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Bisphosphonates May Be Useful In Treatment of Bone Metastases

Jemarion Jones

Data from a new study suggest that the oral drug clodronate can delay the progression of symptoms related to bone metastases in patients with prostate cancer. The results have some researchers optimistic that a new compound will soon be added to the short list of treatment options for the 30% of prostate cancer patients who experience debilitating pain related to bone metastases.

In the study, 311 patients with advanced prostate cancer were randomly assigned to receive oral clodronate or placebo. Patients that took clodronate reported pain from bone metastasis at a median of 24 months, compared with a median of 19 months in patients who took the placebo.

"We have raised the question whether this was an analgesic effect of clodronate or a genuine biological effect on disease progression," said David Dearnaley, M.D., of the Institute for Cancer Research and the U.K. Medical Research Council trial’s principal investigator. "The latter seems more likely due to the reduced [prostate specific antigen] levels seen in patients on active drug, but most particularly because of the intriguing suggestion that there is a prolongation of survival." The study, which was presented at this year’s annual meeting of the American Society of Clinical Oncology, showed a 7-month longer survival among patients who took clodronate, but the difference was not statistically significant.



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Dr. David Dearnaley

 
"It’s too early to make a strong recommendation that the standard of care of metastatic disease should change to use a bisphosphonate drug at this point," he added. "However, the preliminary results indicate something exciting that warrants more study."

Clodronate is a member of a drug class known as bisphosphonates. Bisphosphonates, first synthesized in the 1960s, are known for their ability to inhibit osteoclast-induced bone resorption.

Later studies found that bisphosphonates also reduced the incidence and number of new bony and soft tissue metastases in breast cancer patients. Clodronate is not approved for use in the United States, but its chemical cousin, pamidronate, is used in the treatment of bone metastases associated with breast cancer. Bisphosphonates usually have few side effects and complications.

Dearnaley suggested that the best strategy for future trials for prostate cancer might include using intravenous bisphosphonates at the very beginning of therapy involving total androgen blockade and deprivation.

"My own view is that bisphosphonates will have their maximum advantage used early on in the course of disease when there is the greatest chance of modifying the development of progression of metastases," said Dearnaley.

More information on clodronate may become available in the next 2 years when the results of the London-based Medical Research Council study are published. In the MRC trials, patients with locally advanced prostate cancer and negative bone scans are randomly assigned to receive either clodronate or a placebo over a 5-year period. End points include survival, and surrogate end points include biochemical response, pain control, and overall quality of life.

Other bisphosphonates have shown promise in the treatment of bone metastases. William Dahut, M.D. of the National Cancer Institute’s Medicine Branch, noted that small phase II trials involving allendronate and pamidronate have suggested a decrease in pain progression. These bisphosphonates, along with ibandronate and zolendronate, are hundreds of times more potent than clodronate and may warrant further study.

"With other trials showing positive results, the use of bisphosphonates should increase," said Dahut. "They have palliative benefits now. The hope is that if used even earlier they [bisphosphonates] would have an even greater benefits for prostate cancer patients."

Bisphosphonates also seem to have a favorable clinical profile compared with other treatments for metastatic disease, such as radiation therapy.

"This is probably going to be the one of the most rapidly developing fields in prostate cancer. It will probably keep me busy for the next 10 years." said Dearnaley. "You can’t over-claim the result. There’s now a large onus on us to either confirm or refute the results."



             
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