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Oral Sodium Clodronate for Nonmetastatic Prostate Cancer—Results of a Randomized Double-Blind Placebo-Controlled Trial: Medical Research Council PR04 (ISRCTN61384873)
For the Medical Research Council PR04 Collaborators
Affiliations of authors: Velindre Hospital, Department of Oncology & Palliative Medicine, School of Medicine, Cardiff University, Cardiff, UK (MDM); Medical Research Council Clinical Trials Unit, London, UK (MRS, REL, MKBP); Cancer Research UK Institute for Cancer Studies, University of Birmingham and Birmingham Oncology Centre, Queen Elizabeth Hospital, Birmingham, UK (JG, NDJ); Institute of Cancer Research and Department of Oncology and Radiotherapy, Royal Marsden Hospital, Sutton, UK (RAH, DPD); Department of Oncology, Nottingham City Hospital, Nottingham, UK (M. Sokal); Department of Urology, Royal Devon and Exeter Hospital, Exeter, UK (M. Stott); Department of Oncology, Southend General Hospital, Southend, UK (ACR)
Correspondence to: PR04 Trial, Cancer Group, Medical Research Council Clinical Trials Unit, London, NW1 2DA, UK (e-mail: pr04{at}ctu.mrc.ac.uk).
Background: The most frequent site of metastases from prostate cancer is bone. Adjuvant bisphosphonate treatment improves outcomes of patients with bone metastasis–negative breast cancer, but the effects of bisphosphonates on bone metastases in prostate cancer are not known.
Methods: We performed a randomized double-blind placebo-controlled trial to determine whether a first-generation bisphosphonate could improve symptomatic bone metastasis–free survival (time to symptomatic bone metastases or death from prostate cancer) in men with nonmetastatic prostate cancer who were at high risk of developing bone metastases. Between June 1, 1994, and December 31, 1997, 508 men from 26 UK sites and one New Zealand site who were within 3 years of initial prostate cancer diagnosis with no evidence of metastases from current bone scanning were randomly assigned to daily oral sodium clodronate (2080 mg/day, n = 254) or placebo (n = 254) for a maximum of 5 years. Estimates of outcome risks were compared using Kaplan–Meier analyses.
Results: The groups allocated to each treatment were well balanced. After a median follow-up of nearly 10 years, no evidence of benefit to the clodronate group was observed in terms of bone metastases–free survival (clodronate versus placebo, 80 events versus 68 events; hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 0.88 to 1.68) or overall survival (clodronate versus placebo, 130 deaths versus 127 deaths; HR = 1.02; 95% CI = 0.80 to 1.30). Adverse events, notably gastrointestinal problems and increased lactate dehydrogenase levels, were more frequent in the clodronate group than in the placebo group; otherwise, clodronate was well tolerated. Modification of trial drug dose was more frequent in the clodronate group than the placebo group (HR = 1.63, 95% CI = 1.21 to 2.19).
Conclusion: Adjuvant sodium clodronate does not modify the natural history of nonmetastatic prostate cancer.
| CONTEXT AND CAVEATS Prior knowledge In men with metastatic prostate cancer, the other tissue most often involved is bone. Treatment with bisphosphonates improves the outcomes of patients with metastatic breast cancer. Study design Randomized double-blind placebo-controlled Phase III trial of clodronate among patients with locally advanced prostate cancer. Contribution Clodronate treatment did not improve overall survival or symptomatic bone metastasis–free survival compared with placebo. Although clodronate was well tolerated overall, more men in the clodronate than in the placebo arm reported adverse effects, such as gastrointestinal distress, that led to adjustment of trial medication dosage. Implications Clodronate treatment has no effect on the progression of locally advanced prostate cancer. Limitations Standards for collecting information about toxic effects are higher now than during the time of the trial. Gleason score and prostate-specific antigen levels were not available. Additional treatments were not reported.
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Manuscript received November 9, 2006; revised March 5, 2007; accepted April 2, 2007.
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J Natl Cancer Inst 2007 99: 744-745.
J Natl Cancer Inst 2007 99: 741.
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