that is considerably more potent than clodronate, said Dr. Dearnaley, professor of uro-oncology, Institute of Cancer Research, Royal Marsden Hospitals, London.
“This is a small study and I’m not going to suggest that this should change routine practice, but happily there are other trials going on which may help us untangle the issue,” he said at the symposium, sponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and the Society of Urologic Oncology.
In Dr. Dearnaley’s PRO4 trial, the results in localized disease showed no overall survival benefit for clodronate taken for 5 years or less among 471 men in the PRO4 trial group. In fact, the hazard ratio (1.12) marginally favored the placebo arm and did not reach statistical significance. Median overall survival was 9.3 years with clodronate versus 10.4 years with placebo.
The long-term results from PRO5 support data reported at 59 months’ follow-up showing a nonsignificant advantage with clodronate in metastatic disease in the primary outcome measure of symptomatic bone metastases and overall survival (J. Natl. Cancer Inst. 2003;95:1300-11).
From 1994 to 1998, 508 men with localized disease and 311 men with metastatic disease were accrued from England and Wales. At 8 years’ follow-up, there were 258 deaths among the 278 (93%) men with metastatic disease and 281 deaths among the 471 (60%) men with localized disease.
Unplanned subgroup analyses showed that clodronate’s greatest advantage was in those with adverse prognostic factors – high alkaline phosphatase, high serum creatinine, and a World Health Organization performance status of 1 or higher, Dr. Dearnaley reported.
Study discussant Dr. Robert S. Di Paola, director of the Cancer Institute of New Jersey, in New Brunswick, called the findings “intriguing and important in a number of ways,” and noted that in androgen-independent disease, zoledronic acid has been demonstrated to decrease skeletal metastases.
Both men highlighted two ongoing trials: STAMPEDE (Systemic Therapy for Advancing or Metastatic Prostate Cancer), comprising approximately 3,000 men with high-risk metastatic and localized disease, and CALGB-90202, a randomized phase III study of zoledronate for the prevention of skeletal-related events in patients with prostate cancer and bone metastases.
The trial was conducted by the Medical Research Council Clinical Trials Unit, London.
Published in: Elsevier Global Medical News. 2009 Feb 27, P Wendling
There needs to be a good clinical trial to establish if similar results can be duplicated. However, for my money I would not wait.
Joel T Nowak MA, MSW