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Bisphosphonates for Nonmetastatic Prostate Cancer?

Clodronate did not improve bone-metastasis–free survival or overall survival in patients with nonmetastatic prostate cancer.

Metastatic prostate cancer often spreads to bone: 80% to 90% of patients with advanced disease manifest bone metastases. Bisphosphonates are used widely in prostate cancer patients, both in the early androgen-deprivation setting to prevent osteoporosis and in the castrate metastatic setting to decrease the likelihood of skeletal-related events (i.e., pathologic fracture, new bone metastases, and requirement for radiotherapy).

In the early 1990s, British investigators initiated a series of trials to determine whether the oral bisphosphonate clodronate might alter the natural history of bone metastases in prostate cancer. They hypothesized that bisphosphonates most likely would be beneficial when osteolysis from prostate cancer was minimal. One such trial was the MRC PR04 study, a randomized, multicenter, double-blind, placebo-controlled trial of clodronate for the treatment of recently diagnosed prostate cancer without evidence of bone metastases. Eligible patients had received a diagnosis of locally advanced adenocarcinoma of the prostate (defined as stages T2 through T4, N0, N+ or NX, M0) within 36 months of study entry and had no previous bisphosphonate treatment or long-term hormone therapy. Clodronate (2080 mg daily) was administered for a maximum of 5 years. The primary outcome was symptomatic bone-metastasis–free survival, defined as time from randomization to development of symptomatic bone metastases or death from prostate cancer. The secondary outcomes were overall survival, toxicity, rate of skeletal-related events, and type of progressive disease (bone versus nonbone).

A total of 508 patients from 27 centers were enrolled from June 1994 through December 1997. Median age was 69; 47% of patients had T3/4 disease, 81% had known node-negative disease, and 79% had a WHO performance status of zero. Forty-two percent of patients were being treated with radiotherapy only, 28% with radiotherapy plus hormone therapy, and 24% with hormone therapy only; the proportion receiving hormone therapy was greater in patients with worse tumor stage. After a median follow-up of nearly 10 years, no benefit was observed for the clodronate group in terms of bone-metastasis–free survival or overall survival. Adverse events, notably gastrointestinal problems and increased lactate dehydrogenase levels, were more frequent in the clodronate group than in the placebo group.

Comment: Bone health and metastases remain critical issues in the biology and clinical management of prostate cancer. Given the lack of compelling prospective data showing clinical benefit from bisphosphonate in nonmetastatic prostate cancer patients, this therapy currently cannot be recommended.

— Robert Dreicer, MD, MS, FACP

Published in Journal Watch Oncology and Hematology June 11, 2007

Citation(s):

Mason MD et al. Oral sodium clodronate for nonmetastatic prostate cancer — Results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst 2007 May 16; 99:765-76.

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